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Ding Y, Zhang Y, Wen C, Xie HP, Xie BL, Li L, Wu W, Xie DH, Lai R. Using T7 endonuclease I to detect SLC26A4 mutations in children with large vestibular aqueduct syndrome, with or without Mondini malformation and assess cochlear implant outcomes. Eur Arch Otorhinolaryngol 2025:10.1007/s00405-025-09378-w. [PMID: 40195191 DOI: 10.1007/s00405-025-09378-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 03/24/2025] [Indexed: 04/09/2025]
Abstract
OBJECTIVE To analyze SLC26A4 gene mutations in children with large vestibular aqueduct syndrome (LVAS) with or without Mondini malformation, and to compare their hearing phenotypes, rehabilitation outcomes, and learning performance after cochlear implantation. METHODS We used T7 Endonuclease I enzyme digestion to detect SLC26A4 mutations in 48 children with LVAS without Mondini malformation (EVA group), 29 children with LVAS and Mondini malformation (EVA + MD group). Negative results were confirmed by Sanger sequencing. Auditory performance (CAP) and speech intelligibility (SIR) scores assessed hearing and speech rehabilitation outcomes, while academic performance evaluated learning post-cochlear implantation. RESULTS Electrophoresis showed that the positive detection rates of SLC26A4 mutations were 89.58% in the EVA group, 89.66% in the EVA + MD group, and 0% in the control group. In the EVA group, the most common mutations were in exons 7 + 8 (52.08%), 11 + 12 (22.92%), and 19 (18.75%). In the EVA + MD group, the predominant mutations were in exons 11 + 12 (51.72%), 4 (34.48%), 7 + 8 (27.59%), and 19 (24.14%). The EVA + MD group had higher detection rates for two-site (37.93%) and three-site compound heterozygous mutations (13.79%) compared to the EVA group (22.92% and 10.42%, respectively). The median diagnosis time for profound hearing loss was 6.62 months in the EVA + MD group versus 10.56 months in the EVA group. There were no significant differences in CAP and SIR scores between the groups, but the EVA group showed better learning performance. CONCLUSION This study reports, for the first time, multiple cases exhibiting a three-site compound heterozygous mutation in the SLC26A4 gene. The hotspot exons of the SLC26A4 gene differ between children with simple LVAS and those with LVAS accompanied by Mondini malformation. Children with both conditions show earlier onset of profound hearing loss and poorer learning performance compared to those with only LVAS.
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Affiliation(s)
- Yan Ding
- Department of Otorhinolaryngology-Head & Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yong Zhang
- Department of Otorhinolaryngology-Head & Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Cheng Wen
- Department of Otorhinolaryngology-Head & Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Hua-Ping Xie
- Laboratory of Animal Nutrition and Human Health, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, Hunan, China
| | - Bing-Lin Xie
- Laboratory of Animal Nutrition and Human Health, Hunan International Joint Laboratory of Animal Intestinal Ecology and Health, College of Life Science, Hunan Normal University, Changsha, Hunan, China
- The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Science, Hunan Normal University, Changsha, Hunan, China
| | - Lihua Li
- Department of Otolaryngology Head and Neck Surgery, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Weijing Wu
- Department of Otorhinolaryngology-Head & Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ding-Hua Xie
- Department of Otorhinolaryngology-Head & Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ruosha Lai
- Department of Otorhinolaryngology-Head & Neck Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China.
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Duan S, Hou Y, Li Y, Guo Y. Mutation spectrum of GJB2, SLC26A4 and mtDNA12SrRNA genes in non-syndromic hearing loss patients from Gansu, China. Int J Pediatr Otorhinolaryngol 2025; 191:112298. [PMID: 40054393 DOI: 10.1016/j.ijporl.2025.112298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 02/08/2025] [Accepted: 03/03/2025] [Indexed: 03/16/2025]
Abstract
OBJECTIVE This study examined the mutation spectrum and frequency of three prevalent pathogenic genes in patients with non-syndromic hearing loss (NSHL) from Gansu Province, China. METHODS We analyzed 452 NSHL patients from five special education schools across several cities in Gansu Province using SNPscan technology to determine the mutation spectrum of mtDNA 12S rRNA, GJB2, and SLC26A4 genes. RESULTS Among the 452 patients evaluated, mutations in the GJB2 gene were observed in 91 cases (20.13 %), mutations in the SLC26A4 gene in 81 cases (17.92 %), and homoplasmic mutations in mtDNA 12S rRNA in 26 cases (5.75 %). Significant differences in GJB2 mutations were observed between Han patients and those of Hui, Tibetan and Mongolian ethnicity (χ2 = 4.554, p = 0.033; χ2 = 3.987, p = 0.046; χ2 = 4.041, p = 0.044), as well as in SLC26A4 gene mutations between Han patients and both Hui and Tu patients (χ2 = 4.247, p = 0.039; p = 0.035, two-sided). MT-RNR1 mutations were exclusively identified in Tibetans, Han, and Hui patients. CONCLUSION Our findings demonstrate variations in the mutation spectra of the GJB2, SLC26A4, and mtDNA 12S rRNA genes across different ethnic groups, highlighting ethnic variations in mutation prevalence. This study expands the understanding of the genetic mutation spectrum associated with deafness in Gansu and supports the enhancement of molecular diagnostic accuracy for diverse ethnic populations in the region.
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Affiliation(s)
- Shihong Duan
- Department of Otolaryngology-Head & Neck Surgery, Lanzhou University Second Hospital, Cuiyingmen RoadNo.82, Lanzhou, Gansu, People's Republic of China.
| | - Yuan Hou
- Department of Otolaryngology-Head & Neck Surgery, Lanzhou University Second Hospital, Cuiyingmen RoadNo.82, Lanzhou, Gansu, People's Republic of China.
| | - Yong Li
- Department of Otolaryngology-Head & Neck Surgery, Lanzhou University Second Hospital, Cuiyingmen RoadNo.82, Lanzhou, Gansu, People's Republic of China.
| | - Yufen Guo
- Department of Otolaryngology-Head & Neck Surgery, Lanzhou University Second Hospital, Cuiyingmen RoadNo.82, Lanzhou, Gansu, People's Republic of China.
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Bernardinelli E, Liuni R, Jamontas R, Tesolin P, Morgan A, Girotto G, Roesch S, Dossena S. Novel genetic determinants contribute to hearing loss in a central European cohort with enlarged vestibular aqueduct. Mol Med 2025; 31:111. [PMID: 40121402 PMCID: PMC11929268 DOI: 10.1186/s10020-025-01159-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 03/06/2025] [Indexed: 03/25/2025] Open
Abstract
BACKGROUND The enlarged vestibular aqueduct (EVA) is the most commonly detected inner ear malformation. Biallelic pathogenic variants in the SLC26A4 gene, coding for the anion exchanger pendrin, are frequently involved in determining Pendred syndrome and nonsyndromic autosomal recessive hearing loss DFNB4 in EVA patients. In Caucasian cohorts, the genetic determinants of EVA remain unknown in approximately 50% of cases. We have recruited a cohort of 32 Austrian patients with hearing loss and EVA to define the prevalence and type of pathogenic sequence alterations in SLC26A4 and discover novel EVA-associated genes. METHODS Sanger sequencing, single nucleotide polymorphism (SNP) assays, copy number variation (CNV) testing, and Exome Sequencing (ES) were employed for gene analysis. Cell-based functional and molecular assays were used to discriminate between gene variants with and without impact on protein function. RESULTS SLC26A4 biallelic variants were detected in 5/32 patients (16%) and monoallelic variants in 5/32 patients (16%). The pathogenicity of the uncharacterized SLC26A4 protein variants was assigned or excluded based on their ion transport function and cellular abundance. The monoallelic or biallelic Caucasian EVA haplotype was detected in 7/32 (22%) patients, but its pathogenicity could not be confirmed. X-linked pathogenic variants in POU3F4 (2/32, 6%) and biallelic pathogenic variants in GJB2 (2/32, 6%) were also found. No CNV of SLC26A4 and STRC genes was detected. ES of eleven undiagnosed patients with bilateral EVA detected rare sequence variants in six EVA-unrelated genes (monoallelic variants in SCD5, REST, EDNRB, TJP2, TMC1, and two variants in CDH23) in five patients (5/11, 45%). Cell-based assays showed that the TJP2 variant leads to a mislocalized protein product forming dimers with the wild-type, supporting autosomal dominant pathogenicity. The genetic causes of hearing loss and EVA remained unidentified in (14/32) 44% of patients. CONCLUSIONS The present investigation confirms the role of SLC26A4 in determining hearing loss with EVA, identifies novel genes in this pathophysiological context, highlights the importance of functional testing to exclude or assign pathogenicity of a given gene variant, proposes a possible diagnostic workflow, suggests a novel pathomechanism of disease for TJP2, and highlights voids of knowledge that deserve further investigation.
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Affiliation(s)
- Emanuele Bernardinelli
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria
| | - Raffaella Liuni
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria
| | - Rapolas Jamontas
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria
- Department of Molecular Microbiology and Biotechnology, Institute of Biochemistry, Life Sciences Center, Vilnius University, 10257, Vilnius, Lithuania
| | - Paola Tesolin
- Medical Genetics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137, Trieste, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34137, Trieste, Italy
| | - Anna Morgan
- Medical Genetics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137, Trieste, Italy
| | - Giorgia Girotto
- Medical Genetics, Institute for Maternal and Child Health-IRCCS Burlo Garofolo, 34137, Trieste, Italy
- Department of Medicine, Surgery and Health Sciences, University of Trieste, 34137, Trieste, Italy
| | - Sebastian Roesch
- Department of Otorhinolaryngology, Head and Neck Surgery, Paracelsus Medical University, 5020, Salzburg, Austria
- Department of Otorhinolaryngology, University Hospital Regensburg, 93053, Regensburg, Germany
| | - Silvia Dossena
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, Strubergasse 21, 5020, Salzburg, Austria.
- Research and Innovation Center Regenerative Medicine and Novel Therapies (FIZ RM&NT), Paracelsus Medical University, 5020, Salzburg, Austria.
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Danilchenko VY, Zytsar MV, Panina EA, Orishchenko KE, Posukh OL. Comparative analysis of haplotypes carrying pathogenic variants c.1545T>G, c.2027T>A and c.919-2A>G of the SLC26A4 gene in patients with hearing loss from the Tyva Republic (Southern Siberia). Vavilovskii Zhurnal Genet Selektsii 2025; 29:144-152. [PMID: 40144368 PMCID: PMC11933896 DOI: 10.18699/vjgb-25-17] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 11/07/2024] [Accepted: 11/08/2024] [Indexed: 03/28/2025] Open
Abstract
Pathogenic variants in the SLC26A4 gene (OMIM #605646), leading to non-syndromic recessive hearing loss type 4 (DFNB4) and Pendred syndrome, significantly contribute to the etiology of hearing loss in many populations of the world. The spectrum and prevalence of different pathogenic SLC26A4 variants are characterized by wide ethnogeographical variability. A high frequency of some of them in certain regions of the world may indicate either their independent origin or be a consequence of the founder effect. The proportion of SLC26A4-associated hearing loss in Tuvinian patients (the Tyva Republic, Southern Siberia) is one of the highest in the world (28.2 %) and the vast majority of mutant SLC26A4 alleles are represented by three pathogenic variants c.919-2A>G, c.2027T>A and c.1545T>G (69.3, 17.5 and 8.0 %, respectively). Their overall carrier frequency in the Tuvinian population reaches 7.1 %. The accumulation of these variants in Tuvinian patients suggests a role of the founder effect in their prevalence in Tuva, which can be confirmed by the common genetic background (haplotypes) for each of them. For reconstruction of haplotypes in the carriers of variants c.1545T>G and c.2027T>A, the genotyping data of a panel of polymorphic genetic markers were used: five STRs (four of them flank the SLC26A4 gene at different distances and one is intragenic) and nine intragenic SNPs. Comparative analysis of the reconstructed haplotypes for c.1545T>G and c.2027T>A with previously obtained data on haplotypes for the c.919-2A>G variant showed that each of the analyzed variants has a specific (similar for all carriers of a particular variant) genetic background, apparently inherited from different "founder ancestors". These data confirm the cumulative founder effect in the prevalence of pathogenic variants c.1545T>G, c.2027T>A, and c.919- 2A>G of the SLC26A4 gene in the indigenous population of the Tyva Republic. The obtained data are relevant both for predicting the prevalence of SLC26A4-caused hearing loss and for development of region-specific DNA diagnostics of inherited hearing loss in the Tyva Republic.
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Affiliation(s)
- V Yu Danilchenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - M V Zytsar
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - E A Panina
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - K E Orishchenko
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
| | - O L Posukh
- Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia Novosibirsk State University, Novosibirsk, Russia
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Zhao Y, Long Y, Shi T, Ma X, Lian C, Wang H, Xu H, Yu L, Zhao X. Validating the splicing effect of rare variants in the SLC26A4 gene using minigene assay. BMC Med Genomics 2024; 17:233. [PMID: 39334476 PMCID: PMC11430457 DOI: 10.1186/s12920-024-02007-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 09/06/2024] [Indexed: 09/30/2024] Open
Abstract
BACKGROUND The SLC26A4 gene is the second most common cause of hereditary hearing loss in human. The aim of this study was to utilize the minigene assay in order to identify pathogenic variants of SLC26A4 associated with enlarged vestibular aqueduct (EVA) and hearing loss (HL) in two patients. METHODS The patients were subjected to multiplex PCR amplification and next-generation sequencing of common deafness genes (including GJB2, SLC26A4, and MT-RNR1), then bioinformatics analysis was performed on the sequencing data to identify candidate pathogenic variants. Minigene experiments were conducted to determine the potential impact of the variants on splicing. RESULTS Genetic testing revealed that the first patient carried compound heterozygous variants c.[1149 + 1G > A]; [919-2 A > G] in the SLC26A4 gene, while the second patient carried compound heterozygous variants c.[2089 + 3 A > T]; [919-2 A > G] in the same gene. Minigene experiments demonstrated that both c.1149 + 1G > A and c.2089 + 3 A > T affected mRNA splicing. According to the ACMG guidelines and the recommendations of the ClinGen Hearing Loss Expert Panel for ACMG variant interpretation, these variants were classified as "likely pathogenic". CONCLUSIONS This study identified the molecular etiology of hearing loss in two patients with EVA and elucidated the impact of rare variants on splicing, thus contributing to the mutational spectrum of pathogenic variants in the SLC26A4 gene.
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Affiliation(s)
- Yixin Zhao
- Department of Otorhinolaryngology-Head and Neck Surgery, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Yan Long
- Department of Clinical Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Tao Shi
- Department of Otorhinolaryngology-Head and Neck Surgery, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Xin Ma
- Department of Otorhinolaryngology-Head and Neck Surgery, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, China
| | - Chengyu Lian
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Daxuebei Road No. 40, Zhengzhou, 450052, China
| | - Hanjun Wang
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Daxuebei Road No. 40, Zhengzhou, 450052, China
| | - Hongen Xu
- Precision Medicine Center, Academy of Medical Science, Zhengzhou University, Daxuebei Road No. 40, Zhengzhou, 450052, China
| | - Lisheng Yu
- Department of Otorhinolaryngology-Head and Neck Surgery, Peking University People's Hospital, No.11 Xizhimen South Street, Beijing, 100044, China.
| | - Xiaotao Zhao
- Department of Clinical Laboratory, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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Ruan Y, Wen C, Cheng X, Zhang W, Zhao L, Xie J, Lu H, Ren Y, Meng F, Li Y, Deng L, Huang L, Han D. Genetic screening of newborns for deafness over 11 years in Beijing, China: More infants could benefit from an expanded program. Biosci Trends 2024; 18:303-314. [PMID: 39183030 DOI: 10.5582/bst.2024.01178] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Genetic screening of newborns for deafness plays an important role in elucidating the etiology of deafness, diagnosing it early, and intervening in it. Genetic screening of newborns has been conducted for 11 years in Beijing. It started with a chip to screen for 9 variants of 4 genes in 2012; the chip screened for 15 variants of those genes in 2018, and it now screens for 23 variants of those genes. In the current study, a comparative analysis of three screening protocols and follow-up for infants with pathogenic variants was performed. The rates of detection and hearing test results of infants with pathogenic variants were analyzed. Subjects were 493,821 infants born at 122 maternal and child care centers in Beijing from April 2012 to August 2023. Positivity increased from 4.599% for the chip to screen for 9 variants to 4.971% for the chip to screen for 15 variants, and further to 11.489% for the chip to screen for 23 variants. The carrier frequency of the GJB2 gene increased from 2.489% for the chip to screen for 9 variants and 2.422% for the chip to screen for 15 variants to 9.055% for the chip to screen for 23 variants. The carrier frequency of the SLC26A4 gene increased from 1.621% for the chip to screen for 9 variants to 2.015% for the chip to screen for 15 variants and then to 2.151% for the chip to screen for 23 variants. According to the chip to screen for 9 variants and the chip to screen for 15 variants, the most frequent mutant allele was c.235delC. According to the chip to screen for 23 variants, the most frequent mutant allele was c.109G>A. The chip to screen for 15 variants was used to screen 66.67% (14/21) of newborns with biallelic variants in the SLC26A4 gene for newly added mutations. The chip to screen for 23 variants was used to screen 92.98% (53/57) of newborns with biallelic variants in the GJB2 gene (52 cases were biallelic c.109G>A) and 25% (1/4) of newborns with biallelic variants in the SLC26A4 gene for newly added mutations. Among the infants with pathogenic variants (biallelic variants in GJB2 or SLC26A4), 20.66% (25/121) currently have normal hearing. In addition, 34.62% (9/26) of newborns who passed the hearing screening were diagnosed with hearing loss. Findings indicate that a growing number of newborns have benefited, and especially in the early identification of potential late-onset hearing loss, as the number of screening sites has increased. Conducting long-term audiological monitoring for biallelic variants in individuals with normal hearing is of paramount significance.
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Affiliation(s)
- Yu Ruan
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Cheng Wen
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Xiaohua Cheng
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Wei Zhang
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Liping Zhao
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Jinge Xie
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Hongli Lu
- CapitalBio Corporation & National Engineering Research Center for Beijing Biochip Technology, Beijing, China
| | - Yonghong Ren
- CapitalBio Corporation & National Engineering Research Center for Beijing Biochip Technology, Beijing, China
| | - Fanlin Meng
- CapitalBio Corporation & National Engineering Research Center for Beijing Biochip Technology, Beijing, China
| | - Yue Li
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Lin Deng
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Lihui Huang
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
| | - Demin Han
- Otolaryngology-Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, China
- Beijing Institute of Otolaryngology, Beijing, China
- Key Laboratory of Otolaryngology Head and Neck Surgery (Capital Medical University), Ministry of Education, Beijing, China
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Zonnefeld AG, Cui CY, Tsitsipatis D, Piao Y, Fan J, Mazan-Mamczarz K, Xue Y, Indig FE, De S, Gorospe M. Characterization of age-associated gene expression changes in mouse sweat glands. Aging (Albany NY) 2024; 16:6717-6730. [PMID: 38637019 PMCID: PMC11087089 DOI: 10.18632/aging.205776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/18/2024] [Indexed: 04/20/2024]
Abstract
Evaporation of sweat on the skin surface is the major mechanism for dissipating heat in humans. The secretory capacity of sweat glands (SWGs) declines during aging, leading to heat intolerance in the elderly, but the mechanisms responsible for this decline are poorly understood. We investigated the molecular changes accompanying SWG aging in mice, where sweat tests confirmed a significant reduction of active SWGs in old mice relative to young mice. We first identified SWG-enriched mRNAs by comparing the skin transcriptome of Eda mutant Tabby male mice, which lack SWGs, with that of wild-type control mice by RNA-sequencing analysis. This comparison revealed 171 mRNAs enriched in SWGs, including 47 mRNAs encoding 'core secretory' proteins such as transcription factors, ion channels, ion transporters, and trans-synaptic signaling proteins. Among these, 28 SWG-enriched mRNAs showed significantly altered abundance in the aged male footpad skin, and 11 of them, including Foxa1, Best2, Chrm3, and Foxc1 mRNAs, were found in the 'core secretory' category. Consistent with the changes in mRNA expression levels, immunohistology revealed that higher numbers of secretory cells from old SWGs express the transcription factor FOXC1, the protein product of Foxc1 mRNA. In sum, our study identified mRNAs enriched in SWGs, including those that encode core secretory proteins, and altered abundance of these mRNAs and proteins with aging in mouse SWGs.
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Affiliation(s)
- Alexandra G. Zonnefeld
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Chang-Yi Cui
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Dimitrios Tsitsipatis
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Yulan Piao
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Jinshui Fan
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Krystyna Mazan-Mamczarz
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Yutong Xue
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Fred E. Indig
- Confocal Imaging Core Facility, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Supriyo De
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
| | - Myriam Gorospe
- Laboratory of Genetics and Genomics, National Institute on Aging Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA
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Shadab M, Abbasi AA, Ejaz A, Ben‐Mahmoud A, Gupta V, Kim H, Vona B. Autosomal recessive non-syndromic hearing loss genes in Pakistan during the previous three decades. J Cell Mol Med 2024; 28:e18119. [PMID: 38534090 PMCID: PMC10967143 DOI: 10.1111/jcmm.18119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 11/29/2023] [Accepted: 01/02/2024] [Indexed: 03/28/2024] Open
Abstract
Hearing loss is a clinically and genetically heterogeneous disorder, with over 148 genes and 170 loci associated with its pathogenesis. The spectrum and frequency of causal variants vary across different genetic ancestries and are more prevalent in populations that practice consanguineous marriages. Pakistan has a rich history of autosomal recessive gene discovery related to non-syndromic hearing loss. Since the first linkage analysis with a Pakistani family that led to the mapping of the DFNB1 locus on chromosome 13, 51 genes associated with this disorder have been identified in this population. Among these, 13 of the most prevalent genes, namely CDH23, CIB2, CLDN14, GJB2, HGF, MARVELD2, MYO7A, MYO15A, MSRB3, OTOF, SLC26A4, TMC1 and TMPRSS3, account for more than half of all cases of profound hearing loss, while the prevalence of other genes is less than 2% individually. In this review, we discuss the most common autosomal recessive non-syndromic hearing loss genes in Pakistani individuals as well as the genetic mapping and sequencing approaches used to discover them. Furthermore, we identified enriched gene ontology terms and common pathways involved in these 51 autosomal recessive non-syndromic hearing loss genes to gain a better understanding of the underlying mechanisms. Establishing a molecular understanding of the disorder may aid in reducing its future prevalence by enabling timely diagnostics and genetic counselling, leading to more effective clinical management and treatments of hearing loss.
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Affiliation(s)
- Madiha Shadab
- Department of ZoologyMirpur University of Science and TechnologyMirpurPakistan
| | - Ansar Ahmed Abbasi
- Department of ZoologyMirpur University of Science and TechnologyMirpurPakistan
| | - Ahsan Ejaz
- Department of PhysicsUniversity of Kotli Azad Jammu and KashmirKotliPakistan
- School of Nuclear Science and TechnologyLanzhou UniversityLanzhouChina
| | - Afif Ben‐Mahmoud
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa UniversityDohaQatar
| | - Vijay Gupta
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa UniversityDohaQatar
| | - Hyung‐Goo Kim
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa UniversityDohaQatar
- College of Health & Life SciencesHamad Bin Khalifa University (HBKU)DohaQatar
| | - Barbara Vona
- Institute of Human GeneticsUniversity Medical Center GöttingenGöttingenGermany
- Institute for Auditory Neuroscience and Inner Ear LabUniversity Medical Center GöttingenGöttingenGermany
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9
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Takahashi S, Kojima T, Wasano K, Homma K. Functional Studies of Deafness-Associated Pendrin and Prestin Variants. Int J Mol Sci 2024; 25:2759. [PMID: 38474007 PMCID: PMC10931795 DOI: 10.3390/ijms25052759] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/21/2024] [Accepted: 02/23/2024] [Indexed: 03/14/2024] Open
Abstract
Pendrin and prestin are evolutionary-conserved membrane proteins that are essential for normal hearing. Dysfunction of these proteins results in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here, we report results from our ongoing efforts to experimentally characterize pendrin and prestin variants using in vitro functional assays. With previously established fluorometric anion transport assays, we determined that many of the pendrin variants identified on transmembrane (TM) 10, which contains the essential anion binding site, and on the neighboring TM9 within the core domain resulted in impaired anion transport activity. We also determined the range of functional impairment in three deafness-associated prestin variants by measuring nonlinear capacitance (NLC), a proxy for motor function. Using the results from our functional analyses, we also evaluated the performance of AlphaMissense (AM), a computational tool for predicting the pathogenicity of missense variants. AM prediction scores correlated well with our experimental results; however, some variants were misclassified, underscoring the necessity of experimentally assessing the effects of variants. Together, our experimental efforts provide invaluable information regarding the pathogenicity of deafness-associated pendrin and prestin variants.
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Affiliation(s)
- Satoe Takahashi
- Department of Otolaryngology—Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
| | - Takashi Kojima
- Department of Otolaryngology—Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Department of Otolaryngology, Head and Neck Surgery, National Hospital Organization Tochigi Medical Center, Tochigi 320-0057, Japan
| | - Koichiro Wasano
- Department of Otolaryngology—Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- Department of Otolaryngology, Head and Neck Surgery, Tokai University School of Medicine, Isehara 259-1193, Japan
| | - Kazuaki Homma
- Department of Otolaryngology—Head and Neck Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA
- The Hugh Knowles Center for Clinical and Basic Science in Hearing and Its Disorders, Northwestern University, Evanston, IL 60208, USA
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10
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Takahashi S, Kojima T, Wasano K, Homma K. Functional studies of deafness-associated pendrin and prestin variants. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.23.576877. [PMID: 38328051 PMCID: PMC10849616 DOI: 10.1101/2024.01.23.576877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2024]
Abstract
Pendrin and prestin are evolutionary conserved membrane proteins that are essential for normal hearing. Pendrin is an anion transporter required for normal development and maintenance of ion homeostasis in the inner ear, while prestin is a voltage-dependent motor responsible for cochlear amplification essential for high sensitivity and frequency selectivity of mammalian hearing. Dysfunction of these proteins result in hearing loss in humans, and numerous deafness-associated pendrin and prestin variants have been identified in patients. However, the pathogenic impacts of many of these variants are ambiguous. Here we report results from our ongoing efforts in experimentally characterizing pendrin and prestin variants using in vitro functional assays, providing invaluable information regarding their pathogenicity.
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11
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Danilchenko VY, Zytsar MV, Maslova EA, Orishchenko KE, Posukh OL. Insight into the Natural History of Pathogenic Variant c.919-2A>G in the SLC26A4 Gene Involved in Hearing Loss: The Evidence for Its Common Origin in Southern Siberia (Russia). Genes (Basel) 2023; 14:genes14040928. [PMID: 37107686 PMCID: PMC10137394 DOI: 10.3390/genes14040928] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2023] [Revised: 04/10/2023] [Accepted: 04/12/2023] [Indexed: 04/29/2023] Open
Abstract
Pathogenic variants in the SLC26A4 gene leading to nonsyndromic recessive deafness (DFNB4), or Pendred syndrome, are some of the most common causes of hearing loss worldwide. Earlier, we found a high proportion of SLC26A4-related hearing loss with prevailing pathogenic variant c.919-2A>G (69.3% among all mutated SLC26A4 alleles that have been identified) in Tuvinian patients belonging to the indigenous Turkic-speaking Siberian people living in the Tyva Republic (Southern Siberia, Russia), which implies a founder effect in the accumulation of c.919-2A>G in Tuvinians. To evaluate a possible common origin of c.919-2A>G, we genotyped polymorphic STR and SNP markers, intragenic and flanking SLC26A4, in patients homozygous for c.919-2A>G and in healthy controls. The common STR and SNP haplotypes carrying c.919-2A>G were revealed, which convincingly indicates the origin of c.919-2A>G from a single ancestor, supporting a crucial role of the founder effect in the c.919-2A>G prevalence in Tuvinians. Comparison analysis with previously published data revealed the identity of the small SNP haplotype (~4.5 kb) in Tuvinian and Han Chinese carriers of c.919-2A>G, which suggests their common origin from founder chromosomes. We assume that c.919-2A>G could have originated in the geographically close territories of China or Tuva and subsequently spread to other regions of Asia. In addition, the time intervals of the c.919-2A>G occurrence in Tuvinians were roughly estimated.
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Affiliation(s)
- Valeriia Yu Danilchenko
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Marina V Zytsar
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Ekaterina A Maslova
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Konstantin E Orishchenko
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Olga L Posukh
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
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The Frequency of Common Deafness-Associated Variants Among 3,555,336 Newborns in China and 141,456 Individuals Across Seven Populations Worldwide. Ear Hear 2023; 44:232-241. [PMID: 36149380 DOI: 10.1097/aud.0000000000001274] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
OBJECTIVES Genetic screening can benefit early detection and intervention for hearing loss. The frequency of common deafness-associated variants in general populations is highly important for genetic screening and genetic counseling tailored to different ethnic backgrounds. We aimed to analyze the frequency of common deafness-associated variants in a large population-based Chinese newborn cohort and to explore the population-specific features in diverse populations worldwide. DESIGN This population-based cohort study analyzed the frequency of common deafness-associated variants in 3,555,336 newborns in the Chinese Newborn Concurrent Hearing and Genetic Screening cohort. Participants were newborn infants born between January 2007 and September 2020. Limited genetic screening for 20 variants in 4 common deafness-associated genes and newborn hearing screening were offered concurrently to all newborns in the Chinese Newborn Concurrent Hearing and Genetic Screening cohort. Sequence information of 141,456 individuals was also analyzed from seven ethnic populations from the Genome Aggregation Database for 20 common deafness-related variants. Statistical analysis was performed using R. RESULTS A total of 3,555,326 Chinese neonates completed the Newborn Concurrent Hearing and Genetic Screening were included for analysis. We reported the distinct landscape of common deafness-associated variants in this large population-based cohort. We found that the carrier frequencies of GJB2 , SLC26A4 , GJB3 , and MT-RNR were 2.53%, 2.05%, 0.37%, and 0.25%, respectively. Furthermore, GJB2 c.235delC was the most common variant with an allele frequency of 0.99% in the Chinese newborn population. We also demonstrated nine East-Asia-enriched variants, one Ashkenazi Jewish-enriched variant, and one European/American-enriched variant for hearing loss. CONCLUSIONS We showed the distinct landscape of common deafness-associated variants in the Chinese newborn population and provided insights into population-specific features in diverse populations. These data can serve as a powerful resource for otolaryngologists and clinical geneticists to inform population-adjusted genetic screening programs for hearing loss.
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Analysis of SLC26A4, FOXI1, and KCNJ10 Gene Variants in Patients with Incomplete Partition of the Cochlea and Enlarged Vestibular Aqueduct (EVA) Anomalies. Int J Mol Sci 2022; 23:ijms232315372. [PMID: 36499699 PMCID: PMC9740095 DOI: 10.3390/ijms232315372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/29/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022] Open
Abstract
Pathogenic variants in the SLC26A4, FOXI1, and KCNJ10 genes are associated with hearing loss (HL) and specific inner ear abnormalities (DFNB4). In the present study, phenotype analyses, including clinical data collection, computed tomography (CT), and audiometric examination, were performed on deaf individuals from the Sakha Republic of Russia (Eastern Siberia). In cases with cochleovestibular malformations, molecular genetic analysis of the coding regions of the SLC26A4, FOXI1, and KCNJ10 genes associated with DFNB4 was completed. In six of the 165 patients (3.6%), CT scans revealed an incomplete partition of the cochlea (IP-1 and IP-2), in isolation or combined with an enlarged vestibular aqueduct (EVA) anomaly. Sequencing of the SLC26A4, FOXI1, and KCNJ10 genes was performed in these six patients. In the SLC26A4 gene, we identified four variants, namely c.85G>C p.(Glu29Gln), c.757A>G p.(Ile253Val), c.2027T>A p.(Leu676Gln), and c.2089+1G>A (IVS18+1G>A), which are known as pathogenic, as well as c.441G>A p.(Met147Ile), reported previously as a variant with uncertain significance. Using the AlphaFold algorithm, we found in silico evidence of the pathogenicity of this variant. We did not find any causative variants in the FOXI1 and KCNJ10 genes, nor did we find any evidence of digenic inheritance associated with double heterozygosity for these genes with monoallelic SLC26A4 variants. The contribution of biallelic SLC26A4 variants in patients with IP-1, IP-2, IP-2+EVA, and isolated EVA was 66.7% (DFNB4 in three patients, Pendred syndrome in one patient). Seventy-five percent of SLC26A4-biallelic patients had severe or profound HL. The morphology of the inner ear anomalies demonstrated that, among SLC26A4-biallelic patients, all types of incomplete partition of the cochlea are possible, from IP-1 and IP-2, to a normal cochlea. However, the dominant type of anomaly was IP-2+EVA (50.0%). This finding is very important for cochlear implantation, since the IP-2 anomaly does not have an increased risk of “gushers” and recurrent meningitis.
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14
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Szeto IYY, Chu DKH, Chen P, Chu KC, Au TYK, Leung KKH, Huang YH, Wynn SL, Mak ACY, Chan YS, Chan WY, Jauch R, Fritzsch B, Sham MH, Lovell-Badge R, Cheah KSE. SOX9 and SOX10 control fluid homeostasis in the inner ear for hearing through independent and cooperative mechanisms. Proc Natl Acad Sci U S A 2022; 119:e2122121119. [PMID: 36343245 PMCID: PMC9674217 DOI: 10.1073/pnas.2122121119] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Accepted: 09/10/2022] [Indexed: 11/09/2022] Open
Abstract
The in vivo mechanisms underlying dominant syndromes caused by mutations in SRY-Box Transcription Factor 9 (SOX9) and SOX10 (SOXE) transcription factors, when they either are expressed alone or are coexpressed, are ill-defined. We created a mouse model for the campomelic dysplasia SOX9Y440X mutation, which truncates the transactivation domain but leaves DNA binding and dimerization intact. Here, we find that SOX9Y440X causes deafness via distinct mechanisms in the endolymphatic sac (ES)/duct and cochlea. By contrast, conditional heterozygous Sox9-null mice are normal. During the ES development of Sox9Y440X/+ heterozygotes, Sox10 and genes important for ionic homeostasis are down-regulated, and there is developmental persistence of progenitors, resulting in fewer mature cells. Sox10 heterozygous null mutants also display persistence of ES/duct progenitors. By contrast, SOX10 retains its expression in the early Sox9Y440X/+ mutant cochlea. Later, in the postnatal stria vascularis, dominant interference by SOX9Y440X is implicated in impairing the normal cooperation of SOX9 and SOX10 in repressing the expression of the water channel Aquaporin 3, thereby contributing to endolymphatic hydrops. Our study shows that for a functioning endolymphatic system in the inner ear, SOX9 regulates Sox10, and depending on the cell type and target gene, it works either independently of or cooperatively with SOX10. SOX9Y440X can interfere with the activity of both SOXE factors, exerting effects that can be classified as haploinsufficient/hypomorphic or dominant negative depending on the cell/gene context. This model of disruption of transcription factor partnerships may be applicable to congenital deafness, which affects ∼0.3% of newborns, and other syndromic disorders.
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Affiliation(s)
- Irene Y. Y. Szeto
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Daniel K. H. Chu
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Peikai Chen
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Ka Chi Chu
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Tiffany Y. K. Au
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Keith K. H. Leung
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Yong-Heng Huang
- Genome Regulation Laboratory, CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Guangzhou Medical University, Guangzhou 511436, China
| | - Sarah L. Wynn
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Angel C. Y. Mak
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Ying-Shing Chan
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | - Wood Yee Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China
| | - Ralf Jauch
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
- Genome Regulation Laboratory, CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
- Guangzhou Medical University, Guangzhou 511436, China
| | - Bernd Fritzsch
- Department of Biology, College of Arts & Sciences, University of Iowa, Iowa City, IA 52242
- Department of Otolaryngology, College of Arts & Sciences, University of Iowa, Iowa City, IA 52242
| | - Mai Har Sham
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
| | | | - Kathryn S. E. Cheah
- School of Biomedical Sciences, The University of Hong Kong, Li Ka Shing Faculty of Medicine, Hong Kong, China
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15
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Danilchenko VY, Zytsar MV, Maslova EA, Posukh OL. Selection of Diagnostically Significant Regions of the SLC26A4 Gene Involved in Hearing Loss. Int J Mol Sci 2022; 23:ijms232113453. [PMID: 36362242 PMCID: PMC9655724 DOI: 10.3390/ijms232113453] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 10/23/2022] [Accepted: 11/01/2022] [Indexed: 11/06/2022] Open
Abstract
Screening pathogenic variants in the SLC26A4 gene is an important part of molecular genetic testing for hearing loss (HL) since they are one of the common causes of hereditary HL in many populations. However, a large size of the SLC26A4 gene (20 coding exons) predetermines the difficulties of its complete mutational analysis, especially in large samples of patients. In addition, the regional or ethno-specific prevalence of SLC26A4 pathogenic variants has not yet been fully elucidated, except variants c.919-2A>G and c.2168A>G (p.His723Arg), which have been proven to be most common in Asian populations. We explored the distribution of currently known pathogenic and likely pathogenic (PLP) variants across the SLC26A4 gene sequence presented in the Deafness Variation Database for the selection of potential diagnostically important parts of this gene. As a result of this bioinformatic analysis, we found that molecular testing ten SLC26A4 exons (4, 6, 10, 11, 13−17 and 19) with flanking intronic regions can provide a diagnostic rate of 61.9% for all PLP variants in the SLC26A4 gene. The primary sequencing of these SLC26A4 regions may be applied as an initial effective diagnostic testing in samples of patients of unknown ethnicity or as a subsequent step after the targeted testing of already-known ethno- or region-specific pathogenic SLC26A4 variants.
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Affiliation(s)
- Valeriia Yu. Danilchenko
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Marina V. Zytsar
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
| | - Ekaterina A. Maslova
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
| | - Olga L. Posukh
- Federal Research Center Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, 630090 Novosibirsk, Russia
- Novosibirsk State University, 630090 Novosibirsk, Russia
- Correspondence:
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Matulevičius A, Bernardinelli E, Brownstein Z, Roesch S, Avraham KB, Dossena S. Molecular Features of SLC26A4 Common Variant p.L117F. J Clin Med 2022; 11:5549. [PMID: 36233414 PMCID: PMC9570580 DOI: 10.3390/jcm11195549] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 11/16/2022] Open
Abstract
The SLC26A4 gene, which encodes the anion exchanger pendrin, is involved in determining syndromic (Pendred syndrome) and non-syndromic (DFNB4) autosomal recessive hearing loss. SLC26A4 c.349C>T, p.L117F is a relatively common allele in the Ashkenazi Jewish community, where its minor allele frequency is increased compared to other populations. Although segregation and allelic data support the pathogenicity of this variant, former functional tests showed characteristics that were indistinguishable from those of the wild-type protein. Here, we applied a triad of cell-based assays, i.e., measurement of the ion transport activity by a fluorometric method, determination of the subcellular localization by confocal microscopy, and assessment of protein expression levels, to conclusively assign or exclude the pathogenicity of SLC26A4 p.L117F. This protein variant showed a moderate, but significant, reduction in ion transport function, a partial retention in the endoplasmic reticulum, and a strong reduction in expression levels as a consequence of an accelerated degradation by the Ubiquitin Proteasome System, all supporting pathogenicity. The functional and molecular features of human pendrin p.L117F were recapitulated by the mouse ortholog, thus indicating that a mouse carrying this variant might represent a good model of Pendred syndrome/DFNB4.
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Affiliation(s)
- Arnoldas Matulevičius
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Emanuele Bernardinelli
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Zippora Brownstein
- Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Sebastian Roesch
- Department of Otorhinolaryngology, Head and Neck Surgery, Paracelsus Medical University, 5020 Salzburg, Austria
| | - Karen B. Avraham
- Department of Human Molecular Genetics & Biochemistry, Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Silvia Dossena
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria
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SLC26A4 Mutation Promotes Cell Apoptosis by Inducing Pendrin Transfer, Reducing Cl- Transport, and Inhibiting PI3K/Akt/mTOR Pathway. BIOMED RESEARCH INTERNATIONAL 2022; 2022:6496799. [PMID: 36072472 PMCID: PMC9444440 DOI: 10.1155/2022/6496799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 08/03/2022] [Indexed: 11/18/2022]
Abstract
Objective. Pendrin is encoded by SLC26A4, which is expressed in the apical membrane of inner ear epithelial cells and drives chloride reabsorption in the apical septum. In the inner ear, pendrin dysfunction and hypofunctional mutations lead to vestibular aqueduct (EVA) enlargement and sensory neural hearing loss. Mutations in SLC26A4 are a common reason of deafness. However, the underlying mechanisms of SLC26A4 mutants in hearing loss remain unknown. Methods. In the present study, pEGFP-N1 carrying wild-type and mutant SLC26A4 (c.85G>A, c.2006A>T, and c.853G>A) were transfected into HEK-293T cells. GFP fluorescence and GFP levels were determined. SLC26A4 mRNA levels were examined by quantitative real-time polymerase chain reaction (qRT-PCR). Then, the expression of chloride intracellular channel 1 (CLIC1) and CLIC2 was measured by Immunofluorescence assay. Intracellular chloride concentration and apoptotic rate were analyzed by flow cytometry. The levels of membrane/cytoplasmic pendrin, apoptosis-associated proteins, and the PI3K/Akt/mTOR pathway members were determined by Western blot. Results. Constructed SLC26A4 mutant 1 (c.85G>A), SLC26A4 mutant 2 (c.2006A>T), and SLC26A4 mutant 3 (c.853G>A). The wild-type and 3 mutations were stably expressed in HEK-293T. SLC26A4 mRNA expression was significantly increased after transfection with wild-type SLC26A4 and mutant SLC26A4 compared with the untransfected vector group (
). Compared with the vector group, the expression levels of membrane pendrin, cytoplasmic pendrin, CLIC1, CLIC2, Bcl-2, p-PI3K, p-Akt, and p-mTOR were upregulated. Compared with the vector group, the chloride concentration, cell apoptotic rate, and the expression levels of caspase-3, caspase-9, and Bax were downregulated. Compared with the vector group, the above effects of SLC26A4 were reversed after the SLC26A4 mutant. Conclusion. After SLC26A4 mutation, pendrin was transferred from the membrane, the chloride intracellular channel function was reduced, and the excessive accumulation of chloride in the cytoplasm induced cell apoptosis by inhibited PI3K/Akt/mTOR pathway phosphorylation.
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18
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He X, Zhao S, Shi L, Lu Y, Yang Y, Zhang X. Compound heterozygous variants of the SLC26A4 gene in a Chinese family with enlarged vestibular aqueducts. BMC Med Genomics 2022; 15:152. [PMID: 35804348 PMCID: PMC9270741 DOI: 10.1186/s12920-022-01271-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Accepted: 05/10/2022] [Indexed: 11/21/2022] Open
Abstract
Background To investigate the genetic causes of hearing loss in patients with enlarged vestibular aqueduct (EVA), the SLC26A4-related genotypes and phenotypes were analyzed. SLC26A4 gene is closely associated with EVA and its homozygous mutations or compound heterozygous mutations may cause deafness and strongly affect quality of life. Methods The patients who came to our hospital for hearing test and accompanied by bilateral hearing abnormalities were collected for fifteen deafness-related gene mutations detection. Those who are positive will be verified by Sanger sequencing, combined with family history, hearing test, and computerized tomography (CT) of the temporal bone, aiming to diagnose the enlarged vestibular aqueducts. Whole-exome sequencing were performed when necessary. Results Our patient failed hearing screening on both sides twice, and EVA (> 1.5 mm) was diagnosed by CT. This study has identified a novel missense mutation in the SLC26A4 gene, c.2069T>A, which in compound heterozygosity with c.1174A>T is likely to be the cause of hearing loss. The novel heterozygous c.2069T>A mutation of SLC26A4 gene has been submitted to Clinvar with Variation ID 1,048,780. Conclusion Our findings expand the gene mutation spectrum of SLC26A4 and provide additional knowledge for diagnosis and genetic counseling associated with EVA-induced hearing loss. Supplementary Information The online version contains supplementary material available at 10.1186/s12920-022-01271-3.
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Affiliation(s)
- Xiaohui He
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Shaozhi Zhao
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Lin Shi
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Yitong Lu
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Yintong Yang
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China
| | - Xinwen Zhang
- Xi'an People's Hospital (Xi'an Fourth Hospital), Xi'an, China.
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19
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Rapid Genetic Diagnosis for Okinawan Patients with Enlarged Vestibular Aqueduct Using Single-Stranded Tag Hybridization Chromatographic Printed-Array Strip. J Clin Med 2022; 11:jcm11041099. [PMID: 35207372 PMCID: PMC8880462 DOI: 10.3390/jcm11041099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Revised: 02/11/2022] [Accepted: 02/17/2022] [Indexed: 02/04/2023] Open
Abstract
Both Pendred syndrome (PS) and nonsyndromic hearing loss with an enlarged vestibular aqueduct (EVA) are autosomal recessive disorders caused by SLC26A4 pathogenic variants. The spectrum of SLC26A4 pathogenic variants varies with the ethnic background. Among the patients with EVA in Okinawa, 94% had some combination of NM_000441.2(SLC26A4):c.1707+5G>A and NM_000441.2(SLC26A4):c.2168A>G(p.His723Arg), the two SLC26A4 pathogenic variants that are the most common in this population. We identified these two pathogenic variants using a novel genotyping method that employed an allele-specific polymerase chain reaction (PCR) from a gDNA and single-stranded tag hybridization chromatographic printed-array strip (STH-PAS) in DNA samples obtained from 48 samples in Okinawa, including 34 patients with EVA and 14 carriers of c.1707+5G>A or c.2168A>G. In addition, whole blood and saliva samples were used for analysis in this genotyping method with direct PCR. The results of STH-PAS genotyping were consistent with those obtained using standard Sanger sequencing for all samples. The accuracy of the STH-PAS method is 100% under the optimized conditions. STH-PAS genotyping provided a diagnosis in 30 out of 34 patients (88%) in Okinawan patients with EVA in under 3 h. The turn-around time for STH-PAS genotyping used with direct PCR was 2 h as a result of the omission of the DNA extraction and purification steps. Using information about the ethnic distribution of pathogenic variants in the SLC26A4 gene, STH-PAS genotyping performs a rapid genetic diagnosis that is simple and has a considerably improved efficiency.
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20
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Different Rates of the SLC26A4-Related Hearing Loss in Two Indigenous Peoples of Southern Siberia (Russia). Diagnostics (Basel) 2021; 11:diagnostics11122378. [PMID: 34943614 PMCID: PMC8699871 DOI: 10.3390/diagnostics11122378] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/13/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022] Open
Abstract
Hereditary hearing loss (HL) is known to be highly locus/allelic heterogeneous, and the prevalence of different HL forms significantly varies among populations worldwide. Investigation of region-specific landscapes of hereditary HL is important for local healthcare and medical genetic services. Mutations in the SLC26A4 gene leading to nonsyndromic recessive deafness (DFNB4) and Pendred syndrome are common genetic causes of hereditary HL, at least in some Asian populations. We present for the first time the results of a thorough analysis of the SLC26A4 gene by Sanger sequencing in the large cohorts of patients with HL of unknown etiology belonging to two neighboring indigenous Turkic-speaking Siberian peoples (Tuvinians and Altaians). A definite genetic diagnosis based on the presence of biallelic SLC26A4 mutations was established for 28.2% (62/220) of all enrolled Tuvinian patients vs. 4.3% (4/93) of Altaian patients. The rate of the SLC26A4-related HL in Tuvinian patients appeared to be one of the highest among populations worldwide. The SLC26A4 mutational spectrum was characterized by the presence of Asian-specific mutations c.919-2A>G and c.2027T>A (p.Leu676Gln), predominantly found in Tuvinian patients, and c.2168A>G (p.His723Arg), which was only detected in Altaian patients. In addition, a novel pathogenic variant c.1545T>G (p.Phe515Leu) was found with high frequency in Tuvinian patients. Overall, based on the findings of this study and our previous research, we were able to uncover the genetic causes of HL in 50.5% of Tuvinian patients and 34.5% of Altaian patients.
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21
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Batissoco AC, Pedroso-Campos V, Pardono E, Sampaio-Silva J, Sonoda CY, Vieira-Silva GA, da Silva de Oliveira Longati EU, Mariano D, Hoshino ACH, Tsuji RK, Jesus-Santos R, Abath-Neto O, Bento RF, Oiticica J, Lezirovitz K. Molecular and genetic characterization of a large Brazilian cohort presenting hearing loss. Hum Genet 2021; 141:519-538. [PMID: 34599368 DOI: 10.1007/s00439-021-02372-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Accepted: 09/15/2021] [Indexed: 12/16/2022]
Abstract
Hearing loss is one of the most common sensory defects, affecting 5.5% of the worldwide population and significantly impacting health and social life. It is mainly attributed to genetic causes, but their relative contribution reflects the geographical region's socio-economic development. Extreme genetic heterogeneity with hundreds of deafness genes involved poses challenges for molecular diagnosis. Here we report the investigation of 542 hearing-impaired subjects from all Brazilian regions to search for genetic causes. Biallelic GJB2/GJB6 causative variants were identified in 12.9% (the lowest frequency was found in the Northern region, 7.7%), 0.4% carried GJB2 dominant variants, and 0.6% had the m.1555A > G variant (one aminoglycoside-related). In addition, other genetic screenings, employed in selected probands according to clinical presentation and presumptive inheritance patterns, identified causative variants in 2.4%. Ear malformations and auditory neuropathy were diagnosed in 10.8% and 3.5% of probands, respectively. In 3.8% of prelingual/perilingual cases, Waardenburg syndrome was clinically diagnosed, and in 71.4%, these diagnoses were confirmed with pathogenic variants revealed; seven out of them were novel, including one CNV. All these genetic screening strategies revealed causative variants in 16.2% of the cases. Based on causative variants in the molecular diagnosis and genealogy analyses, a probable genetic etiology was found in ~ 50% of the cases. The present study highlights the relevance of GJB2/GJB6 as a cause of hearing loss in all Brazilian regions and the importance of screening unselected samples for estimating frequencies. Moreover, when a comprehensive screening is not available, molecular diagnosis can be enhanced by selecting probands for specific screenings.
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Affiliation(s)
- Ana Carla Batissoco
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- ENT Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Vinicius Pedroso-Campos
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Eliete Pardono
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- Instituto de Ciências de Saúde da UNIP, São Paulo, SP, Brasil
| | - Juliana Sampaio-Silva
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Cindy Yukimi Sonoda
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Gleiciele Alice Vieira-Silva
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | | | - Diego Mariano
- Department of Computer Science, Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brasil
| | - Ana Cristina Hiromi Hoshino
- ENT Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Robinson Koji Tsuji
- ENT Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Rafaela Jesus-Santos
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Osório Abath-Neto
- Departamento de Neurologia, Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo, SP, Brasil
| | - Ricardo Ferreira Bento
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- ENT Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Jeanne Oiticica
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil
- ENT Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil
| | - Karina Lezirovitz
- Laboratório de Otorrinolaringologia/LIM 32, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brasil.
- ENT Department, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, SP, Brasil.
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Roesch S, Rasp G, Sarikas A, Dossena S. Genetic Determinants of Non-Syndromic Enlarged Vestibular Aqueduct: A Review. Audiol Res 2021; 11:423-442. [PMID: 34562878 PMCID: PMC8482117 DOI: 10.3390/audiolres11030040] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/02/2021] [Accepted: 08/24/2021] [Indexed: 12/13/2022] Open
Abstract
Hearing loss is the most common sensorial deficit in humans and one of the most common birth defects. In developed countries, at least 60% of cases of hearing loss are of genetic origin and may arise from pathogenic sequence alterations in one of more than 300 genes known to be involved in the hearing function. Hearing loss of genetic origin is frequently associated with inner ear malformations; of these, the most commonly detected is the enlarged vestibular aqueduct (EVA). EVA may be associated to other cochleovestibular malformations, such as cochlear incomplete partitions, and can be found in syndromic as well as non-syndromic forms of hearing loss. Genes that have been linked to non-syndromic EVA are SLC26A4, GJB2, FOXI1, KCNJ10, and POU3F4. SLC26A4 and FOXI1 are also involved in determining syndromic forms of hearing loss with EVA, which are Pendred syndrome and distal renal tubular acidosis with deafness, respectively. In Caucasian cohorts, approximately 50% of cases of non-syndromic EVA are linked to SLC26A4 and a large fraction of patients remain undiagnosed, thus providing a strong imperative to further explore the etiology of this condition.
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Affiliation(s)
- Sebastian Roesch
- Department of Otorhinolaryngology, Head and Neck Surgery, Paracelsus Medical University, 5020 Salzburg, Austria; (S.R.); (G.R.)
| | - Gerd Rasp
- Department of Otorhinolaryngology, Head and Neck Surgery, Paracelsus Medical University, 5020 Salzburg, Austria; (S.R.); (G.R.)
| | - Antonio Sarikas
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria;
| | - Silvia Dossena
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, 5020 Salzburg, Austria;
- Correspondence: ; Tel.: +43-(0)662-2420-80564
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23
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Honda K, Griffith AJ. Genetic architecture and phenotypic landscape of SLC26A4-related hearing loss. Hum Genet 2021; 141:455-464. [PMID: 34345941 DOI: 10.1007/s00439-021-02311-1] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Accepted: 06/29/2021] [Indexed: 12/15/2022]
Abstract
Mutations of coding regions and splice sites of SLC26A4 cause Pendred syndrome and nonsyndromic recessive hearing loss DFNB4. SLC26A4 encodes pendrin, a transmembrane exchanger of anions and bases. The mutant SLC26A4 phenotype is characterized by inner ear malformations, including an enlarged vestibular aqueduct (EVA), incomplete cochlear partition type II and modiolar hypoplasia, progressive and fluctuating hearing loss, and vestibular dysfunction. A thyroid iodine organification defect can lead to multinodular goiter and distinguishes Pendred syndrome from DFNB4. Pendred syndrome and DFNB4 are each inherited as an autosomal recessive trait caused by biallelic mutations of SLC26A4 (M2). However, there are some EVA patients with only one detectable mutant allele (M1) of SLC26A4. In most European-Caucasian M1 patients, there is a haplotype that consists of 12 variants upstream of SLC26A4, called CEVA (Caucasian EVA), which acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. This combination of an M1 genotype with the CEVA haplotype is associated with a less severe phenotype than the M2 genotype. The phenotype in EVA patients with no mutant alleles of SLC26A4 (M0) has a very low recurrence probability and is likely to be caused by other factors.
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Affiliation(s)
- Keiji Honda
- Department of Otorhinolaryngology, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, Japan
| | - Andrew J Griffith
- Department of Otolaryngology, College of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA.
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24
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Abstract
Congenital hearing loss is the most common birth defect, estimated to affect 2-3 in every 1000 births. Currently there is no cure for hearing loss. Treatment options are limited to hearing aids for mild and moderate cases, and cochlear implants for severe and profound hearing loss. Here we provide a literature overview of the environmental and genetic causes of congenital hearing loss, common animal models and methods used for hearing research, as well as recent advances towards developing therapies to treat congenital deafness. © 2021 The Authors.
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Affiliation(s)
- Justine M Renauld
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Martin L Basch
- Department of Otolaryngology, Head & Neck Surgery, Case Western Reserve University School of Medicine, Cleveland, Ohio.,Department of Genetics and Genome Sciences, Case Western Reserve School of Medicine, Cleveland, Ohio.,Department of Biology, Case Western Reserve University, Cleveland, Ohio.,Department of Otolaryngology, Head & Neck Surgery, University Hospitals, Cleveland, Ohio
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25
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Absence of Endolymphatic Sac Ion Transport Proteins in Large Vestibular Aqueduct Syndrome-A Human Temporal Bone Study. Otol Neurotol 2021; 41:e1256-e1263. [PMID: 32890293 DOI: 10.1097/mao.0000000000002832] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
HYPOTHESIS Epithelial ion transport pathologies of the endolymphatic sac (ES) are associated with large vestibular aqueduct syndrome (LVAS). BACKGROUND LVAS is defined by the pathognomonic features of a widened bony vestibular aqueduct (VA) and an enlarged ES. The underlying cause of its associated cochleovestibular symptoms remains elusive. Disturbances in epithelial ion transport in the enlarged ES, affecting inner ear fluid regulation, were proposed as a possible pathophysiology. However, although respective epithelial ion transport pathologies have been demonstrated in the enlarged ES from transgenic LVAS mouse models, these pathologies have not been investigated in human LVAS cases. METHODS Histological and immunohistochemical analysis of the enlarged ES epithelium in postmortem temporal bones from two individuals with a clinical diagnosis of LVAS. RESULTS The enlarged ES epithelium demonstrated an overall atypical epithelial differentiation and a lack of the immunolocalization of signature ion transport proteins. Notably, in both cases, a rudimentary branch of the ES with a typically differentiated ES epithelium was present. CONCLUSIONS The described cellular and molecular pathologies of the enlarged ES in humans provide evidence of epithelial transport pathology as one potential cause of cochleovestibular symptoms in LVAS. The present findings also emphasize the clinical relevance of already established LVAS mouse models.
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26
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Xiao C, Liu S, Wang H, Ding Y, Chen Y, Liu H. Genetic etiology study of four Chinese families with two nonsyndromic deaf children in succession by targeted next-generation sequencing. Mol Genet Genomic Med 2021; 9:e1634. [PMID: 33638616 PMCID: PMC8123758 DOI: 10.1002/mgg3.1634] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 12/09/2020] [Accepted: 02/10/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Genetic components contribute significantly to the cause of hearing loss. Nonsyndromic hearing loss has been shown to have high genetic heterogeneity. For families who had given birth to two nonsyndromic deaf children in succession, it seems that their deafness was highly related to genetics. OBJECTIVES This study aimed to disclose the genetic causes of the subjects from the four Chinese families with two nonsyndromic deaf children in succession who failed to find the genetic etiology of the hearing loss by common deafness genetic screening (GJB2, GJB3, SLC26A4, and MT-RNR1, including 20 hot variants in 4 genes). METHODS Targeted next-generation sequencing (NGS) of 127 known deafness genes was performed in probands of four families, followed by a series of comprehensive analyses of all family members combined with a literature review of related genes. RESULTS We identified pathogenic variants in three families including c.919-2A>G/c.1985G>A in SLC26A4; c.109G>A (p.V37I) in GJB2; and m.7505T>C in MT-TS1. Sanger sequencing confirmed that these variants segregated with the hearing impairment of each family. We also identified c.331C>T/c.625-5C>T/c.5717G>A in CDH23; c.138T>C in POU3F4 in two families, in which the pathogenicity in clinical was likely pathogenic or unknown. CONCLUSIONS Using the NGS detection technology, we found the genetic etiology of the HL in part of deaf families. Our study provided a useful piece of information for the variant spectrum of hearing loss in Chinese families with two deaf children in succession.
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Affiliation(s)
- Caixia Xiao
- Tianjin Women and Children Healthcare CenterTianjinChina
| | - Shuang Liu
- Tianjin Women and Children Healthcare CenterTianjinChina
| | - Hongyue Wang
- Tianjin Women and Children Healthcare CenterTianjinChina
| | - Yibing Ding
- Tianjin Women and Children Healthcare CenterTianjinChina
| | - Yaqiu Chen
- Tianjin Women and Children Healthcare CenterTianjinChina
| | - Haiyan Liu
- Tianjin Women and Children Healthcare CenterTianjinChina
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27
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Simon F, Denoyelle F, Beraneck M. Interpreting pendred syndrome as a foetal hydrops: Clinical and animal model evidence. J Vestib Res 2021; 31:315-321. [PMID: 33579884 DOI: 10.3233/ves-200789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
BACKGROUND Menière disease (MD) and SLC26A4 related deafness (Pendred syndrome (PS) or DFNB4) are two different inner ear disorders which present with fluctuating and progressive hearing loss, which could be a direct consequence of endolymphatic hydrops. OBJECTIVE To present similarities between both pathologies and explore how the concept of hydrops may be applied to PS/DFNB4. METHODS Review of the literature on MD, PS/DFNB4 and mouse model of PS/DFNB4. RESULTS MD and PS/DFNB4 share a number of similarities such as fluctuating and progressive hearing loss, acute episodes with vertigo and tinnitus, MRI and histological evidence of endolymphatic hydrops (although with different underlying mechanisms). MD is usually diagnosed during the fourth decade of life whereas PS/DFNB4 is congenital. The PS/DFNB4 mouse models have shown that biallelic slc26a4 mutations lead to Na+ and water retention in the endolymph during the perinatal period, which in turn induces degeneration of the stria vascularis and hearing loss. Crossing clinical/imagery characteristics and animal models, evidence seems to support the hypothesis of PS being a foetal hydrops. CONCLUSIONS When understanding PS/DFNB4 as a developmental hydrops, treatments used in MD could be repositioned to PS.
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Affiliation(s)
- François Simon
- Université de Paris, INCC UMR 8002, CNRS, F-75006 Paris, France.,Université de Paris, Faculté de Médecine, F-75006 Paris, France.,Department of Paediatric Otolaryngology, AP-HP, Hôpital Necker-Enfants Malades, F-75015 Paris, France
| | - Françoise Denoyelle
- Université de Paris, Faculté de Médecine, F-75006 Paris, France.,Department of Paediatric Otolaryngology, AP-HP, Hôpital Necker-Enfants Malades, F-75015 Paris, France
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28
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Mei C, Dong H, Nisenbaum E, Thielhelm T, Nourbakhsh A, Yan D, Smeal M, Lundberg Y, Hoffer ME, Angeli S, Telischi F, Nie G, Blanton SH, Liu X. Genetics and the Individualized Therapy of Vestibular Disorders. Front Neurol 2021; 12:633207. [PMID: 33613440 PMCID: PMC7892966 DOI: 10.3389/fneur.2021.633207] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/13/2021] [Indexed: 02/06/2023] Open
Abstract
Background: Vestibular disorders (VDs) are a clinically divergent group of conditions that stem from pathology at the level of the inner ear, vestibulocochlear nerve, or central vestibular pathway. No etiology can be identified in the majority of patients with VDs. Relatively few families have been reported with VD, and so far, no causative genes have been identified despite the fact that more than 100 genes have been identified for inherited hearing loss. Inherited VDs, similar to deafness, are genetically heterogeneous and follow Mendelian inheritance patterns with all modes of transmission, as well as multifactorial inheritance. With advances in genetic sequencing, evidence of familial clustering in VD has begun to highlight the genetic causes of these disorders, potentially opening up new avenues of treatment, particularly in Meniere's disease and disorders with comorbid hearing loss, such as Usher syndrome. In this review, we aim to present recent findings on the genetics of VDs, review the role of genetic sequencing tools, and explore the potential for individualized medicine in the treatment of these disorders. Methods: A search of the PubMed database was performed for English language studies relevant to the genetic basis of and therapies for vestibular disorders, using search terms including but not limited to: “genetics,” “genomics,” “vestibular disorders,” “hearing loss with vestibular dysfunction,” “individualized medicine,” “genome-wide association studies,” “precision medicine,” and “Meniere's syndrome.” Results: Increasing numbers of studies on vestibular disorder genetics have been published in recent years. Next-generation sequencing and new genetic tools are being utilized to unearth the significance of the genomic findings in terms of understanding disease etiology and clinical utility, with growing research interest being shown for individualized gene therapy for some disorders. Conclusions: The genetic knowledge base for vestibular disorders is still in its infancy. Identifying the genetic causes of balance problems is imperative in our understanding of the biology of normal function of the vestibule and the disease etiology and process. There is an increasing effort to use new and efficient genetic sequencing tools to discover the genetic causes for these diseases, leading to the hope for precise and personalized treatment for these patients.
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Affiliation(s)
- Christine Mei
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Hongsong Dong
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States.,Shenzhen Second People's Hospital, Shenzhen, China
| | - Eric Nisenbaum
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Torin Thielhelm
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Aida Nourbakhsh
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Denise Yan
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Molly Smeal
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Yesha Lundberg
- Department of Otolaryngology, Boys Town National Research Hospital, Omaha, NE, United States
| | - Michael E Hoffer
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Simon Angeli
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Fred Telischi
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Guohui Nie
- Shenzhen Second People's Hospital, Shenzhen, China
| | - Susan H Blanton
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
| | - Xuezhong Liu
- Department of Otolaryngology, University of Miami, Coral Gables, FL, United States
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29
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Koohiyan M, Hashemzadeh-Chaleshtori M, Tabatabaiefar MA. Molecular diagnosis of SLC26A4-related hereditary hearing loss in a group of patients from two provinces of Iran. Intractable Rare Dis Res 2021; 10:23-30. [PMID: 33614372 PMCID: PMC7882080 DOI: 10.5582/irdr.2020.03090] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
The SLC26A4 gene has been described as the second gene involved in most cases of autosomal recessive non-syndromic hearing loss (ARNSHL), after GJB2. Over 500 different SLC26A4 mutations have been reported, with each ethnic population having its own distinctive mutations. Here, we aimed to determine the frequency and mutation profile of the SLC26A4 gene from two different provinces (center and west) of Iran. This study included 50 nuclear families with two or more siblings segregating presumed ARNSHL. All affected tested negative for mutations in GJB2 at the DFNB1 locus and were therefore screened for autozygosity by descent using short tandem repeat polymorphisms (STRPs) of DFNB4. Sanger sequencing was performed to screen the 20 exons of the SLC26A4 gene for the families linked to this locus. In silico analyses were also performed using available software tools. Four out of 25 (16%) and 3 of 25 (12%) studied families of Isfahan and Hamedan provinces, respectively. were linked to DFNB4. Sanger sequencing led to the identification of six different mutations, one of which (c.919-2A>G) was recurrent and accounted for 31% of all mutant alleles. One out of 7 (14.3%) families with mutations were confirmed to be Pendred syndrome (PS). The SLC26A4 mutations have a high carrying rate in ARNSHL Iranian patients. The identification of a disease causing mutation can be used to establish a genotypic diagnosis and provide important information to the patients and their families.
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Affiliation(s)
- Mahbobeh Koohiyan
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Cancer Research Center, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Morteza Hashemzadeh-Chaleshtori
- Cellular and Molecular Research Center, Basic Health Research Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Noncommunicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
- Address correspondence to:Mohammad Amin Tabatabaiefar, Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Hezarjarib St., Isfahan 81746-7346, Iran. E-mail:
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Saeed HS, Kenth J, Black G, Saeed SR, Stivaros S, Bruce IA. Hearing Loss in Enlarged Vestibular Aqueduct: A Prognostic Factor Systematic Review of the Literature. Otol Neurotol 2021; 42:99-107. [PMID: 33026783 DOI: 10.1097/mao.0000000000002843] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
OBJECTIVE There is a need to highlight individual prognostic factors determining hearing loss in enlarged (wide) vestibular aqueduct, as currently clinicians cannot counsel parents about the expected clinical course, nor provide individualized hearing rehabilitation plans following identification at newborn screening. We apply a novel methodology to specifically outline and assess the accuracy of prognostic factors reporting for hearing loss in enlarged vestibular aqueduct. DATA SOURCES A preferred reporting items for systematic reviews and meta-analyses compliant systematic review (Prospero ID: CRD42019151199), with searches applied to Medline, EMBASE, and Cochrane. Studies with longitudinal design were included between 1995 and 2019. STUDY SELECTION The CHARMS-PF tool was used to assess robustness of prognostic factor study designs. DATA EXTRACTION The QUIPS tool was used to assess for individual study risk of bias. DATA SYNTHESIS & RESULTS Seventy papers were suitable for data extraction. In the six studies with low risk of bias, the domains of enlarged vestibular aqueduct (EVA) morphology, age, hearing thresholds, sex, head trauma, and genotype provided exploratory prognostic factors for hearing loss associated with enlarged vestibular aqueduct. Overall, study heterogeneity and risk of bias precluded reporting by forest plots and meta-analysis. CONCLUSIONS The majority of exploratory prognostic factor studies for hearing loss associated with enlarged vestibular aqueduct are hampered by risk of bias. However, this systematic review identifies potential independent prognostic factors which should be measured, and adjusted for, in subsequent confirmatory studies utilizing multivariate analysis. This would determine the true independent prognostic effects associated with hearing loss in enlarged vestibular aqueduct, while facilitating prognostic model development and the ability to predict individual hearing loss trajectory.
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Affiliation(s)
- Haroon Shakeel Saeed
- Paediatric ENT, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health University of Manchester, UK
| | | | - Graeme Black
- Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Manchester University NHS Foundation Trust, St Mary's Hospital
- Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine and Health, University of Manchester
| | - Shakeel R Saeed
- University College London Ear Institute and University College London Hospitals NHS Foundation Trust, London
| | - Stavros Stivaros
- Department of Paediatric Radiology, Royal Manchester Children's Hospital, Manchester, United Kingdom
| | - Iain A Bruce
- Paediatric ENT, Royal Manchester Children's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health University of Manchester, UK
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Kınoğlu K, Orhan KS, Kara H, Öztürk O, Polat B, Aydoğan H, Çelik M, Ceviz AB, Güldiken Y. Investigation of DFNB4 SLC26A4 mutation in patients with enlarged vestibular aquaduct. Int J Pediatr Otorhinolaryngol 2020; 138:110379. [PMID: 33152970 DOI: 10.1016/j.ijporl.2020.110379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 08/02/2020] [Accepted: 09/09/2020] [Indexed: 11/30/2022]
Abstract
OBJECTIVES Mutations of the SLC26A4 gene causing enlarged vestibular aqueduct (EVA) syndrome have not yet been fully elucidated. The study aimed to investigate SLC26A4 mutations in patients with EVA syndrome in the Turkish population. Identifying these mutations may play an essential role in determining the prognosis, follow-up, and management options of these patients. METHODS Whole exome sequencing and/or Sanger sequencing of SLC26A4 in 22 patients with sensorineural hearing loss associated with isolated EVA without inner ear anomalies, and 22 controls were performed. RESULTS Twenty-two patients and 22 control subjects were included in the study. The onset of hearing loss was pre-lingual in 15 patients, and post-lingual in 7. The mean (standard deviation) vestibular aqueduct width of the patients was 3.23 mm (1.28). Twenty SLC26A4 variants, 15 of them unique, were identified in 22 patients. Among them, seven variants were heterozygous, and 13 were homozygous. The variants p.E37X (c.109G > T), p.Y27H (c.79T > C), p.C706Y (c.2117G > A) have not been previously reported. CONCLUSION The detection of rare and previously unreported mutations in our study showed that studies with a larger number of patients with EVA might reveal more role of the SLC26A4 gene. Besides, to understand the etiopathogenesis of the disease, other related genes also should be investigated.
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Affiliation(s)
- Kubilay Kınoğlu
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Turkey
| | - Kadir Serkan Orhan
- Istanbul University, Istanbul Faculty of Medicine, Department of Otorhinolaryngology
| | - Hakan Kara
- Istanbul University, Istanbul Faculty of Medicine, Department of Otorhinolaryngology.
| | - Oğuz Öztürk
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Turkey
| | - Beldan Polat
- Istanbul University, Istanbul Faculty of Medicine, Department of Otorhinolaryngology
| | - Hülya Aydoğan
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Turkey
| | - Mehmet Çelik
- Istanbul University, Istanbul Faculty of Medicine, Department of Otorhinolaryngology
| | - Ayşe Begüm Ceviz
- Istanbul University, Aziz Sancar Institute of Experimental Medicine, Turkey
| | - Yahya Güldiken
- Istanbul University, Istanbul Faculty of Medicine, Department of Otorhinolaryngology
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Brownstein Z, Gulsuner S, Walsh T, Martins FTA, Taiber S, Isakov O, Lee MK, Bordeynik-Cohen M, Birkan M, Chang W, Casadei S, Danial-Farran N, Abu-Rayyan A, Carlson R, Kamal L, Arnþórsson ÁÖ, Sokolov M, Gilony D, Lipschitz N, Frydman M, Davidov B, Macarov M, Sagi M, Vinkler C, Poran H, Sharony R, Samara N, Zvi N, Baris-Feldman H, Singer A, Handzel O, Hertzano R, Ali-Naffaa D, Ruhrman-Shahar N, Madgar O, Sofrin E, Peleg A, Khayat M, Shohat M, Basel-Salmon L, Pras E, Lev D, Wolf M, Steingrimsson E, Shomron N, Kelley MW, Kanaan M, Allon-Shalev S, King MC, Avraham KB. Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1. Clin Genet 2020; 98:353-364. [PMID: 33111345 PMCID: PMC8045518 DOI: 10.1111/cge.13817] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 07/13/2020] [Accepted: 07/15/2020] [Indexed: 12/26/2022]
Abstract
Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results show that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.
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Affiliation(s)
- Zippora Brownstein
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Suleyman Gulsuner
- Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA, USA
| | - Tom Walsh
- Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA, USA
| | - Fábio Tadeu Arrojo Martins
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Shahar Taiber
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Ofer Isakov
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Ming K. Lee
- Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA, USA
| | - Mor Bordeynik-Cohen
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Maria Birkan
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Raphael Recanati Genetic Institute, Rabin Medical Center–Beilinson Hospital, Tel Aviv University Felsenstein Medical Research Center, Petach Tikva, Israel
| | - Weise Chang
- Laboratory of Cochlear Development, National Institute on Deafness and Other Communications Disorders, NIH, Bethesda, MD, USA
| | - Silvia Casadei
- Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA, USA
| | - Nada Danial-Farran
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Genetics Institute, Ha'Emek Medical Center, Afula, Israel
- Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Amal Abu-Rayyan
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Department of Biological Sciences, Bethlehem University, Bethlehem, Palestine
| | - Ryan Carlson
- Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA, USA
| | - Lara Kamal
- Department of Biological Sciences, Bethlehem University, Bethlehem, Palestine
| | - Ásgeir Örn Arnþórsson
- Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Meirav Sokolov
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Department of Otolaryngology - Head and Neck Surgery, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Dror Gilony
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Department of Otolaryngology - Head and Neck Surgery, Schneider Children's Medical Center, Petach Tikva, Israel
| | - Noga Lipschitz
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Department of Otolaryngology - Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | - Moshe Frydman
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel
| | - Bella Davidov
- Raphael Recanati Genetic Institute, Rabin Medical Center–Beilinson Hospital, Tel Aviv University Felsenstein Medical Research Center, Petach Tikva, Israel
| | - Michal Macarov
- Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Michal Sagi
- Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | - Chana Vinkler
- Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel
| | - Hana Poran
- Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel
| | - Reuven Sharony
- Genetics Institute, Meir Medical Center, Kfar Saba and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | | | - Na’ama Zvi
- Department of Human Genetics and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
| | | | - Amihood Singer
- Community Genetics Department, Public Health Services, Ministry of Health, Ramat Gan, Israel
| | - Ophir Handzel
- Department of Otolaryngology Head and Neck Surgery and Maxillofacial Surgery, Tel-Aviv Sourasky Medical Center, Tel Aviv, Israel
| | - Ronna Hertzano
- Department of Otorhinolaryngology Head and Neck Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Doaa Ali-Naffaa
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Human Genetics Institute, Lady Davis Carmel Medical Center, Haifa, Israel
| | - Noa Ruhrman-Shahar
- Raphael Recanati Genetic Institute, Rabin Medical Center–Beilinson Hospital, Tel Aviv University Felsenstein Medical Research Center, Petach Tikva, Israel
| | - Ory Madgar
- Department of Otolaryngology - Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | - Efrat Sofrin
- Raphael Recanati Genetic Institute, Rabin Medical Center–Beilinson Hospital, Tel Aviv University Felsenstein Medical Research Center, Petach Tikva, Israel
| | - Amir Peleg
- Human Genetics Institute, Lady Davis Carmel Medical Center, Haifa, Israel
| | - Morad Khayat
- Genetics Institute, Ha'Emek Medical Center, Afula, Israel
| | - Mordechai Shohat
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Israel
- Institute of Medical Genetics, Maccabi HMO, Rehovot, Israel
| | - Lina Basel-Salmon
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Raphael Recanati Genetic Institute, Rabin Medical Center–Beilinson Hospital, Tel Aviv University Felsenstein Medical Research Center, Petach Tikva, Israel
| | - Elon Pras
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Institute of Human Genetics, Sheba Medical Center, Tel Hashomer, Israel
| | - Dorit Lev
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
- Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel
| | - Michael Wolf
- Department of Otolaryngology - Head and Neck Surgery, Sheba Medical Center, Tel Hashomer, Israel
| | - Eirikur Steingrimsson
- Department of Biochemistry and Molecular Biology, BioMedical Center, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Noam Shomron
- Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Matthew W. Kelley
- Laboratory of Cochlear Development, National Institute on Deafness and Other Communications Disorders, NIH, Bethesda, MD, USA
| | - Moien Kanaan
- Department of Biological Sciences, Bethlehem University, Bethlehem, Palestine
| | - Stavit Allon-Shalev
- Genetics Institute, Ha'Emek Medical Center, Afula, Israel
- Rappaport Faculty of Medicine, Technion, Haifa, Israel
| | - Mary-Claire King
- Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA, USA
| | - Karen B. Avraham
- Department of Human Molecular Genetics & Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
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Zhou Y, Tariq M, He S, Abdullah U, Zhang J, Baig SM. Whole exome sequencing identified mutations causing hearing loss in five consanguineous Pakistani families. BMC MEDICAL GENETICS 2020; 21:151. [PMID: 32682410 PMCID: PMC7368710 DOI: 10.1186/s12881-020-01087-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 07/06/2020] [Indexed: 12/20/2022]
Abstract
Background Hearing loss is the most common sensory defect, and it affects over 6% of the population worldwide. Approximately 50–60% of hearing loss patients are attributed to genetic causes. Currently, more than 100 genes have been reported to cause non-syndromic hearing loss. It is possible and efficient to screen all potential disease-causing genes for hereditary hearing loss by whole exome sequencing (WES). Methods We collected 5 consanguineous pedigrees from Pakistan with hearing loss and applied WES in selected patients for each pedigree, followed by bioinformatics analysis and Sanger validation to identify the causal genes. Results Variants in 7 genes were identified and validated in these pedigrees. We identified single candidate variant for 3 pedigrees: GIPC3 (c.937 T > C), LOXHD1 (c.6136G > A) and TMPRSS3 (c.941 T > C). The remaining 2 pedigrees each contained two candidate variants: TECTA (c.4045G > A) and MYO15A (c.3310G > T and c.9913G > C) for one pedigree and DFNB59 (c.494G > A) and TRIOBP (c.1952C > T) for the other pedigree. The candidate variants were validated in all available samples by Sanger sequencing. Conclusion The candidate variants in hearing-loss genes were validated to be co-segregated in the pedigrees, and they may indicate the aetiologies of hearing loss in such patients. We also suggest that WES may be a suitable strategy for hearing-loss gene screening in clinical detection.
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Affiliation(s)
- Yingjie Zhou
- Seven Section of Department of Gynaecology, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Muhammad Tariq
- Human Molecular Genetics, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad, 38000, Pakistan
| | - Sijie He
- BGI-Shenzhen, Shenzhen, 518083, China.,BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China
| | - Uzma Abdullah
- Human Molecular Genetics, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad, 38000, Pakistan
| | - Jianguo Zhang
- BGI-Shenzhen, Shenzhen, 518083, China. .,BGI Genomics, BGI-Shenzhen, Shenzhen, 518083, China.
| | - Shahid Mahmood Baig
- Human Molecular Genetics, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS, Faisalabad, 38000, Pakistan.
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Cochlear Implant Outcomes in Large Vestibular Aqueduct Syndrome-Should We Provide Cochlear Implants Earlier? Otol Neurotol 2020; 40:e769-e773. [PMID: 31348128 DOI: 10.1097/mao.0000000000002314] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Examine postoperative speech perception outcomes in a large vestibular aqueduct syndrome (LVAS) patients at a major cochlear implantation center. STUDY DESIGN Retrospective analysis of the Sydney Cochlear Implant Centre (SCIC) database and medical records from January 1994 to December 2015 was performed. SETTING Tertiary referral center. PATIENTS Patients with a diagnosis of LVAS who received a cochlear implant (CI). Only those with speech perception outcomes recorded at least 12 months post implant were included in our analysis. INTERVENTION(S) Therapeutic. MAIN OUTCOME MEASURE(S) Postoperative speech perception scores. RESULTS Between 1994 and 2015, 176 adult and pediatric patients with a diagnosis of LVAS underwent cochlear implantation at SCIC. Postoperative Bamford-Kowal Bench (BKB) sentence test scores were obtained for 97 patients. The postoperative median BKB score was 93% with a lower quartile score of 85% and an upper quartile score of 98%. Smaller numbers were available for post-CI City University of New York (CUNY) and Consonant-Nucleus-Consonant (CNC) word scores yet similar excellent results were seen. CONCLUSIONS Our study results suggest the CI should be considered when BKB scores have dropped to 85%. We suggest that rather than LVAS cases representing a challenge to cochlear implantation, they are amongst the best candidates for surgery, and should receive a CI at an earlier stage in hearing loss, when they have better speech perception. This allows stable hearing to be established earlier along with excellent speech perception outcomes.
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Li Yim AY, Duijvis NW, Ghiboub M, Sharp C, Ferrero E, Mannens MM, D’Haens GR, de Jonge WJ, te Velde AA, Henneman P. Whole-Genome DNA Methylation Profiling of CD14+ Monocytes Reveals Disease Status and Activity Differences in Crohn's Disease Patients. J Clin Med 2020; 9:E1055. [PMID: 32276386 PMCID: PMC7230341 DOI: 10.3390/jcm9041055] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 04/04/2020] [Accepted: 04/06/2020] [Indexed: 12/13/2022] Open
Abstract
Crohn's disease (CD) is a multifactorial incurable chronic disorder. Current medical treatment seeks to induce and maintain a state of remission. During episodes of inflammation, monocytes infiltrate the inflamed mucosa whereupon they differentiate into macrophages with a pro-inflammatory phenotype. Here, we sought to characterize the circulating monocytes by profiling their DNA methylome and relate it to the level of CD activity. We gathered an all-female age-matched cohort of 16 CD patients and 7 non-CD volunteers. CD patients were further subdivided into 8 CD patients with active disease (CD-active) and 8 CD patients in remission (CD-remissive) as determined by the physician global assessment. We identified 15 and 12 differentially methylated genes (DMGs) when comparing CD with non-CD and CD-active with CD-remissive, respectively. Differential methylation was predominantly found in the promoter regions of inflammatory genes. Comparing our observations with gene expression data on classical (CD14++CD16-), non-classical (CD14+CD16++) and intermediate (CD14++CD16+) monocytes indicated that while 7 DMGs were differentially expressed across the 3 subsets, the remaining DMGs could not immediately be associated with differences in known populations. We conclude that CD activity is associated with differences in DNA methylation at the promoter region of inflammation-associated genes.
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Affiliation(s)
- Andrew Y.F. Li Yim
- Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, 1105 AZ Amsterdam, The Netherlands
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
| | - Nicolette W. Duijvis
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 AZ Amsterdam, The Netherlands;
| | - Mohammed Ghiboub
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
| | - Catriona Sharp
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
| | - Enrico Ferrero
- R&D GlaxoSmithKline, Stevenage SG1 2NY, UK; (M.G.); (C.S.); (E.F.)
| | - Marcel M.A.M. Mannens
- Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, 1105 AZ Amsterdam, The Netherlands
| | - Geert R. D’Haens
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 AZ Amsterdam, The Netherlands;
| | - Wouter J. de Jonge
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
- Department of Surgery, University Clinic of Bonn, 53127 Bonn, Germany
| | - Anje A. te Velde
- Tytgat Institute for Liver and Intestinal Research, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam Gastroenterology & Metabolism, 1105 BK Amsterdam, The Netherlands; (N.W.D.); (W.J.d.J.)
| | - Peter Henneman
- Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam, Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, 1105 AZ Amsterdam, The Netherlands
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Cong T, Liu L, Zhang H, Wang L, Jiang X. Port-wine stains associated with large vestibular aqueduct syndrome caused by mutations in GNAQ and SLC26A4 genes: A case report. J Dermatol 2020; 47:78-81. [PMID: 31692010 DOI: 10.1111/1346-8138.15130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 09/29/2019] [Indexed: 02/05/2023]
Abstract
Port-wine stains (PWS) are capillary malformations associated with mutation in the GNAQ (NM_000441.1) gene. Large vestibular aqueduct syndrome (LVAS), caused by mutation in the SLC26A4 (NM_002072) gene, is an inner ear malformation that can lead to hearing loss. To our knowledge, LVAS in PWS patients has never been reported. Here, we describe a case of a 9-year-old female patient diagnosed with PWS on the face and neck, coexisting with large vestibular aqueduct syndrome. Further analyses revealed a somatic mutation in GNAQ and a compound heterozygous mutation in the SLC26A4 gene. Some PWS patients have associated abnormalities, such as glaucoma and choroidal hemangioma, leptomeningeal angiomas and atrophy or hypertrophy of bone and soft tissue. We present here the first case that reveals the possibility that capillary malformations are associated with inner ear malformation. More case reports and further studies are needed to determine whether these conditions coexist in other patients.
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Affiliation(s)
- Tianxin Cong
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Lian Liu
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Haoyi Zhang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Lian Wang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
| | - Xian Jiang
- Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China
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Wen C, Wang S, Zhao X, Wang X, Wang X, Cheng X, Huang L. Mutation analysis of the SLC26A4 gene in three Chinese families. Biosci Trends 2019; 13:441-447. [PMID: 31656273 DOI: 10.5582/bst.2019.01282] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
In order to investigate the genetic causes of hearing loss in a Chinese proband (in Family A) with enlarged vestibular aqueduct (EVA) and to investigate the genotype of two Chinese probands with SLC26A4 singe-allelic mutation and normal hearing (in Families B and C, respectively), the three probands and their parents were clinically and genetically evaluated. Twenty exons and flanking splice sites of the SLC26A4 gene were screened for pathogenic mutations via amplification with PCR and bidirectional sequencing. As controls, a group of 400 healthy newborns from the same ethnic background underwent SLC26A4 gene screening using the same method. The three probands all harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. The genotypes of mutations in Families A, B, and C are c.1211C>A/c.919-2A>G, c.1729G>A/c.919-2A>G, and c.1286C>A/c.919-2A>G, respectively. The missense mutations c.1211C>A (p.T430Q) in exon 10 and c.1729G>A (p.V577I) in exon 16 are both reported for the first time and were absent in 400 healthy newborns. c.1211C>A has Glutamine (Gln) at amino acid 430 instead of Threonine (Thr), and c.1729G>A has Isoleucine (Ile) at amino acid 577 instead of Valine (Val). c.1286C>A, a mutation previously reported in DVD and HGMD, was associated with Mondini deformity, but a proband with the c.1286C>A mutation in this study was normal. This study has demonstrated that the novel missense mutation c.1211C>A in compound heterozygosity with c.919-2A>G in the SLC26A4 gene is likely to be the cause of deafness in Family A. A novel variant, c.1729G>A, was identified and is likely benign. The pathogenicity of the c.1286C>A mutation warrants more in-depth study. These findings will broaden the spectrum of known SLC26A4 mutations in the Chinese population, providing more information for genetic counseling and diagnosis of hearing loss with EVA.
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Affiliation(s)
- Cheng Wen
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Shijie Wang
- No. 731 Hospital of China Aerospace Science and Industry Corp, Beijing, China
| | - Xuelei Zhao
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Xianlei Wang
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Xueyao Wang
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Xiaohua Cheng
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Lihui Huang
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
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Mey K, Muhamad AA, Tranebjaerg L, Rendtorff ND, Rasmussen SH, Bille M, Cayé-Thomasen P. Association of SLC26A4 mutations, morphology, and hearing in pendred syndrome and NSEVA. Laryngoscope 2019; 129:2574-2579. [PMID: 31633822 DOI: 10.1002/lary.27319] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Revised: 04/07/2018] [Accepted: 05/03/2018] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the relations of monoallelic (M1), biallelic (M2), or the absence of mutations (M0) in SLC26A4 to inner ear morphology and hearing levels in individuals with Pendred syndrome (PS) or nonsyndromic enlarged vestibular aqueduct (NSEVA) associated with hearing loss. METHODS In a cohort of 139 PS/NSEVA individuals, 115 persons from 95 unrelated families had full genetic sequencing of SLC26A4, and 113 had retrievable images for re-assessment of inner ear morphology. The association between the number of mutant alleles in SLC26A4, inner ear morphology (including endolymphatic sac size and protein content on magnetic resonance imaging), and hearing level (pure tone average) was explored. RESULTS Biallelic SLC26A4 mutations (M2) occurred in three-quarters of the cohort and was invariably associated with poor hearing; in 87%, it was associated with incomplete partition type II of the cochlea as well as enlarged endolymphatic sac and vestibular aqueduct. M1 or M0 individuals exhibited a greater variability in inner ear morphology. Endolymphatic sac size and presence of "high-protein" sac contents were significantly higher in M2 individuals compared to M1 and M0 individuals. CONCLUSION The number of SLC26A4 mutations is associated with severity and variability of inner ear morphology and hearing level in individuals with PS or NSEVA. M2 individuals have poorer hearing and present largely incomplete partition type II of the cochleas with enlarged endolymphatic sacs, whereas individuals with M1 and no detectable SLC26A4 mutations have less severe hearing loss and more diverse inner ear morphology. LEVEL OF EVIDENCE 4. Laryngoscope, 129:2574-2579, 2019.
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Affiliation(s)
- Kristianna Mey
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology Rigshospitalet/Gentofte, Hellerup
| | | | - Lisbeth Tranebjaerg
- the Department of Clinical Genetics, Rigshospitalet/The Kennedy Center.,the Institute of Clinical Medicine
| | - Nanna D Rendtorff
- the Department of Clinical Genetics, Rigshospitalet/The Kennedy Center
| | | | - Michael Bille
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology Rigshospitalet/Gentofte, Hellerup
| | - Per Cayé-Thomasen
- Department of Otorhinolaryngology, Head and Neck Surgery and Audiology Rigshospitalet/Gentofte, Hellerup.,Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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Outcomes and Predictive Factors of Electroacoustic Stimulation Rehabilitation in Children With Limited Low-Frequency Hearing. Otol Neurotol 2019; 40:e894-e900. [DOI: 10.1097/mao.0000000000002369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Wu CC, Tsai CY, Lin YH, Chen PY, Lin PH, Cheng YF, Wu CM, Lin YH, Lee CY, Erdenechuluun J, Liu TC, Chen PL, Hsu CJ. Genetic Epidemiology and Clinical Features of Hereditary Hearing Impairment in the Taiwanese Population. Genes (Basel) 2019; 10:genes10100772. [PMID: 31581539 PMCID: PMC6826657 DOI: 10.3390/genes10100772] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 09/19/2019] [Accepted: 09/27/2019] [Indexed: 12/11/2022] Open
Abstract
Hereditary hearing impairment (HHI) is a common but heterogeneous clinical entity caused by mutations in a plethora of deafness genes. Research over the past few decades has shown that the genetic epidemiology of HHI varies significantly across populations. In this study, we used different genetic examination strategies to address the genetic causes of HHI in a large Taiwanese cohort composed of >5000 hearing-impaired families. We also analyzed the clinical features associated with specific genetic mutations. Our results demonstrated that next-generation sequencing-based examination strategies could achieve genetic diagnosis in approximately half of the families. Common deafness-associated genes in the Taiwanese patients assessed, in the order of prevalence, included GJB2, SLC26A4, OTOF, MYO15A, and MTRNR1, which were similar to those found in other populations. However, the Taiwanese patients had some unique mutations in these genes. These findings may have important clinical implications for refining molecular diagnostics, facilitating genetic counseling, and enabling precision medicine for the management of HHI.
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Affiliation(s)
- Chen-Chi Wu
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Cheng-Yu Tsai
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10002, Taiwan.
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei 10055, Taiwan.
| | - Yi-Hsin Lin
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Pey-Yu Chen
- Department of Otolaryngology, Mackay Memorial Hospital, Taipei 10449, Taiwan.
| | - Pei-Hsuan Lin
- Department of Otolaryngology, National Taiwan University Hospital Yunlin Branch, Yunlin 64041, Taiwan.
| | - Yen-Fu Cheng
- Department of Medical Research, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
- Department of Otolaryngology-Head and Neck Surgery, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
| | - Che-Ming Wu
- Department of Otolaryngology-Head and Neck Surgery, Chang Gung Memorial Hospital, Chang Gung University, Linkou 33302, Taiwan.
| | - Yin-Hung Lin
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei 10055, Taiwan.
| | - Chee-Yee Lee
- Department of Otolaryngology, Buddhist Tzuchi General Hospital, Taichung Branch, Taichung 42743, Taiwan.
| | - Jargalkhuu Erdenechuluun
- Department of Otolaryngology, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia.
- The EMJJ Otolaryngology Hospital, Ulaanbaatar 14210, Mongolia.
- Department of Otolaryngology, National Center for Maternal and Child Health, Ulaanbaatar 16060, Mongolia.
| | - Tien-Chen Liu
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10002, Taiwan.
| | - Pei-Lung Chen
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei 10055, Taiwan.
- Department of Medical Genetics, National Taiwan University Hospital, Taipei 10041, Taiwan.
| | - Chuan-Jen Hsu
- Department of Otolaryngology, National Taiwan University Hospital, Taipei 10002, Taiwan.
- Department of Otolaryngology, Buddhist Tzuchi General Hospital, Taichung Branch, Taichung 42743, Taiwan.
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41
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Koohiyan M. A systematic review of SLC26A4 mutations causing hearing loss in the Iranian population. Int J Pediatr Otorhinolaryngol 2019; 125:1-5. [PMID: 31228605 DOI: 10.1016/j.ijporl.2019.06.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 05/19/2019] [Accepted: 06/12/2019] [Indexed: 11/16/2022]
Abstract
OBJECTIVES The genetics of sensorineural hearing loss is characterized by a high degree of heterogeneity. In spite of this, mutations in the SLC26A4 gene, have been reported to be the second most common contributor after those of GJB2 in many populations. However, different results have been reported for the frequency of SLC26A4 mutations in Iran, which varies between 0 and 12.3%. Here, we have taken together and reviewed the spectrum and frequency of the reported SLC26A4 mutations to provide a comprehensive collection of data for SLC26A4 mutations and HL in the Iranian population and considered founder mutations. METHODS A systematic literature review of the PubMed, Google Scholar, Web of Science, and Science Direct databases was conducted for articles published before March 2019. The primary data of these studies including the number of samples, mutation frequency and so on were extracted. RESULTS Nine studies involved 827 unrelated families were included and analyzed for the type and prevalence of the SLC26A4 gene mutations. Altogether 39 different genetic mutations were detected. SLC26A4 mutations were found to be 6.39% in the population studied which is significantly lower than that identified in the east Asia. However, c.1334T > G was the most common mutation accounting for 10% of the populations studied. CONCLUSIONS This data gives an overview of the SLC26A4 mutations in Iran, which could be used for screening, diagnostic programs of live births and genetic counseling.
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Affiliation(s)
- Mahbobeh Koohiyan
- Cancer Research Center, Shahrekord University of Medical Sciences, Rahmatieh, Shahrekord, 8813833435, Iran.
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42
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Comprehensive genetic testing of Chinese SNHL patients and variants interpretation using ACMG guidelines and ethnically matched normal controls. Eur J Hum Genet 2019; 28:231-243. [PMID: 31541171 PMCID: PMC6974605 DOI: 10.1038/s41431-019-0510-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Revised: 05/10/2019] [Accepted: 08/29/2019] [Indexed: 11/10/2022] Open
Abstract
Hereditary hearing loss is a monogenic disease with high genetic heterogeneity. Variants in more than 100 deafness genes underlie the basis of its pathogenesis. The aim of this study was to assess the ratio of SNVs in known deafness genes contributing to the etiology of both sporadic and familial sensorineural hearing loss patients from China. DNA samples from 1127 individuals, including normal hearing controls (n = 616), sporadic SNHL patients (n = 433), and deaf individuals (n = 78) from 30 hearing loss pedigrees were collected. The NGS tests included analysis of sequence alterations in 129 genes. The variants were interpreted according to the ACMG/AMP guidelines for genetic hearing loss combined with NGS data from 616 ethnically matched normal hearing adult controls. We identified a positive molecular diagnosis in 226 patients with sporadic SNHL (52.19%) and in patients from 17 deafness pedigrees (56.67%). Ethnically matched MAF filtering reduced the variants of unknown significance by 8.7%, from 6216 to 5675. Some complexities that may restrict causative variant identification are discussed. This report highlight the clinical utility of NGS panels identifying disease-causing variants for the diagnosis of hearing loss and underlines the importance of a broad data of control and ACMG/AMP standards for accurate clinical delineation of VUS variants.
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Oza AM, DiStefano MT, Hemphill SE, Cushman BJ, Grant AR, Siegert RK, Shen J, Chapin A, Boczek NJ, Schimmenti LA, Murry JB, Hasadsri L, Nara K, Kenna M, Booth KT, Azaiez H, Griffith A, Avraham KB, Kremer H, Rehm HL, Amr SS, Abou Tayoun AN. Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss. Hum Mutat 2019; 39:1593-1613. [PMID: 30311386 DOI: 10.1002/humu.23630] [Citation(s) in RCA: 338] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2018] [Revised: 07/23/2018] [Accepted: 08/25/2018] [Indexed: 12/23/2022]
Abstract
Due to the high genetic heterogeneity of hearing loss (HL), current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of HL. As one of its major tasks, our Expert Panel has adapted the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for the interpretation of sequence variants in HL genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP HL rules. Three rules remained unchanged, four rules were removed, and the remaining 21 rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and disease experts. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These HL-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with HL.
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Affiliation(s)
- Andrea M Oza
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.,Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts
| | - Marina T DiStefano
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Sarah E Hemphill
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Brandon J Cushman
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Andrew R Grant
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Rebecca K Siegert
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Jun Shen
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | | | - Nicole J Boczek
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Lisa A Schimmenti
- Department of Otorhinolaryngology, Clinical Genomics and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota
| | - Jaclyn B Murry
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts
| | - Linda Hasadsri
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Kiyomitsu Nara
- Division of Hearing and Balance Research, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, Tokyo, Japan
| | - Margaret Kenna
- Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Boston, Massachusetts.,Harvard Medical School, Boston, Massachusetts
| | - Kevin T Booth
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and Clinics, Iowa City, Iowa.,The Interdisciplinary Graduate Program in Molecular Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa
| | - Hela Azaiez
- Molecular Otolaryngology and Renal Research Laboratories, Department of Otolaryngology, University of Iowa Hospital and Clinics, Iowa City, Iowa
| | - Andrew Griffith
- Audiology Unit, National Institute on Deafness and Other Communication Disorders (NIDCD), NIH, Bethesda, Maryland
| | - Karen B Avraham
- Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel
| | - Hannie Kremer
- Department of Otorhinolaryngology and Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Heidi L Rehm
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts.,The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Sami S Amr
- Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts.,Harvard Medical School, Boston, Massachusetts.,Department of Pathology, Brigham & Women's Hospital, Boston, Massachusetts
| | - Ahmad N Abou Tayoun
- The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.,The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania
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Zhao X, Cheng X, Huang L, Wang X, Wen C, Wang X, Zhao L. Analysis of mutations in the FOXI1 and KCNJ10 genes in infants with a single-allele SLC26A4 mutation. Biosci Trends 2019; 13:261-266. [PMID: 31243244 DOI: 10.5582/bst.2019.01142] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The current study investigated how the FOXI1 and KCNJ10 genes were affected in infants with a single-allele mutation in the SLC26A4 gene, and it determined the audiological phenotypes of infants with double heterozygous mutations (DHMs) in the three genes. Subjects were 562 infants with a single-allele SLC26A4 mutation detected during neonatal deafness genetic screening; the infants were seen as outpatients by Otology at Beijing Tongren Hospital. All subjects underwent SLC26A4 sequencing. Twenty infants had a second-allele variant while the remaining 542 had an SLC26A4 single-allele mutation. Infants also underwent FOXI1 and KCNJ10 sequencing. All patients with double heterozygous mutations in the aforementioned genes underwent an audiological evaluation and a limited imaging study; variants and audiological phenotypes were analyzed. Of 562 patients, 20 had SLC26A4 bi-allelic mutations; 8 carried single mutations in both SLC26A4 and KCNJ10. No pathogenic mutations in the FOXI1 gene were found. Four missense mutations in KCNJ10 were detected, including c.812G>A, c.800A>G, c.53G>A, and c.1042C>T. Eight individuals with a DHMs all passed universal newborn hearing screening, and all were found to have normal hearing. These data suggest that individuals with an SLC26A4 single-allele mutation, combined with FOXI1 or KCNJ10 gene mutations, do not suffer hearing loss during infancy, though this finding is worthy of further follow-up and in-depth discussion.
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Affiliation(s)
- Xuelei Zhao
- Beijing Tongren Hospital, Capital Medical University.,Beijing Institute of Otolaryngology.,Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Xiaohua Cheng
- Beijing Tongren Hospital, Capital Medical University.,Beijing Institute of Otolaryngology.,Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Lihui Huang
- Beijing Tongren Hospital, Capital Medical University.,Beijing Institute of Otolaryngology.,Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Xianlei Wang
- Beijing Tongren Hospital, Capital Medical University.,Beijing Institute of Otolaryngology.,Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Cheng Wen
- Beijing Tongren Hospital, Capital Medical University.,Beijing Institute of Otolaryngology.,Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Xueyao Wang
- Beijing Tongren Hospital, Capital Medical University.,Beijing Institute of Otolaryngology.,Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Liping Zhao
- Beijing Tongren Hospital, Capital Medical University.,Beijing Institute of Otolaryngology.,Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
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45
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Liu H, Zhou K, Zhang X, Peng KA. Fluctuating Sensorineural Hearing Loss. Audiol Neurootol 2019; 24:109-116. [PMID: 31315108 DOI: 10.1159/000500658] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 04/29/2019] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Several otologic conditions can present with fluctuating sensorineural hearing loss, including Ménière's disease, autoimmune inner ear disease, and enlarged vestibular aqueduct. Although these 3 etiologies vary greatly, distinguishing between these conditions at initial presentation can be challenging. Furthermore, initial treatment of these conditions is often similar. In this review, we discuss historical and current perspectives on diagnosis and treatment of these conditions. SUMMARY A literature search was performed regarding fluctuating hearing loss, and current treatment of these etiologies of fluctuating hearing loss was summarized. Immediate measures at the onset of acute hearing loss include corticosteroid therapy, while preventative and chronic therapies, which can limit disease severity and frequency, vary based on the specific condition treated. Key Messages: Fluctuating hearing loss can represent a range of pathologies, but the precise etiology may not be clear at initial presentation. Timely treatment and long-term follow-up, along with appropriate diagnostics, are necessary to optimize long-term hearing.
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Affiliation(s)
- Hui Liu
- First Hospital of Shijiazhuang City, Shijiazhuang City, China,
| | - Kunpeng Zhou
- First Hospital of Shijiazhuang City, Shijiazhuang City, China
| | - Xuemei Zhang
- First Hospital of Shijiazhuang City, Shijiazhuang City, China
| | - Kevin A Peng
- House Clinic and House Ear Institute, Los Angeles, California, USA
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Lee B, Kim YR, Kim SJ, Goh SH, Kim JH, Oh SK, Baek JI, Kim UK, Lee KY. Modified U1 snRNA and antisense oligonucleotides rescue splice mutations in SLC26A4 that cause hereditary hearing loss. Hum Mutat 2019; 40:1172-1180. [PMID: 31033086 DOI: 10.1002/humu.23774] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 04/15/2019] [Accepted: 04/23/2019] [Indexed: 11/11/2022]
Abstract
One of most important factors for messenger RNA (mRNA) transcription is the spliceosomal component U1 small nuclear RNA (snRNA), which recognizes 5' splicing donor sites at specific regions in pre-mRNA. Mutations in these sites disrupt U1 snRNA binding and cause abnormal splicing. In this study, we investigated mutations at splice sites in SLC26A4 (HGNC 8818), one of the major causative genes of hearing loss, which may result in the synthesis of abnormal pendrin, the channel protein encoded by the gene. Seventeen SLC26A4 variants with mutations in the U1 snRNA binding sites were assessed by minigene splicing assays, and 11 were found to result in abnormal splicing. Interestingly, eight of the 11 pathogenic mutations were intronic, suggesting the importance of conserved sequences at the intronic splice site. The application of modified U1 snRNA effectively rescued the abnormal splicing for most of these mutations. Although three were cryptic mutations, they were rescued by cotransfection of modified U1 snRNA and modified antisense oligonucleotides. Our results demonstrate the important role of snRNA in SLC26A4 mutations, suggesting the therapeutic potential of modified U1 snRNA and antisense oligonucleotides for neutralizing the pathogenic effect of the splice-site mutations that may result in hearing loss.
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Affiliation(s)
- Byeonghyeon Lee
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Ye-Ri Kim
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Sang-Joo Kim
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Sung-Ho Goh
- Therapeutic Target Discovery Branch, National Cancer Center, Goyang-si, Gyeonggi-do, Republic of Korea
| | - Jong-Heun Kim
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Se-Kyung Oh
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, Republic of Korea
| | - Jeong-In Baek
- Department of Aroma-Applied Industry, Daegu Haany University, Gyeongsan, Republic of Korea
| | - Un-Kyung Kim
- Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, Republic of Korea.,BK21 Plus KNU Creative BioResearch Group, School of Life Sciences, Kyungpook National University, Daegu, Republic of Korea
| | - Kyu-Yup Lee
- Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
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Alimardani M, Hosseini SM, Khaniani MS, Haghi MR, Eslahi A, Farjami M, Chezgi J, Derakhshan SM, Mojarrad M. Targeted Mutation Analysis of the SLC26A4, MYO6, PJVK and CDH23 Genes in Iranian Patients with AR Nonsyndromic Hearing Loss. Fetal Pediatr Pathol 2019; 38:93-102. [PMID: 30582396 DOI: 10.1080/15513815.2018.1547336] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Hearing loss (HL) is the most prevalent sensory disorder. The over 100 genes implicated in autosomal recessive nonsyndromic hearing loss (ARNSHL) makes it difficult to analyze and determine the accurate genetic causes of hearing loss. We sought to de?ne the frequency of seven hearing loss-Causing causing genetic Variants in four genes in an Iranian population with hearing loss. MATERIALS AND METHODS One hundred ARNSHL patients with normal GJB2/GJB6 genes were included, and targeted mutations in SLC26A4, MYO6, PJVK and CDH23 genes were analyzed by ARMS-PCR. The negative and positive results were confirmed by the Sanger sequencing. RESULTS We found only two mutations, one in MYO6 (c.554-1 G > A) gene and another in PJVK (c.547C > T). CONCLUSION c.554-1G > A and c.547C > T mutations are responsible for 1% each of the Iranian ARNSHL patients. These genes are not a frequent cause of ARNSHL in an Iranian population.
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Affiliation(s)
- Maliheh Alimardani
- a Neurosciences Research Center , Tabriz University of Medical Science , Tabriz , Iran.,b Department of Medical Genetics , Tabriz University of Medical Sciences , Tabriz , Iran.,c Student Research Committee, Faculty of Medicine , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Seyed Mojtaba Hosseini
- c Student Research Committee, Faculty of Medicine , Mashhad University of Medical Sciences , Mashhad , Iran.,d Department of Medical Genetics , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Mahmoud Shekari Khaniani
- b Department of Medical Genetics , Tabriz University of Medical Sciences , Tabriz , Iran.,e Ebne Sina Medical Genetic Diagnostic Laboratory , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Mohsen Rajati Haghi
- f Department of Head and Neck Surgery, ENT Research Center , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Atieh Eslahi
- c Student Research Committee, Faculty of Medicine , Mashhad University of Medical Sciences , Mashhad , Iran.,d Department of Medical Genetics , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Mashsa Farjami
- c Student Research Committee, Faculty of Medicine , Mashhad University of Medical Sciences , Mashhad , Iran.,d Department of Medical Genetics , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Javad Chezgi
- c Student Research Committee, Faculty of Medicine , Mashhad University of Medical Sciences , Mashhad , Iran.,d Department of Medical Genetics , Mashhad University of Medical Sciences , Mashhad , Iran
| | - Sima Mansoori Derakhshan
- a Neurosciences Research Center , Tabriz University of Medical Science , Tabriz , Iran.,b Department of Medical Genetics , Tabriz University of Medical Sciences , Tabriz , Iran.,e Ebne Sina Medical Genetic Diagnostic Laboratory , Tabriz University of Medical Sciences , Tabriz , Iran
| | - Majid Mojarrad
- d Department of Medical Genetics , Mashhad University of Medical Sciences , Mashhad , Iran.,g Medical Genetics Research Center, School of Medicine , Mashhad University of Medical Sciences , Mashhad , Iran
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Study on the relationship between the pathogenic mutations of SLC26A4 and CT phenotypes of inner ear in patient with sensorineural hearing loss. Biosci Rep 2019; 39:BSR20182241. [PMID: 30842343 PMCID: PMC6430729 DOI: 10.1042/bsr20182241] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 02/11/2019] [Accepted: 02/28/2019] [Indexed: 11/23/2022] Open
Abstract
To investigate the possible association of pathogenic mutations of SLC26A4 and computerized tomography (CT) phenotypes of inner ear, and explore the feasibility of using the method of gene sequence analysis. A total of 155 patients with bilateral hearing loss carrying SLC26A4 gene mutations were further subjected to high-resolution temporal bone CT and thyroid B ultrasound tests. The potential relationship between the pathogenic mutations of gene and the CT phenotypes were analyzed. As a result, 65 patients (41.9%, 65/155) carried SLC26A4 gene mutations, and 27 cases were detected with pathogenic mutations of SLC26A4 where IVS7-2A>G (55.6%, 15/27) was the most common pathogenic mutation. Amongst them, 19 patients carrying bi-allelic SLC26A4 mutations were all confirmed to have inner ear malformation by CT scan including four cases of enlarged vestibular aqueduct (EVA) and 15 cases of Mondini dysplasia (MD). However, there was only one in eight cases of single allele pathogenic mutation who was confirmed to have EVA by CT scan. Further, only one patient with EVA was confirmed to be slightly higher of total T3 than normal by thyroid ultrasound scan and thyroid hormone assays. These findings suggested that CT detection and SLC26A4 gene detection are efficient methods to diagnose EVA, which can complement each other. Also, the bi-allelic pathogenic mutations of SLC26A4 are more likely to induce inner ear malformation than single allele pathogenic mutation.
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Zhao X, Huang L, Wang X, Wang X, Zhao L, Cheng X, Ruan Y. Genotyping and audiological characteristics of infants with a single-allele SLC26A4 mutation. Int J Pediatr Otorhinolaryngol 2019; 116:153-158. [PMID: 30554688 DOI: 10.1016/j.ijporl.2018.10.046] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Revised: 10/26/2018] [Accepted: 10/28/2018] [Indexed: 11/16/2022]
Abstract
OBJECTIVES To identify second-allele variant in infants with a known single-allele mutation of the SLC26A4 gene and to determine the frequency of their occurrence; and to investigate the clinical audiological characteristics of infants with bi-allelic mutations in SLC26A4. METHODS The study subjects were 371 patients with a single-allele SLC26A4 mutation detected by neonatal deafness gene screening (4 genes and 9 pathogenic variants) who were treated at the otology outpatient department of Beijing Tongren Hospital. The exonic and flanking splice site regions of the SLC26A4 gene were sequenced for all patients. All patients with bi-allelic SLC26A4 mutations underwent audiological evaluation, and some also underwent temporal bone computed tomography and/or inner ear magnetic resonance imaging. RESULTS Of the 371 patients, 314 (84.64%) had an c.919-2A > G heterozygous mutation and 57 (15.36%) had a c.2168A > G (p.H723R) heterozygous mutation. 13 patients (3.50%) had a second-allele variant, including 11 (2.96%) with pathogenic mutations and 1 (0.27%) with a likely benign variant. Of the 13 patients with bi-allelic mutations, 11 had hearing loss and 2 had normal hearing, the latter of whom had c.919-2A > G/c.1766A > G and c.919-2A > G/c.757A > G compound heterozygous mutations, respectively. Four of the 13 patients with bi-allelic mutations had passed the universal newborn hearing screening, including 2 cases (15.38%) with hearing loss. The most prevalent degree of hearing loss was profound (40.91%), followed by severe (36.36%). The most prevalent audiometric configuration was sloping hearing loss (50.00%), followed by flat-type hearing loss (40.91%). CONCLUSIONS This is the first report in China of the frequency of occurrence of second-allele variant in infants with a known single-allele mutation of the SLC26A4 gene; the frequency was 3.50% for any type of variant and 2.96% for pathogenic mutations. A novel variant, c.1766A > G (p.Q589R), which is likely benign, was identified. The pathogenicity of c.757A > G (p.I253V) mutation deserves more in-depth research. For infants with bi-allelic SLC26A4 mutations, the degree of hearing loss was mainly severe-to-profound and the audiometric configuration was mainly sloping.
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Affiliation(s)
- Xuelei Zhao
- Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing, China; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Lihui Huang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing, China; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China.
| | - Xueyao Wang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing, China; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Xianlei Wang
- Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing, China; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Liping Zhao
- Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing, China; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Xiaohua Cheng
- Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing, China; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
| | - Yu Ruan
- Beijing Tongren Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing, China; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education, Beijing, China
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Zhao X, Cheng X, Huang L, Wang X, Wen C, Wang X. Novel compound heterozygous mutations in SLC26A4 gene in a Chinese family with enlarged vestibular aqueduct. Biosci Trends 2018; 12:502-506. [PMID: 30473558 DOI: 10.5582/bst.2018.01260] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
In order to investigate the genetic causes of hearing loss in a Chinese proband with nonsyndromic hearing loss and enlarged vestibular aqueduct (EVA), we conducted clinical and genetic evaluations in a deaf proband and her parents with normal hearing. 20 exons and flanking splice sites of the SLC26A4 gene were screened for pathogenic mutations by PCR amplification and bidirectional sequencing. As a control, a group of 400 healthy newborns from the same ethnic background were subjected to SLC26A4 gene screening using the same method. The proband harbored two mutations in the SLC26A4 gene in the form of compound heterozygosity. She was found to be heterozygous for a novel mutation c.574delC (p.Leu192Ter) in exon 5 and for the known mutation c.919-2A>G(c.IVS7-2A>G). Her mother was a heterozygous carrier of the c.919-2A>G mutation, and her father was a heterozygous carrier of the c.574delC and therefore co-segregated with the genetic disease. The c.574delC mutation was absent in 400 healthy newborns. The frameshift mutation causes the leucine (Leu) at amino acid position 192 to become a termination codon, leading to termination of protein sequence coding. This study demonstrates that the novel frameshift mutation c.574delC (p.Leu192Ter) in compound heterozygosity with c.919-2A>G in the SLC26A4 gene is the main cause of deafness in a family. Our study will expand the spectrum of known SLC26A4 mutations in the Chinese population, providing more information on genetic counseling, and diagnosis in hearing loss with EVA.
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Affiliation(s)
- Xuelei Zhao
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Xiaohua Cheng
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Lihui Huang
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Xianlei Wang
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Cheng Wen
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
| | - Xueyao Wang
- Beijing Tongren Hospital, Capital Medical University; Beijing Institute of Otolaryngology; Key Laboratory of Otolaryngology, Head and Neck Surgery, Ministry of Education
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