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Kang H, Chen Y, Wang L, Gao C, Li X, Hu Y. Pathogenic recurrent copy number variants in 7,078 pregnancies via chromosomal microarray analysis. J Perinat Med 2024; 52:171-180. [PMID: 38081620 DOI: 10.1515/jpm-2022-0580] [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: 11/30/2022] [Accepted: 09/30/2023] [Indexed: 02/09/2024]
Abstract
OBJECTIVES To investigate the incidence of pathogenic recurrent CNVs in fetuses with different referral indications and review the intrauterine phenotypic features of each CNV. METHODS A total of 7,078 amniotic fluid samples were collected for chromosome microarray analysis (CMA) and cases carrying pathogenic recurrent CNVs were further studied. RESULTS The highest incidence of pathogenic recurrent CNVs was 2.25 % in fetal ultrasound anomalies (FUA) group. Moreover, regardless of other indications, pregnant women with advanced maternal age have a lower incidence compared with whom less than 35 years old (p<0.05). In total 1.17 % (83/7,078) samples carried pathogenic recurrent CNVs: 20 cases with 22q11.2 recurrent region (12 microdeletion and eight microduplication), 11 with 1q21.1 (five microdeletion and six microduplication) and 16p13.11 (four microdeletion and seven microduplication), 10 with 15q11.2 recurrent microdeletion, seven with Xp22.31 recurrent microdeletion and 16p11.2 (three microdeletion and four microduplication), four with 7q11.23 (two microdeletion and two microduplication), three with 17p11.2 (three microdeletion), 17p12 (two microdeletion and one microduplication) and 17q12 (two microdeletion and one microduplication). The rest ones were rare in this study. CONCLUSIONS Pathogenic recurrent CNVs are more likely to be identified in FUA group. Pregnant women with advanced maternal age have a lower incidence of pathogenic recurrent CNVs. The profile of pathogenic recurrent CNVs between prenatal and postnatal is different, especially in 22q11.2, 1q21.1, 15q13.3 recurrent region and 15q11.2 deletion.
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Affiliation(s)
- Han Kang
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Yifei Chen
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Lingxi Wang
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Chonglan Gao
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Xingyu Li
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
| | - Yu Hu
- Prenatal Diagnosis Department, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, P.R. China
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2
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Hinch R, Donnelly P, Hinch AG. Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line. Science 2023; 382:eadh2531. [PMID: 38033082 PMCID: PMC7615360 DOI: 10.1126/science.adh2531] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Accepted: 09/29/2023] [Indexed: 12/02/2023]
Abstract
Meiotic recombination commences with hundreds of programmed DNA breaks; however, the degree to which they are accurately repaired remains poorly understood. We report that meiotic break repair is eightfold more mutagenic for single-base substitutions than was previously understood, leading to de novo mutation in one in four sperm and one in 12 eggs. Its impact on indels and structural variants is even higher, with 100- to 1300-fold increases in rates per break. We uncovered new mutational signatures and footprints relative to break sites, which implicate unexpected biochemical processes and error-prone DNA repair mechanisms, including translesion synthesis and end joining in meiotic break repair. We provide evidence that these mechanisms drive mutagenesis in human germ lines and lead to disruption of hundreds of genes genome wide.
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Affiliation(s)
- Robert Hinch
- Big Data Institute, University of Oxford; Oxford, UK
| | - Peter Donnelly
- Wellcome Centre for Human Genetics, University of Oxford; Oxford, UK
- Genomics plc; Oxford, UK
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3
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Wu Y, Wu D, Lan Y, Lan S, Li D, Zheng Z, Wang H, Ma L. Case report: Sex-specific characteristics of epilepsy phenotypes associated with Xp22.31 deletion: a case report and review. Front Genet 2023; 14:1025390. [PMID: 37347056 PMCID: PMC10280017 DOI: 10.3389/fgene.2023.1025390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 05/23/2023] [Indexed: 06/23/2023] Open
Abstract
Deletion in the Xp22.31 region is increasingly suggested to be involved in the etiology of epilepsy. Little is known regarding the genomic and clinical delineations of X-linked epilepsy in the Chinese population or the sex-stratified difference in epilepsy characteristics associated with deletions in the Xp22.31 region. In this study, we reported two siblings with a 1.69 Mb maternally inherited microdeletion at Xp22.31 involving the genes VCX3A, HDHD1, STS, VCX, VCX2, and PNPLA4 presenting with easily controlled focal epilepsy and language delay with mild ichthyosis in a Chinese family with a traceable 4-generation history of skin ichthyosis. Both brain magnetic resonance imaging results were normal, while EEG revealed epileptic abnormalities. We further performed an exhaustive literature search, documenting 25 patients with epilepsy with gene defects in Xp22.31, and summarized the epilepsy heterogeneities between sexes. Males harboring the Xp22.31 deletion mainly manifested with child-onset, easily controlled focal epilepsy accompanied by X-linked ichthyosis; the deletions were mostly X-linked recessive, with copy number variants (CNVs) in the classic region of deletion (863.38 kb-2 Mb). In contrast, epilepsy in females tended to be earlier-onset, and relatively refractory, with pathogenic CNV sizes varying over a larger range (859 kb-56.36 Mb); the alterations were infrequently inherited and almost combined with additional CNVs. A candidate region encompassing STS, HDHD1, and MIR4767 was the likely pathogenic epilepsy-associated region. This study filled in the knowledge gap regarding the genomic and clinical delineations of X-linked recessive epilepsy in the Chinese population and extends the understanding of the sex-specific characteristics of Xp22.31 deletion in regard to epilepsy.
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Affiliation(s)
- Yi Wu
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Dan Wu
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
| | - Yulong Lan
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia
- Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Shaocong Lan
- Department of clinical Medicine, Guangdong Medical University, Zhanjiang, China
| | - Duo Li
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Zexin Zheng
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Hongwu Wang
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Lian Ma
- Department of Pediatrics, Second Affiliated Hospital of Shantou University Medical College, Shantou, China
- Department of Hematology and Oncology, Shenzhen Children’s Hospital of China Medical University, Shenzhen, China
- Shenzhen Public Service Platform of Molecular Medicine in Pediatric Hematology and Oncology, Shenzhen, China
- Department of Pediatrics, The Third Affiliated Hospital of Guangzhou Medical University (The Women and Children’s Hospital of Guangzhou Medical University), Guangzhou, China
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4
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Bonito M, Ravasini F, Novelletto A, D'Atanasio E, Cruciani F, Trombetta B. Disclosing complex mutational dynamics at a Y chromosome palindrome evolving through intra- and inter-chromosomal gene conversion. Hum Mol Genet 2023; 32:65-78. [PMID: 35921243 DOI: 10.1093/hmg/ddac144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 06/21/2022] [Accepted: 06/21/2022] [Indexed: 01/17/2023] Open
Abstract
The human MSY ampliconic region is mainly composed of large duplicated sequences that are organized in eight palindromes (termed P1-P8), and may undergo arm-to-arm gene conversion. Although the importance of these elements is widely recognized, their evolutionary dynamics are still nuanced. Here, we focused on the P8 palindrome, which shows a complex evolutionary history, being involved in intra- and inter-chromosomal gene conversion. To disclose its evolutionary complexity, we performed a high-depth (50×) targeted next-generation sequencing of this element in 157 subjects belonging to the most divergent lineages of the Y chromosome tree. We found a total of 72 polymorphic paralogous sequence variants that have been exploited to identify 41 Y-Y gene conversion events that occurred during recent human history. Through our analysis, we were able to categorize P8 arms into three portions, whose molecular diversity was modelled by different evolutionary forces. Notably, the outer region of the palindrome is not involved in any gene conversion event and evolves exclusively through the action of mutational pressure. The inner region is affected by Y-Y gene conversion occurring at a rate of 1.52 × 10-5 conversions/base/year, with no bias towards the retention of the ancestral state of the sequence. In this portion, GC-biased gene conversion is counterbalanced by a mutational bias towards AT bases. Finally, the middle region of the arms, in addition to intra-chromosomal gene conversion, is involved in X-to-Y gene conversion (at a rate of 6.013 × 10-8 conversions/base/year) thus being a major force in the evolution of the VCY/VCX gene family.
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Affiliation(s)
- Maria Bonito
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome 00185, Italy
| | - Francesco Ravasini
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome 00185, Italy
| | - Andrea Novelletto
- Department of Biology, University of Rome Tor Vergata, Rome 00133, Italy
| | - Eugenia D'Atanasio
- Institute of Molecular Biology and Pathology (IBPM), CNR, Rome 00185, Italy
| | - Fulvio Cruciani
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome 00185, Italy.,Institute of Molecular Biology and Pathology (IBPM), CNR, Rome 00185, Italy
| | - Beniamino Trombetta
- Department of Biology and Biotechnology 'Charles Darwin', Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Rome 00185, Italy
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5
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Chouk H, Saad S, Dimassi S, Fetoui NG, Bennour A, Gammoudi R, Elmabrouk H, Saad A, Denguezli M, H'mida D. X-linked recessive ichthyosis in 8 Tunisian patients: awareness of misdiagnosis due to the technical trap of the STS pseudogene. BMC Med Genomics 2022; 15:165. [PMID: 35883075 PMCID: PMC9317125 DOI: 10.1186/s12920-022-01319-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 07/18/2022] [Indexed: 11/24/2022] Open
Abstract
Introduction X-linked recessive ichthyosis (XLI) is a genodermatosis, caused by a deficiency of the steroid sulphatase enzyme encoded by the STS gene (OMIM # 300,747). Adopted XLI molecular diagnosis approaches differ from one laboratory to another depending on available technical facilities. Our work aims to figure out a sound diagnostic strategy for XLI.
Patients and methods We collected 8 patients with XLI, all males, from 3 unrelated Tunisian families from central Tunisia. Genetic diagnosis was conducted through a large panel of genetic techniques including: Sanger Sequencing, haplotype analysis of STR markers, MLPA analysis, FISH and array CGH.
Results Direct Sanger sequencing of the STS gene showed the same deletion of 13 base pairs within the exon 4 in all patients resulting in a premature stop codon. However, all patients’ mothers were not carriers of this variant and no common haplotype flanking STS gene was shared between affected patients. Sequence alignment with reference human genome revealed an unprocessed pseudogene of the STS gene located on the Y chromosome, on which the 13 bp deletion was actually located. STS MLPA analysis identified a deletion of the entire STS gene on X chromosome for all affected patients. This deletion was confirmed by FISH and delineated by array CGH. Conclusion All our patients shared a deletion of the entire STS gene revealed by MLPA, confirmed by FISH and improved by array CGH. Geneticists must be aware of the presence of pseudogenes that can lead to XLI genetic misdiagnosis.
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Affiliation(s)
- Hamza Chouk
- Department of Cytogenetics, Molecular Genetic and Biology of Human Reproduction, Farhat Hached of Sousse, Sousse, Tunisia.,Higher Institute of Biotechnology of Monastir, Monastir, Tunisia
| | - Sarra Saad
- Faculty of Medicine of Sousse, Sousse, Tunisia.,Department of Dermatology, Farhat Hached, Sousse, Tunisia
| | - Sarra Dimassi
- Department of Cytogenetics, Molecular Genetic and Biology of Human Reproduction, Farhat Hached of Sousse, Sousse, Tunisia.,Faculty of Medicine of Sousse, Sousse, Tunisia
| | - Nadia Ghariani Fetoui
- Faculty of Medicine of Sousse, Sousse, Tunisia.,Department of Dermatology, Farhat Hached, Sousse, Tunisia
| | - Ayda Bennour
- Department of Cytogenetics, Molecular Genetic and Biology of Human Reproduction, Farhat Hached of Sousse, Sousse, Tunisia.,Faculty of Medicine of Sousse, Sousse, Tunisia
| | - Rima Gammoudi
- Faculty of Medicine of Sousse, Sousse, Tunisia.,Department of Dermatology, Farhat Hached, Sousse, Tunisia
| | - Haifa Elmabrouk
- Department of Cytogenetics, Molecular Genetic and Biology of Human Reproduction, Farhat Hached of Sousse, Sousse, Tunisia.,Higher Institute of Biotechnology of Monastir, Monastir, Tunisia
| | - Ali Saad
- Department of Cytogenetics, Molecular Genetic and Biology of Human Reproduction, Farhat Hached of Sousse, Sousse, Tunisia.,Faculty of Medicine of Sousse, Sousse, Tunisia
| | - Mohamed Denguezli
- Faculty of Medicine of Sousse, Sousse, Tunisia.,Department of Dermatology, Farhat Hached, Sousse, Tunisia
| | - Dorra H'mida
- Department of Cytogenetics, Molecular Genetic and Biology of Human Reproduction, Farhat Hached of Sousse, Sousse, Tunisia. .,Faculty of Medicine of Sousse, Sousse, Tunisia.
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6
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Further evidence for lack of association of PRDM9 polymorphisms and 22q11.2 deletion syndrome. Meta Gene 2021. [DOI: 10.1016/j.mgene.2021.100927] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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7
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Ma W, Mao J, Wang X, Duan L, Song Y, Lian X, Zheng J, Liu Z, Nie M, Wu X. Novel Microdeletion in the X Chromosome Leads to Kallmann Syndrome, Ichthyosis, Obesity, and Strabismus. Front Genet 2020; 11:596. [PMID: 32670353 PMCID: PMC7327112 DOI: 10.3389/fgene.2020.00596] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 05/15/2020] [Indexed: 11/23/2022] Open
Abstract
Background A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively. Method Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype–phenotype association for each patient were analyzed. Results We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838–9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083–8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient. Conclusion We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.
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Affiliation(s)
- Wanlu Ma
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Jiangfeng Mao
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xi Wang
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Lian Duan
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Yuwen Song
- Department of Endocrinology, The Second Hospital of Shandong University, Jinan, China
| | - Xiaolan Lian
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Junjie Zheng
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Zhaoxiang Liu
- Department of Endocrinology, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Min Nie
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
| | - Xueyan Wu
- Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, China
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Labonne JDJ, Driessen TM, Harris ME, Kong IK, Brakta S, Theisen J, Sangare M, Layman LC, Kim CH, Lim J, Kim HG. Comparative Genomic Mapping Implicates LRRK2 for Intellectual Disability and Autism at 12q12, and HDHD1, as Well as PNPLA4, for X-Linked Intellectual Disability at Xp22.31. J Clin Med 2020; 9:jcm9010274. [PMID: 31963867 PMCID: PMC7019335 DOI: 10.3390/jcm9010274] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/28/2019] [Accepted: 12/06/2019] [Indexed: 01/01/2023] Open
Abstract
We report a genomic and phenotypic delineation for two chromosome regions with candidate genes for syndromic intellectual disability at 12q12 and Xp22.31, segregating independently in one family with four affected members. Fine mapping of three affected members, along with six unreported small informative CNVs, narrowed down the candidate chromosomal interval to one gene LRRK2 at 12q12. Expression studies revealed high levels of LRRK2 transcripts in the whole human brain, cerebral cortex and hippocampus. RT-qPCR assays revealed that LRRK2 transcripts were dramatically reduced in our microdeletion patient DGDP289A compared to his healthy grandfather with no deletion. The decreased expression of LRRK2 may affect protein–protein interactions between LRRK2 and its binding partners, of which eight have previously been linked to intellectual disability. These findings corroborate with a role for LRRK2 in cognitive development, and, thus, we propose that intellectual disability and autism, displayed in the 12q12 microdeletions, are likely caused by LRRK2. Using another affected member, DGDP289B, with a microdeletion at Xp22.31, in this family, we performed the genomic and clinical delineation with six published and nine unreported cases. We propose HDHD1 and PNPLA4 for X-linked intellectual disability in this region, since their high transcript levels in the human brain substantiate their role in intellectual functioning.
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Affiliation(s)
- Jonathan D. J. Labonne
- Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA (M.E.H.); (S.B.); (J.T.); (L.C.L.)
| | - Terri M. Driessen
- Department of Genetics, Yale University, New Haven, CT 06510, USA; (T.M.D.); (J.L.)
| | - Marvin E. Harris
- Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA (M.E.H.); (S.B.); (J.T.); (L.C.L.)
| | - Il-Keun Kong
- Department of Animal Science, Division of Applied Life Science (BK21plus), Institute of Agriculture and Life Science, Gyeongsang National University, Jinju 52828, Korea;
| | - Soumia Brakta
- Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA (M.E.H.); (S.B.); (J.T.); (L.C.L.)
| | - John Theisen
- Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA (M.E.H.); (S.B.); (J.T.); (L.C.L.)
| | - Modibo Sangare
- Faculty of Medicine and Odontostomatology (FMOS), University of Sciences, Techniques and Technologies of Bamako (USTTB), Bamako, Mali;
| | - Lawrence C. Layman
- Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA (M.E.H.); (S.B.); (J.T.); (L.C.L.)
- Department of Neuroscience and Regenerative Medicine, Augusta University, Augusta, GA 30912, USA
| | - Cheol-Hee Kim
- Department of Biology, Chungnam National University, Daejeon 34134, Korea;
| | - Janghoo Lim
- Department of Genetics, Yale University, New Haven, CT 06510, USA; (T.M.D.); (J.L.)
- Department of Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale Stem Cell Center, Yale University, New Haven, CT 06510, USA
| | - Hyung-Goo Kim
- Section of Reproductive Endocrinology, Infertility & Genetics, Department of Obstetrics & Gynecology, Augusta University, Augusta, GA 30912, USA (M.E.H.); (S.B.); (J.T.); (L.C.L.)
- Neurological Disorders Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Doha P.O. Box 34110, Qatar
- Correspondence:
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Zhuang J, Wang Y, Zeng S, Lv C, Lin Y, Jiang Y. A prenatal diagnosis and genetics study of five pedigrees in the Chinese population with Xp22.31 microduplication. Mol Cytogenet 2019; 12:50. [PMID: 31857824 PMCID: PMC6907354 DOI: 10.1186/s13039-019-0461-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 11/26/2019] [Indexed: 11/16/2022] Open
Abstract
Background Copy number variations (CNVs) can contribute to human phenotype, phenotypic diversity and disease susceptibility, while others may benign. In the current study, an attempt to investigate the pathogenicity of CNVs in chromosome Xp22.31 was explored. Methods G-banding and SNP-array techniques were used to analyze chromosome karyotypes and CNVs in fetuses. Parents associate with five different pedigrees possessing high risk factors in pregnancy were considered with such parameters as advanced age, high risk of serological screening and ultrasound abnormalities. Results The fetuses’ amniotic fluid karyotypes were 46, XX and those of their parents with the five pedigrees revealed no abnormalities. Here, we noticed a series of individuals with Xp22.31 duplications ranging from 534.6 kb to 1.6 Mb. It was detected through SNP array that the fetuses in Pedigree 1 and 2 had ~ 600 kb duplications in the Xp22.31 region of their X chromosomes which contained two OMIM genes, HDHD1 (OMIM: 306480) and part of STS (OMIM: 300747). The fetuses of Pedigrees 3, 4 and 5 had 1.6 Mb duplication in the same chromosome which contained four OMIM genes: HDHD1 (OMIM: 306480), STS (OMIM: 300747), PNPLA4 (OMIM: 300102) and VCX (OMIM: 300229). The duplications in the fetuses of Pedigrees 1 and 5 were inherited from the non-phenotypic parents. Pedigrees 3 and 4 refused to perform parental verification. Finally, four of the five pedigrees continue towards pregnancy with no abnormalities being observed during followed-ups. Conclusion Our study first showed duplications of Xp22.31 in Chinese population. Clinical and genetic investigation on five different pedigrees, we consider the duplication of these fragments as likely benign copy number variants (CNVs). We suggest that the duplications of Xp22.31 with recurrent duplication as a benign CNVs .
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Affiliation(s)
- Jianlong Zhuang
- Prenatal Diagnosis Center, Quanzhou Women's and Children's Hospital, Fujian Province, People's Republic of China
| | - Yuanbai Wang
- Prenatal Diagnosis Center, Quanzhou Women's and Children's Hospital, Fujian Province, People's Republic of China
| | - Shuhong Zeng
- Prenatal Diagnosis Center, Quanzhou Women's and Children's Hospital, Fujian Province, People's Republic of China
| | - Chunling Lv
- Zhejiang Biosan technology Co., Ltd, Zhejiang, People's Republic of China
| | - Yiming Lin
- Neonatal Disease Screening Center of Quanzhou, Quanzhou Women's and Children's Hospital, Fujian Province, People's Republic of China
| | - Yuying Jiang
- Prenatal Diagnosis Center, Quanzhou Women's and Children's Hospital, Fujian Province, People's Republic of China
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10
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Abstract
In sexual reproduction, opportunities are limited and the stakes are high. This inevitably leads to conflict. One pervasive conflict occurs within genomes between alternative alleles at heterozygous loci. Each gamete and thus each offspring will inherit only one of the two alleles from a heterozygous parent. Most alleles 'play fair' and have a 50% chance of being included in any given gamete. However, alleles can gain an enormous advantage if they act selfishly to force their own transmission into more than half, sometimes even all, of the functional gametes. These selfish alleles are known as 'meiotic drivers', and their cheating often incurs a high cost on the fertility of eukaryotes ranging from plants to mammals. Here, we review how several types of meiotic drivers directly and indirectly contribute to infertility, and argue that a complete picture of the genetics of infertility will require focusing on both the standard alleles - those that play fair - as well as selfish alleles involved in genetic conflict.
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Affiliation(s)
- Sarah E Zanders
- Stowers Institute for Medical Research, Kansas City, MO, USA; Department of Molecular and Integrative Physiology, University of Kansas Medical Center, Kansas City, KS, USA.
| | - Robert L Unckless
- Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA
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11
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DNA Methylation and SNPs in VCX are Correlated with Sex Differences in the Response to Chronic Hepatitis B. Virol Sin 2019; 34:489-500. [PMID: 31161555 DOI: 10.1007/s12250-019-00117-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2018] [Accepted: 03/25/2019] [Indexed: 02/07/2023] Open
Abstract
The study was conducted to explore the mechanisms of sex differences in the response to chronic hepatitis B (CHB) in terms of DNA methylation, SNP genotype, and gene expression. Genomic DNA was isolated from peripheral blood mononuclear cells (PBMCs) of CHB patients and healthy controls and evaluated using the Human Methylation 450 K Assay. The DNA methylation level at hg37 chromosome (CHR) X: 7810800 was further validated using pyrosequencing. SNP genotypes, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were further examined using SNaPshot, RT-qPCR, and Western blot, respectively. Results showed that a total of 5529 CpG loci were differentially methylated between male and female CHB patients. DNA methylation level and CC + CT frequency at CHR X: 7810800, VCX mRNA expression of PBMCs, and plasma VCX protein concentration were higher in female than in male CHB patients. The CHR X: 7810800 locus was hypermethylated in CHB patients with CC + CT genotypes in comparison with those with the TT genotype. In cases of CC + CT genotypes, VCX mRNA expression was negatively correlated with the DNA methylation level. CHB patients with higher levels of HBV DNA, AST, and GGT or higher GPRI scores exhibited lower VCX expression. In conclusion, SNPs and DNA methylation at the CHR X: 7810800 locus cooperatively regulate VCX expression in CHB. The upregulated VCX expression in female CHB patients might represent a mechanism of protection from more severe liver dysfunction and extensive fibrosis, as observed in male CHB patients.
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Rodrigo-Nicolás B, Bueno-Martínez E, Martín-Santiago A, Cañueto J, Vicente A, Torrelo A, Noguera-Morel L, Duat-Rodríguez A, Jorge-Finnigan C, Palacios-Álvarez I, García-Hernández J, Sebaratnam D, González-Sarmiento R, Hernández-Martín A. Evidence of the high prevalence of neurological disorders in nonsyndromic X-linked recessive ichthyosis: a retrospective case series. Br J Dermatol 2018; 179:933-939. [DOI: 10.1111/bjd.16826] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/16/2018] [Indexed: 12/11/2022]
Affiliation(s)
| | - E. Bueno-Martínez
- Molecular Medicine Unit-Department of Medicine; IBSAL and IBMCC and University Hospital of Salamanca; CSIC, University of Salamanca; Spain
| | - A. Martín-Santiago
- Department of Dermatology; Hospital Son Espases; Palma de Mallorca Spain
| | - J. Cañueto
- Department of Dermatology; Hospital Universitario de Salamanca; Salamanca Spain
| | - A. Vicente
- Department of Dermatology; Hospital Sant Joan de Deu; Barcelona Spain
| | - A. Torrelo
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | - L. Noguera-Morel
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | | | - C. Jorge-Finnigan
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | | | - J.L. García-Hernández
- Molecular Medicine Unit-Department of Medicine; IBSAL and IBMCC and University Hospital of Salamanca; CSIC, University of Salamanca; Spain
| | - D.F. Sebaratnam
- Department of Dermatology; Hospital Infantil Niño Jesús; Madrid Spain
| | - R. González-Sarmiento
- Molecular Medicine Unit-Department of Medicine; IBSAL and IBMCC and University Hospital of Salamanca; CSIC, University of Salamanca; Spain
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13
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Addis L, Sproviero W, Thomas SV, Caraballo RH, Newhouse SJ, Gomez K, Hughes E, Kinali M, McCormick D, Hannan S, Cossu S, Taylor J, Akman CI, Wolf SM, Mandelbaum DE, Gupta R, van der Spek RA, Pruna D, Pal DK. Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses. J Med Genet 2018; 55:607-616. [PMID: 29789371 PMCID: PMC6119347 DOI: 10.1136/jmedgenet-2018-105319] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Revised: 04/18/2018] [Accepted: 04/28/2018] [Indexed: 12/25/2022]
Abstract
BACKGROUND Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. OBJECTIVE To identify rare, causal CNV in patients with RE. METHODS We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. RESULTS We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. CONCLUSION Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.
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Affiliation(s)
- Laura Addis
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK
- Neuroscience Discovery Research, Eli Lilly and Company, Surrey, UK
| | - William Sproviero
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK
| | - Sanjeev V Thomas
- Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
| | - Roberto H Caraballo
- Department of Neurology, Hospital de Pediatría Prof. Dr. J.P. Garrahan, Combate de los Pozos 1881, Buenos Aires, Argentina
| | - Stephen J Newhouse
- Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
- NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, UK
- Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK
| | - Kumudini Gomez
- Department of Paediatrics, University Hospital Lewisham, Lewisham and Greenwich NHS Trust, London, UK
| | - Elaine Hughes
- Department of Paediatric Neurosciences, Evelina London Children’s Hospital, St Thomas’ Hospital, London, UK
| | - Maria Kinali
- Department of Paediatric Neurology, Chelsea and Westminster Hospital, London, UK
| | - David McCormick
- Department of Paediatric Neurosciences, Evelina London Children’s Hospital, St Thomas’ Hospital, London, UK
| | - Siobhan Hannan
- Department of Paediatric Neurology, Chelsea and Westminster Hospital, London, UK
| | - Silvia Cossu
- Neurosurgery Unit, Neuroscience and Neurorehabilitation Department, Bambino Gesù Children Hospital, Rome, Italy
- Neurology Unit, Pediatric Hospital A. Cao, Brotzu Hospital Trust, Cagliari, Italy
| | | | - Cigdem I Akman
- Division of Pediatric Neurology, College of Physicians and Surgeons of Columbia University, New York City, New York, USA
| | - Steven M Wolf
- Department of Neurology, Mount Sinai Health System, New York City, New York, USA
| | - David E Mandelbaum
- Departments of Pediatrics, Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Rajesh Gupta
- Department of Paediatrics, Tunbridge Wells Hospital, Pembury, UK
| | - Rick A van der Spek
- Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Dario Pruna
- Neurology Unit, Pediatric Hospital A. Cao, Brotzu Hospital Trust, Cagliari, Italy
| | - Deb K Pal
- Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK
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Copy Number Variants and Exome Sequencing Analysis in Six Pairs of Chinese Monozygotic Twins Discordant for Congenital Heart Disease. Twin Res Hum Genet 2018; 20:521-532. [PMID: 29192580 PMCID: PMC5729853 DOI: 10.1017/thg.2017.57] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Congenital heart disease (CHD) is one of the most common birth defects. More than 200 susceptibility loci have been identified for CHDs, yet a large part of the genetic risk factors remain unexplained. Monozygotic (MZ) twins are thought to be completely genetically identical; however, discordant phenotypes have been found in MZ twins. Recent studies have demonstrated genetic differences between MZ twins. We aimed to test whether copy number variants (CNVs) and/or genetic mutation differences play a role in the etiology of CHDs by using single nucleotide polymorphism (SNP) genotyping arrays and whole exome sequencing of twin pairs discordant for CHDs. Our goal was to identify mutations present only in the affected twins, which could identify novel candidates for CHD susceptibility loci. We present a comprehensive analysis for the CNVs and genetic mutation results of the selected individuals but detected no consistent differences within the twin pairs. Our study confirms that chromosomal structure or genetic mutation differences do not seem to play a role in the MZ twins discordant for CHD.
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15
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Qiao Y, Bagheri H, Tang F, Badduke C, Martell S, Lewis SME, Robinson W, Connolly MB, Arbour L, Rajcan-Separovic E. Exome sequencing identified a de novo mutation of PURA gene in a patient with familial Xp22.31 microduplication. Eur J Med Genet 2018; 62:103-108. [PMID: 29908350 DOI: 10.1016/j.ejmg.2018.06.010] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2018] [Revised: 06/08/2018] [Accepted: 06/10/2018] [Indexed: 11/28/2022]
Abstract
The clinical significance of Xp22.31 microduplication is controversial as it is reported in subjects with developmental delay (DD), their unaffected relatives and unrelated controls. We performed multifaceted studies in a family of a boy with hypotonia, dysmorphic features and DD who carried a 600 Kb Xp22.31 microduplication (7515787-8123310bp, hg19) containing two genes, VCX and PNPLA4. The duplication was transmitted from his cognitively normal maternal grandfather. We found no evidence of the duplication causing the proband's DD and congenital anomalies based on unaltered expression of PNPLA4 in the proband and his mother in comparison to controls and preferential activation of the paternal chromosome X with Xp22.31 duplication in proband's mother. However, a de novo, previously reported deleterious, missense mutation in Pur-alpha gene (PURA) (5q31.2), with a role in neuronal differentiation was detected in the proband by exome sequencing. We propose that the variability in the phenotype in carriers of Xp22.31 microduplication can be due to a second and more deleterious genetic mutation in more severely affected carriers. Widespread use of whole genome next generation sequencing in families with Xp22.31 CNV could help identify such cases.
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Affiliation(s)
- Ying Qiao
- Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada
| | - Hani Bagheri
- Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada
| | - Flamingo Tang
- Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada
| | | | - Sally Martell
- Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada
| | - Suzanne M E Lewis
- BC Children's Hospital Research Institute, Vancouver, BC, Canada; Department of Medical Genetics, UBC, Vancouver, BC, Canada
| | - Wendy Robinson
- Department of Medical Genetics, UBC, Vancouver, BC, Canada
| | - Mary B Connolly
- Division of Pediatric Neurology, Department of Pediatrics, UBC and BC Children's Hospital, Vancouver, BC, Canada
| | - Laura Arbour
- Department of Medical Genetics, University of Victoria, Victoria, BC, Canada.
| | - Evica Rajcan-Separovic
- Department of Pathology and Laboratory Medicine, UBC, Vancouver, BC, Canada; BC Children's Hospital Research Institute, Vancouver, BC, Canada.
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Deng H, Zeng J, Zhang T, Gong L, Zhang H, Cheung E, Jones C, Li G. Histone H3.3K27M Mobilizes Multiple Cancer/Testis (CT) Antigens in Pediatric Glioma. Mol Cancer Res 2018; 16:623-633. [DOI: 10.1158/1541-7786.mcr-17-0460] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 12/07/2017] [Accepted: 01/16/2018] [Indexed: 11/16/2022]
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Brabbing-Goldstein D, Reches A, Svirsky R, Bar-Shira A, Yaron Y. Dilemmas in genetic counseling for low-penetrance neuro-susceptibility loci detected on prenatal chromosomal microarray analysis. Am J Obstet Gynecol 2018; 218:247.e1-247.e12. [PMID: 29146387 DOI: 10.1016/j.ajog.2017.11.559] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2017] [Revised: 10/14/2017] [Accepted: 11/06/2017] [Indexed: 01/03/2023]
Abstract
BACKGROUND Chromosomal microarray analysis is standard of care in fetuses with malformations, detecting clinically significant copy number variants in 5-7% of cases over conventional karyotyping. However, it also detects variants of uncertain significance in 1.6-4.2% of the cases, some of which are low-penetrance neuro-susceptibility loci. The interpretation of these variants in pregnancy is particularly challenging because the significance is often unclear and the clinical implications may be difficult to predict. OBJECTIVE The purpose of this study was to describe counseling dilemmas regarding low-penetrance neuro-susceptibility loci that are detected by prenatal chromosomal microarray analysis. STUDY DESIGN During the study period (January 2014 to December 2015), 700 prenatal chromosomal microarray analyses were performed. Cases were categorized as "indicated" (n=375) if there were abnormal sonographic findings or suggestive medical history and "patient choice" (n=325) in the presence of a structurally normal fetus with no other particular indication. The laboratory reported on copy number variants ≥400 Kb in size in loci known to be associated with genetic syndromes and ≥1 Mb in other areas of genome. Results were classified as gross aneuploidy, copy number variants, and normal. Copy number variants were categorized according to the American College of Medical Genetics standards and guidelines: pathogenic, variants of uncertain significance, or benign. Variants of uncertain significance were further subdivided into categories of likely pathogenic, variants of uncertain significance with no subclassification, and likely benign. Statistical analysis was performed with the use of Chi square test and Fisher's exact test to compare intergroup differences in incidence of the different result categories and demographic data. RESULTS Patient choice cases became more prevalent with time (35.5% in the beginning of the study, compared with 48.4% at the end of the study period). Clinically significant copy number variants were found in 14 of 375 (3.7%) of indicated cases vs only 2 of 325 (0.6%) of patient choice cases (P=.009). All "likely benign" variants consisted of low-penetrance neuro-susceptibility loci. The incidence thereof was similar between the indicated and patient choice groups (3.7% vs 3.4%; P=.85). In the indicated group, some variants of uncertain significance may have contributed to the abnormal anatomic findings. Conversely, in the patient choice group, the finding of low-penetrance neuro-susceptibility loci was often unexpected and confounding for prospective parents. CONCLUSION Prenatal chromosomal microarray analysis added clinically significant information in both groups. However, it also detected low-penetrance neuro-susceptibility loci in approximately 3.5% of the cases. This fact should be conveyed during pretest counseling to allow patients to make informed choices, particularly when chromosomal microarray is to be performed for patient choice.
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18
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Altemose N, Noor N, Bitoun E, Tumian A, Imbeault M, Chapman JR, Aricescu AR, Myers SR. A map of human PRDM9 binding provides evidence for novel behaviors of PRDM9 and other zinc-finger proteins in meiosis. eLife 2017; 6:e28383. [PMID: 29072575 PMCID: PMC5705219 DOI: 10.7554/elife.28383] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2017] [Accepted: 10/24/2017] [Indexed: 12/31/2022] Open
Abstract
PRDM9 binding localizes almost all meiotic recombination sites in humans and mice. However, most PRDM9-bound loci do not become recombination hotspots. To explore factors that affect binding and subsequent recombination outcomes, we mapped human PRDM9 binding sites in a transfected human cell line and measured PRDM9-induced histone modifications. These data reveal varied DNA-binding modalities of PRDM9. We also find that human PRDM9 frequently binds promoters, despite their low recombination rates, and it can activate expression of a small number of genes including CTCFL and VCX. Furthermore, we identify specific sequence motifs that predict consistent, localized meiotic recombination suppression around a subset of PRDM9 binding sites. These motifs strongly associate with KRAB-ZNF protein binding, TRIM28 recruitment, and specific histone modifications. Finally, we demonstrate that, in addition to binding DNA, PRDM9's zinc fingers also mediate its multimerization, and we show that a pair of highly diverged alleles preferentially form homo-multimers.
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Affiliation(s)
- Nicolas Altemose
- The Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUnited Kingdom
- Department of StatisticsUniversity of OxfordOxfordUnited Kingdom
| | - Nudrat Noor
- The Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUnited Kingdom
| | - Emmanuelle Bitoun
- The Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUnited Kingdom
| | - Afidalina Tumian
- Department of StatisticsUniversity of OxfordOxfordUnited Kingdom
| | - Michael Imbeault
- Global Health InstituteÉcole Polytechnique Fédérale de LausanneLausanneSwitzerland
| | - J Ross Chapman
- The Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUnited Kingdom
| | - A Radu Aricescu
- The Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUnited Kingdom
| | - Simon R Myers
- The Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUnited Kingdom
- Department of StatisticsUniversity of OxfordOxfordUnited Kingdom
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Polo-Antúnez A, Arroyo-Carrera I. Severe Neurological Phenotype in a Girl with Xp22.31 Triplication. Mol Syndromol 2017; 8:219-223. [PMID: 28690489 DOI: 10.1159/000475795] [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] [Accepted: 03/06/2017] [Indexed: 11/19/2022] Open
Abstract
The Xp22.31 duplication is a copy number variant which is challenging to categorize as pathogenic or benign. There is an increasing number of patients with the duplication and a neurobehavioral phenotype, but the duplication is almost always inherited from a parent, who in some cases is phenotypically normal. Also, the duplication is detected in the general population, though in a smaller percentage than in clinically ascertained populations. The Xp22.31 triplication has only been identified in 3 individuals of a large cohort of developmental delay cases but never in the control cohorts or general population. We report a severely affected female with an Xp22.31 tetrasomy, inherited from duplications identified in both phenotypically normal parents. Although our study has limitations, it suggests that the Xp22.31 triplication seems to be more penetrant than the duplication and is associated with a neurological phenotype.
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Affiliation(s)
| | - Ignacio Arroyo-Carrera
- Neonatology Unit, San Pedro de Alcántara Hospital, Cáceres, Spain.,CIBER de Enfermedades Raras (CIBERER) (U724), Instituto de Salud Carlos III, Madrid, Spain
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20
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Derlig K, Gießl A, Brandstätter JH, Enz R, Dahlhaus R. Studying Protein Function and the Role of Altered Protein Expression by Antibody Interference and Three-dimensional Reconstructions. J Vis Exp 2016:53049. [PMID: 27167171 PMCID: PMC4941955 DOI: 10.3791/53049] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
A strict management of protein expression is not only essential to every organism alive, but also an important strategy to investigate protein functions in cellular models. Therefore, recent research invented different tools to target protein expression in mammalian cell lines or even animal models, including RNA and antibody interference. While the first strategy has gathered much attention during the past two decades, peptides mediating a translocation of antibody cargos across cellular membranes and into cells, obtained much less interest. In this publication, we provide a detailed protocol how to utilize a peptide carrier named Chariot in human embryonic kidney cells as well as in primary hippocampal neurons to perform antibody interference experiments and further illustrate the application of three-dimensional reconstructions in analyzing protein function. Our findings suggest that Chariot is, probably due to its nuclear localization signal, particularly well-suited to target proteins residing in the soma and the nucleus. Remarkably, when applying Chariot to primary hippocampal cultures, the reagent turned out to be surprisingly well accepted by dissociated neurons.
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Affiliation(s)
- Kristin Derlig
- Institute for Biochemistry, Emil-Fischer Centre, University of Erlangen-Nuremberg
| | - Andreas Gießl
- Department of Biology, Animal Physiology, University of Erlangen-Nuremberg
| | | | - Ralf Enz
- Institute for Biochemistry, Emil-Fischer Centre, University of Erlangen-Nuremberg
| | - Regina Dahlhaus
- Institute for Biochemistry, Emil-Fischer Centre, University of Erlangen-Nuremberg;
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21
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Ali RH, Mahmood S, Raza SI, Aziz A, Irfanullah, Naqvi SKUH, Wasif N, Ansar M, Ahmad W, Shah SH, Khan BT, Zaman Q, Gul A, Wali A, Ali G, Khan S, Khisroon M, Basit S. Genetic analysis of Xp22.3 micro-deletions in seventeen families segregating isolated form of X-linked ichthyosis. J Dermatol Sci 2015; 80:214-7. [PMID: 26481779 DOI: 10.1016/j.jdermsci.2015.09.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 09/17/2015] [Accepted: 09/24/2015] [Indexed: 11/25/2022]
Affiliation(s)
- Raja Hussain Ali
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Sabba Mahmood
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Syed Irfan Raza
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Abdul Aziz
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Irfanullah
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | | | - Naveed Wasif
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Muhammad Ansar
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan
| | - Wasim Ahmad
- Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
| | - Sayed Hajan Shah
- Center for Human Genetics and Molecular Medicine, Sindh Institute of Urology and Transplantation (SIUT), Karachi, Pakistan
| | - Bakht Tarin Khan
- Department of Zoology, University of Peshawar, KPK, Pakistan; Department of Zoology, Abdul Wali Khan University, Mardan, KPK, Pakistan
| | - Qaiser Zaman
- Department of Zoology, University of Peshawar, KPK, Pakistan
| | - Ajab Gul
- Department of Biotechnology and Informatics, BUITEMS, Quetta 87100, Pakistan
| | - Abdul Wali
- Department of Biotechnology and Informatics, BUITEMS, Quetta 87100, Pakistan
| | - Ghazanfar Ali
- Department of Biotechnology, Azad Jammu & Kashmir, Pakistan
| | - Saadulah Khan
- Department of Biotechnology & Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan
| | | | - Sulman Basit
- Center for Genetics and Inherited Diseases, Taibah University Almadinah Almunawarah, Saudi Arabia
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22
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Ahmed I, Buchert R, Zhou M, Jiao X, Mittal K, Sheikh TI, Scheller U, Vasli N, Rafiq MA, Brohi MQ, Mikhailov A, Ayaz M, Bhatti A, Sticht H, Nasr T, Carter MT, Uebe S, Reis A, Ayub M, John P, Kiledjian M, Vincent JB, Jamra RA. Mutations in DCPS and EDC3 in autosomal recessive intellectual disability indicate a crucial role for mRNA decapping in neurodevelopment. Hum Mol Genet 2015; 24:3172-80. [PMID: 25701870 DOI: 10.1093/hmg/ddv069] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2014] [Accepted: 02/16/2015] [Indexed: 01/09/2023] Open
Abstract
There are two known mRNA degradation pathways, 3' to 5' and 5' to 3'. We identified likely pathogenic variants in two genes involved in these two pathways in individuals with intellectual disability. In a large family with multiple branches, we identified biallelic variants in DCPS in three affected individuals; a splice site variant (c.636+1G>A) that results in an in-frame insertion of 45 nucleotides and a missense variant (c.947C>T; p.Thr316Met). DCPS decaps the cap structure generated by 3' to 5' exonucleolytic degradation of mRNA. In vitro decapping assays showed an ablation of decapping function for both variants in DCPS. In another family, we identified a homozygous mutation (c.161T>C; p.Phe54Ser) in EDC3 in two affected children. EDC3 stimulates DCP2, which decaps mRNAs at the beginning of the 5' to 3' degradation pathway. In vitro decapping assays showed that altered EDC3 is unable to enhance DCP2 decapping at low concentrations and even inhibits DCP2 decapping at high concentration. We show that individuals with biallelic mutations in these genes of seemingly central functions are viable and that these possibly lead to impairment of neurological functions linking mRNA decapping to normal cognition. Our results further affirm an emerging theme linking aberrant mRNA metabolism to neurological defects.
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Affiliation(s)
- Iltaf Ahmed
- Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | | | - Mi Zhou
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | - Xinfu Jiao
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | - Kirti Mittal
- Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8
| | - Taimoor I Sheikh
- Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8
| | | | - Nasim Vasli
- Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8
| | - Muhammad Arshad Rafiq
- Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8
| | - M Qasim Brohi
- Sir Cowasji Jehangir Institute of Psychiatry, Hyderabad, Sindh 71000, Pakistan
| | - Anna Mikhailov
- Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8
| | - Muhammad Ayaz
- Lahore Institute of Research and Development, Lahore 51000, Pakistan
| | - Attya Bhatti
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Heinrich Sticht
- Bioinformatics, Institute of Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91054, Germany
| | - Tanveer Nasr
- Department of Psychiatry, Mayo Hospital, Lahore 54000, Pakistan Department of Psychiatry, Chaudhary Hospital, Gujranwala 52250, Pakistan
| | - Melissa T Carter
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, The Hospital for Sick Children, Toronto, Ontario, Canada M5G1X8
| | | | | | - Muhammad Ayub
- Lahore Institute of Research and Development, Lahore 51000, Pakistan Division of Developmental Disabilities, Department of Psychiatry, Queen's University, Kingston, Ontario, Canada K7L 3N6
| | - Peter John
- Atta-ur-Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), Islamabad 44000, Pakistan
| | - Megerditch Kiledjian
- Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, NJ 08854, USA
| | - John B Vincent
- Molecular Neuropsychiatry and Development Lab, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8 Department of Psychiatry and Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada M5S 2J7
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Szelinger S, Malenica I, Corneveaux JJ, Siniard AL, Kurdoglu AA, Ramsey KM, Schrauwen I, Trent JM, Narayanan V, Huentelman MJ, Craig DW. Characterization of X chromosome inactivation using integrated analysis of whole-exome and mRNA sequencing. PLoS One 2014; 9:e113036. [PMID: 25503791 PMCID: PMC4264736 DOI: 10.1371/journal.pone.0113036] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Accepted: 09/23/2014] [Indexed: 12/30/2022] Open
Abstract
In females, X chromosome inactivation (XCI) is an epigenetic, gene dosage compensatory mechanism by inactivation of one copy of X in cells. Random XCI of one of the parental chromosomes results in an approximately equal proportion of cells expressing alleles from either the maternally or paternally inherited active X, and is defined by the XCI ratio. Skewed XCI ratio is suggestive of non-random inactivation, which can play an important role in X-linked genetic conditions. Current methods rely on indirect, semi-quantitative DNA methylation-based assay to estimate XCI ratio. Here we report a direct approach to estimate XCI ratio by integrated, family-trio based whole-exome and mRNA sequencing using phase-by-transmission of alleles coupled with allele-specific expression analysis. We applied this method to in silico data and to a clinical patient with mild cognitive impairment but no clear diagnosis or understanding molecular mechanism underlying the phenotype. Simulation showed that phased and unphased heterozygous allele expression can be used to estimate XCI ratio. Segregation analysis of the patient's exome uncovered a de novo, interstitial, 1.7 Mb deletion on Xp22.31 that originated on the paternally inherited X and previously been associated with heterogeneous, neurological phenotype. Phased, allelic expression data suggested an 83∶20 moderately skewed XCI that favored the expression of the maternally inherited, cytogenetically normal X and suggested that the deleterious affect of the de novo event on the paternal copy may be offset by skewed XCI that favors expression of the wild-type X. This study shows the utility of integrated sequencing approach in XCI ratio estimation.
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Affiliation(s)
- Szabolcs Szelinger
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
- Molecular and Cellular Biology Interdisciplinary Graduate Program, College of Liberal Arts and Sciences, Arizona State University, Tempe, Arizona, United States of America
| | - Ivana Malenica
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Jason J. Corneveaux
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Ashley L. Siniard
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Ahmet A. Kurdoglu
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Keri M. Ramsey
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Isabelle Schrauwen
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
| | - Jeffrey M. Trent
- Genetic Basis of Human Disease Division, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Vinodh Narayanan
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
- Neurology Research, Barrow Neurological Institute, Phoenix, Arizona, United States of America
| | - Matthew J. Huentelman
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - David W. Craig
- Center for Rare Childhood Disorders, The Translational Genomics Research Institute, Phoenix, Arizona, United States of America
- * E-mail:
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24
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Pratto F, Brick K, Khil P, Smagulova F, Petukhova GV, Camerini-Otero RD. DNA recombination. Recombination initiation maps of individual human genomes. Science 2014; 346:1256442. [PMID: 25395542 DOI: 10.1126/science.1256442] [Citation(s) in RCA: 211] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
DNA double-strand breaks (DSBs) are introduced in meiosis to initiate recombination and generate crossovers, the reciprocal exchanges of genetic material between parental chromosomes. Here, we present high-resolution maps of meiotic DSBs in individual human genomes. Comparing DSB maps between individuals shows that along with DNA binding by PRDM9, additional factors may dictate the efficiency of DSB formation. We find evidence for both GC-biased gene conversion and mutagenesis around meiotic DSB hotspots, while frequent colocalization of DSB hotspots with chromosome rearrangement breakpoints implicates the aberrant repair of meiotic DSBs in genomic disorders. Furthermore, our data indicate that DSB frequency is a major determinant of crossover rate. These maps provide new insights into the regulation of meiotic recombination and the impact of meiotic recombination on genome function.
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Affiliation(s)
- Florencia Pratto
- National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Kevin Brick
- National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Pavel Khil
- National Institute of Diabetes, Digestive and Kidney Diseases, NIH, Bethesda, MD, USA
| | - Fatima Smagulova
- Department of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, USA
| | - Galina V Petukhova
- Department of Biochemistry and Molecular Biology, Uniformed Services University of Health Sciences, Bethesda, MD, USA.
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25
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Esplin ED, Li B, Slavotinek A, Novelli A, Battaglia A, Clark R, Curry C, Hudgins L. Nine patients with Xp22.31 microduplication, cognitive deficits, seizures, and talipes anomalies. Am J Med Genet A 2014; 164A:2097-103. [DOI: 10.1002/ajmg.a.36598] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2013] [Accepted: 04/13/2014] [Indexed: 12/13/2022]
Affiliation(s)
- Edward D. Esplin
- Division of Medical Genetics, Department of Pediatrics; Stanford University School of Medicine; Stanford California
| | - Ben Li
- Division of Medical Genetics, Department of Pediatrics; University of California San Francisco; San Francisco California
| | - Anne Slavotinek
- Division of Medical Genetics, Department of Pediatrics; University of California San Francisco; San Francisco California
| | - Antonio Novelli
- Mendel Laboratory, IRCCS Casa Sollievo della Sofferenza Hospital; San Giovanni Rotondo (FG) Italy
| | - Agatino Battaglia
- The Stella Maris Clinical Research Institute for Child and Adolescent Neurology and Psychiatry; Calambrone (Pisa) Italy
| | - Robin Clark
- Division of Medical Genetics, Department of Pediatrics; Loma Linda University; Loma Linda California
| | - Cynthia Curry
- Division of Medical Genetics, Department of Pediatrics; UCSF Fresno; Fresno California
| | - Louanne Hudgins
- Division of Medical Genetics, Department of Pediatrics; Stanford University School of Medicine; Stanford California
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26
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Watson CT, Marques-Bonet T, Sharp AJ, Mefford HC. The genetics of microdeletion and microduplication syndromes: an update. Annu Rev Genomics Hum Genet 2014; 15:215-244. [PMID: 24773319 DOI: 10.1146/annurev-genom-091212-153408] [Citation(s) in RCA: 115] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Chromosomal abnormalities, including microdeletions and microduplications, have long been associated with abnormal developmental outcomes. Early discoveries relied on a common clinical presentation and the ability to detect chromosomal abnormalities by standard karyotype analysis or specific assays such as fluorescence in situ hybridization. Over the past decade, the development of novel genomic technologies has allowed more comprehensive, unbiased discovery of microdeletions and microduplications throughout the human genome. The ability to quickly interrogate large cohorts using chromosome microarrays and, more recently, next-generation sequencing has led to the rapid discovery of novel microdeletions and microduplications associated with disease, including very rare but clinically significant rearrangements. In addition, the observation that some microdeletions are associated with risk for several neurodevelopmental disorders contributes to our understanding of shared genetic susceptibility for such disorders. Here, we review current knowledge of microdeletion/duplication syndromes, with a particular focus on recurrent rearrangement syndromes.
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Affiliation(s)
- Corey T Watson
- Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.,Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Tomas Marques-Bonet
- Institut de Biologia Evolutiva, Universitat Pompeu Fabra/CSIC, 08003 Barcelona, Spain.,Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Spain.,Centro Nacional de Análisis Genómico, 08023 Barcelona, Spain
| | - Andrew J Sharp
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029
| | - Heather C Mefford
- Department of Pediatrics, University of Washington, Seattle, Washington 98195
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27
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Hadziselimovic F, Hadziselimovic NO, Demougin P, Oakeley EJ. Decreased expression of genes associated with memory and x-linked mental retardation in boys with non-syndromic cryptorchidism and high infertility risk. Mol Syndromol 2014; 5:76-80. [PMID: 24715854 DOI: 10.1159/000357931] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/05/2013] [Indexed: 02/05/2023] Open
Abstract
An elevated odds ratio for low IQ has been found for cryptorchid boys. Furthermore, poor school performance has been observed in cryptorchid boys with impaired mini-puberty. Gene expression analysis, qPCR and immunohistology were performed on testicular biopsies from 7 boys who underwent orchiopexy and had testicular histology typical of a high risk of infertility (HIR). The results were compared with 12 biopsies from cryptorchid boys with a low risk for developing infertility. The following genes associated with mental retardation were identically expressed: GDI1, OPHN1, PAK3, ARHGEF6, IL1RAPL, ACSL4, MECP2, RPS6KA3, ARX, and ATRX. However, boys in the HIR group had low or no expression of EGR4, FMR2 (AFF2) and VCX3A. In conclusion, impaired expression of genes known to encode proteins involved in signaling pathways that regulate cytoskeletal organization, synaptic vesicle transport and the establishment of connections between neuronal cells may contribute to reduced intellectual and cognitive functioning in infertile cryptorchid males.
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Affiliation(s)
- F Hadziselimovic
- Institute of Andrology, Liestal, University of Basel, Basel, Switzerland
| | - N O Hadziselimovic
- Institute of Andrology, Liestal, University of Basel, Basel, Switzerland ; Division of Molecular Neuroscience, Department of Psychology, University of Basel, Basel, Switzerland
| | - P Demougin
- Department of Molecular Biology, Biozentrum, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - E J Oakeley
- Department of Molecular Biology, Novartis Institutes for Biomedical Research, Basel, Switzerland
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28
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Derlig K, Gießl A, Brandstätter JH, Enz R, Dahlhaus R. Identification and characterisation of Simiate, a novel protein linked to the fragile X syndrome. PLoS One 2013; 8:e83007. [PMID: 24349419 PMCID: PMC3859600 DOI: 10.1371/journal.pone.0083007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2013] [Accepted: 11/07/2013] [Indexed: 11/19/2022] Open
Abstract
A strict regulation of protein expression during developmental stages and in response to environmental signals is essential to every cell and organism. Recent research has shown that the mammalian brain is particularly sensitive to alterations in expression patterns of specific proteins and cognitive deficits as well as autistic behaviours have been linked to dysregulated protein expression. An intellectual disability characterised by changes in the expression of a variety of proteins is the fragile X syndrome. Due to the loss of a single mRNA binding protein, the Fragile X Mental Retardation Protein FMRP, vast misregulation of the mRNA metabolism is taking place in the disease. Here, we present the identification and characterisation of a novel protein named Simiate, whose mRNA contains several FMRP recognition motifs and associates with FMRP upon co-precipitation. Sequence analysis revealed that the protein evolved app. 1.7 billion years ago when eukaryotes developed. Applying antibodies generated against Simiate, the protein is detected in a variety of tissues, including the mammalian brain. On the subcellular level, Simiate localises to somata and nuclear speckles. We show that Simiate and nuclear speckles experience specific alterations in FMR1(-/-) mice. An antibody-based block of endogenous Simiate revealed that the protein is essential for cell survival. These findings suggest not only an important role for Simiate in gene transcription and/or RNA splicing, but also provide evidence for a function of nuclear speckles in the fragile X syndrome. Indeed, transcription and splicing are two fundamental mechanisms to control protein expression, that underlie not only synaptic plasticity and memory formation, but are also affected in several diseases associated with mental disabilities.
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Affiliation(s)
- Kristin Derlig
- Institute for Biochemistry, Emil-Fischer Centre, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Andreas Gießl
- Department of Biology, Animal Physiology, University of Erlangen- Nuremberg, Erlangen, Germany
| | | | - Ralf Enz
- Institute for Biochemistry, Emil-Fischer Centre, University of Erlangen-Nuremberg, Erlangen, Germany
| | - Regina Dahlhaus
- Institute for Biochemistry, Emil-Fischer Centre, University of Erlangen-Nuremberg, Erlangen, Germany
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29
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Xp22.3 interstitial deletion: A recognizable chromosomal abnormality encompassing VCX3A and STS genes in a patient with X-linked ichthyosis and mental retardation. Gene 2013; 527:578-83. [DOI: 10.1016/j.gene.2013.06.018] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2012] [Revised: 06/06/2013] [Accepted: 06/07/2013] [Indexed: 12/18/2022]
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30
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Isidor B, Lefebvre T, Barbarot S, Perrier J, Mercier S, Péréon Y, Le Caignec C, David A. Palmo-Plantar hyperkeratosis, intellectual disability, and spastic paraplegia in two maternal half brothers: Further evidence for an X-linked inheritance. Am J Med Genet A 2013; 161A:1390-3. [DOI: 10.1002/ajmg.a.35871] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2012] [Accepted: 12/23/2012] [Indexed: 11/10/2022]
Affiliation(s)
| | | | | | | | - Sandra Mercier
- CHU Nantes, Service de Génétique Médicale; Nantes; France
| | | | | | - Albert David
- CHU Nantes, Service de Génétique Médicale; Nantes; France
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31
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Trent S, Davies W. Cognitive, behavioural and psychiatric phenotypes associated with steroid sulfatase deficiency. World J Transl Med 2013; 2:1-12. [DOI: 10.5528/wjtm.v2.i1.1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 01/24/2013] [Accepted: 02/08/2013] [Indexed: 02/05/2023] Open
Abstract
The enzyme steroid sulfatase (STS) desulfates a variety of steroid compounds thereby altering their activity. STS is expressed in the skin, and its deficiency in this tissue has been linked to the dermatological condition X-linked ichthyosis. STS is also highly expressed in the developing and adult human brain, and in a variety of steroidogenic organs (including the placenta and gonads); therefore it has the potential to influence brain development and function directly and/or indirectly (through influencing the hormonal milieu). In this review, we first discuss evidence from human and animal model studies suggesting that STS deficiency might predispose to neurobehavioural abnormalities and certain psychiatric disorders. We subsequently discuss potential mechanisms that may underlie these vulnerabilities. The data described herein have potential implications for understanding the complete spectrum of clinical phenotypes associated with X-linked ichthyosis, and may indicate novel pathogenic mechanisms underlying psychological dysfunction in developmental disorders such as attention deficit hyperactivity disorder and Turner syndrome.
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32
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Zarate YA, Dwivedi A, Bartel FO, Bellomo MA, Cathey SS, Champaigne NL, Clarkson LK, Dupont BR, Everman DB, Geer JS, Gordon BC, Lichty AW, Lyons MJ, Rogers RC, Saul RA, Schroer RJ, Skinner SA, Stevenson RE. Clinical utility of the X-chromosome array. Am J Med Genet A 2012. [PMID: 23208842 DOI: 10.1002/ajmg.a.35698] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
Previous studies have limited the use of specific X-chromosome array designed platforms to the evaluation of patients with intellectual disability. In this retrospective analysis, we reviewed the clinical utility of an X-chromosome array in a variety of scenarios. We divided patients according to the indication for the test into four defined categories: (1) autism spectrum disorders and/or developmental delay and/or intellectual disability (ASDs/DD/ID) with known family history of neurocognitive disorders; (2) ASDs/DD/ID without known family history of neurocognitive disorders; (3) breakpoint definition of an abnormality detected by a different cytogenetic test; and (4) evaluation of suspected or known X-linked conditions. A total of 59 studies were ordered with 27 copy number variants detected in 25 patients (25/59 = 42%). The findings were deemed pathogenic/likely pathogenic (16/59 = 27%), benign (4/59 = 7%) or uncertain (7/59 = 12%). We place particular emphasis on the utility of this test for the diagnostic evaluation of families affected with X-linked conditions and how it compares to whole genome arrays in this setting. In conclusion, the X-chromosome array frequently detects genomic alterations of the X chromosome and it has advantages when evaluating some specific X-linked conditions. However, careful interpretation and correlation with clinical findings is needed to determine the significance of such changes. When the X-chromosome array was used to confirm a suspected X-linked condition, it had a yield of 63% (12/19) and was useful in the evaluation and risk assessment of patients and families.
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33
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Stouffs K, Lissens W. X chromosomal mutations and spermatogenic failure. Biochim Biophys Acta Mol Basis Dis 2012; 1822:1864-72. [DOI: 10.1016/j.bbadis.2012.05.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2011] [Revised: 02/24/2012] [Accepted: 05/14/2012] [Indexed: 01/11/2023]
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34
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Willemsen MH, de Leeuw N, de Brouwer AP, Pfundt R, Hehir-Kwa JY, Yntema HG, Nillesen WM, de Vries BB, van Bokhoven H, Kleefstra T. Interpretation of clinical relevance of X-chromosome copy number variations identified in a large cohort of individuals with cognitive disorders and/or congenital anomalies. Eur J Med Genet 2012; 55:586-98. [DOI: 10.1016/j.ejmg.2012.05.001] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2012] [Revised: 05/05/2012] [Accepted: 05/05/2012] [Indexed: 01/01/2023]
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35
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Katsura Y, Iwase M, Satta Y. Evolution of genomic structures on Mammalian sex chromosomes. Curr Genomics 2012; 13:115-23. [PMID: 23024603 PMCID: PMC3308322 DOI: 10.2174/138920212799860625] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2011] [Revised: 09/13/2011] [Accepted: 10/19/2011] [Indexed: 11/22/2022] Open
Abstract
Throughout mammalian evolution, recombination between the two sex chromosomes was suppressed in a stepwise manner. It is thought that the suppression of recombination led to an accumulation of deleterious mutations and frequent genomic rearrangements on the Y chromosome. In this article, we review three evolutionary aspects related to genomic rearrangements and structures, such as inverted repeats (IRs) and palindromes (PDs), on the mammalian sex chromosomes. First, we describe the stepwise manner in which recombination between the X and Y chromosomes was suppressed in placental mammals and discuss a genomic rearrangement that might have led to the formation of present pseudoautosomal boundaries (PAB). Second, we describe ectopic gene conversion between the X and Y chromosomes, and propose possible molecular causes. Third, we focus on the evolutionary mode and timing of PD formation on the X and Y chromosomes. The sequence of the chimpanzee Y chromosome was recently published by two groups. Both groups suggest that rapid evolution of genomic structure occurred on the Y chromosome. Our re-analysis of the sequences confirmed the species-specific mode of human and chimpanzee Y chromosomal evolution. Finally, we present a general outlook regarding the rapid evolution of mammalian sex chromosomes.
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Affiliation(s)
- Yukako Katsura
- Department of Evolutionary Studies of Biosystems, The Graduate University for Advanced Studies, Hayama, Kanagawa 240-0193, Japan
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36
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Hoppe T, Winge M, Bradley M, Nordenskjöld M, Vahlquist A, Berne B, Törmä H. X-linked recessive ichthyosis: an impaired barrier function evokes limited gene responses before and after moisturizing treatments. Br J Dermatol 2012; 167:514-22. [DOI: 10.1111/j.1365-2133.2012.10979.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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37
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Sporadic male patients with intellectual disability: contribution of X-chromosome copy number variants. Eur J Med Genet 2012; 55:577-85. [PMID: 22659343 DOI: 10.1016/j.ejmg.2012.05.005] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Revised: 05/19/2012] [Accepted: 05/20/2012] [Indexed: 12/18/2022]
Abstract
Genome-wide array comparative genome hybridization has become the first in line diagnostic tool in the clinical work-up of patients presenting with intellectual disability. As a result, chromosome X-copy number variations are frequently being detected in routine diagnostics. We retrospectively reviewed genome wide array-CGH data in order to determine the frequency and nature of chromosome X-copy number variations (X-CNV) in a cohort of 2222 sporadic male patients with intellectual disability (ID) referred to us for diagnosis. In this cohort, 68 males were found to have at least one X-CNV (3.1%). However, correct interpretation of causality remains a challenging task, and is essential for proper counseling, especially when the CNV is inherited. On the basis of these data, earlier experience and literature data we designed and propose an algorithm that can be used to evaluate the clinical relevance of X-CNVs detected in sporadic male ID patients. Applied to our cohort, 19 male ID patients (0.85%) were found to carry a (likely) pathogenic X-CNV.
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38
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Mechanisms for recurrent and complex human genomic rearrangements. Curr Opin Genet Dev 2012; 22:211-20. [PMID: 22440479 DOI: 10.1016/j.gde.2012.02.012] [Citation(s) in RCA: 256] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2011] [Revised: 02/20/2012] [Accepted: 02/21/2012] [Indexed: 01/07/2023]
Abstract
During the last two decades, the importance of human genome copy number variation (CNV) in disease has become widely recognized. However, much is not understood about underlying mechanisms. We show how, although model organism research guides molecular understanding, important insights are gained from study of the wealth of information available in the clinic. We describe progress in explaining nonallelic homologous recombination (NAHR), a major cause of copy number change occurring when control of allelic recombination fails, highlight the growing importance of replicative mechanisms to explain complex events, and describe progress in understanding extreme chromosome reorganization (chromothripsis). Both nonhomologous end-joining and aberrant replication have significant roles in chromothripsis. As we study CNV, the processes underlying human genome evolution are revealed.
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39
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Bardoni B, Abekhoukh S, Zongaro S, Melko M. Intellectual disabilities, neuronal posttranscriptional RNA metabolism, and RNA-binding proteins: three actors for a complex scenario. PROGRESS IN BRAIN RESEARCH 2012; 197:29-51. [PMID: 22541287 DOI: 10.1016/b978-0-444-54299-1.00003-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intellectual disability (ID) is the most frequent cause of serious handicap in children and young adults and interests 2-3% of worldwide population, representing a serious problem from the medical, social, and economic points of view. The causes are very heterogeneous. Genes involved in ID have various functions altering different pathways important in neuronal function. Regulation of mRNA metabolism is particularly important in neurons for synaptic structure and function. Here, we review ID due to alteration of mRNA metabolism. Functional absence of some RNA-binding proteins--namely, FMRP, FMR2P, PQBP1, UFP3B, VCX-A--causes different forms of ID. These proteins are involved in different steps of RNA metabolism and, even if a detailed analysis of their RNA targets has been performed so far only for FMRP, it appears clear that they modulate some aspects (translation, stability, transport, and sublocalization) of a subset of RNAs coding for proteins, whose function must be relevant for neurons. Two other proteins, DYRK1A and CDKL5, involved in Down syndrome and Rett syndrome, respectively, have been shown to have an impact on splicing efficiency of specific mRNAs. Both proteins are kinases and their effect is indirect. Interestingly, both are localized in nuclear speckles, the nuclear domains where splicing factors are assembled, stocked, and recycled and influence their biogenesis and/or their organization.
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Affiliation(s)
- Barbara Bardoni
- Institute of Molecular and Cellular Pharmacology, CNRS-UMR6097, Université de Nice Sophia-Antipolis,Valbonne, France.
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Giorda R, Beri S, Bonaglia MC, Spaccini L, Scelsa B, Manolakos E, Della Mina E, Ciccone R, Zuffardi O. Common structural features characterize interstitial intrachromosomal Xp and 18q triplications. Am J Med Genet A 2011; 155A:2681-7. [PMID: 21965167 DOI: 10.1002/ajmg.a.34248] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2011] [Accepted: 06/18/2011] [Indexed: 11/07/2022]
Abstract
Rare intrachromosomal triplications producing partial tetrasomies have been reported for a number of chromosomes. A detailed molecular characterization, necessary to define the mechanism of their formation, has so far been lacking. We report on the detailed clinical, cytogenetic, and molecular characterization of two triplications, one de novo involving chromosome 18q, the other familial on chromosome Xp. The clinical phenotype of the patient with 18q triplication, very likely due to overexpression of one or more of the genes in the region, consists mainly of facial dysmorphisms and developmental delay. The familial Xp triplication does not cause an increase in the number of copies of any gene and is almost certainly a polymorphism. The rearrangements are actually complex duplications/triplications. In both patients, their proximal breakpoints are located within complex segmental duplications, one containing the VCX gene cluster on chromosome Xp, the other the TCEB3 genes on chromosome 18q. A proximal duplicated region is also present in both patients. All junctions we analyzed were formed by non-homologous end joining (NHEJ). The structural features shared between our patients suggest the involvement of a common mechanism in the genesis of interstitial intrachromosomal triplications.
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Affiliation(s)
- Roberto Giorda
- Istituto Scientifico E. Medea, Bosisio Parini (LC), Italy.
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Park SJ, Jung EH, Ryu RS, Kang HW, Ko JM, Kim HJ, Cheon CK, Hwang SH, Kang HY. Clinical implementation of whole-genome array CGH as a first-tier test in 5080 pre and postnatal cases. Mol Cytogenet 2011; 4:12. [PMID: 21549014 PMCID: PMC3114015 DOI: 10.1186/1755-8166-4-12] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2011] [Accepted: 05/09/2011] [Indexed: 01/08/2023] Open
Abstract
Background Array comparative genomic hybridization (CGH) is currently the most powerful method for detecting chromosomal alterations in pre and postnatal clinical cases. In this study, we developed a BAC based array CGH analysis platform for detecting whole genome DNA copy number changes including specific micro deletion and duplication chromosomal disorders. Additionally, we report our experience with the clinical implementation of our array CGH analysis platform. Array CGH was performed on 5080 pre and postnatal clinical samples from patients referred with a variety of clinical phenotypes. Results A total of 4073 prenatal cases (4033 amniotic fluid and 40 chorionic villi specimens) and 1007 postnatal cases (407 peripheral blood and 600 cord blood) were studied with complete concordance between array CGH, karyotype and fluorescence in situ hybridization results. Among 75 positive prenatal cases with DNA copy number variations, 60 had an aneuploidy, seven had a deletion, and eight had a duplication. Among 39 positive postnatal cases samples, five had an aneuploidy, 23 had a deletion, and 11 had a duplication. Conclusions This study demonstrates the utility of using our newly developed whole-genome array CGH as first-tier test in 5080 pre and postnatal cases. Array CGH has increased the ability to detect segmental deletion and duplication in patients with variable clinical features and is becoming a more powerful tool in pre and postnatal diagnostics.
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Affiliation(s)
| | | | | | | | - Jung-Min Ko
- Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea
| | - Hyon J Kim
- Department of Medical Genetics, Ajou University School of Medicine, Suwon, Korea
| | - Chong Kun Cheon
- Department of Pediatrics, School of Medicine, Pusan National University Children's Hospital, Yangsan, Korea
| | - Sang-Hyun Hwang
- Department of Laboratory Medicine, Center for Diagnostic Oncology, National Cancer Center, Gyeonggi-do, Korea
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Gijsbers ACJ, den Hollander NS, Helderman-van de Enden ATJM, Schuurs-Hoeijmakers JHM, Vijfhuizen L, Bijlsma EK, van Haeringen A, Hansson KBM, Bakker E, Breuning MH, Ruivenkamp CAL. X-chromosome duplications in males with mental retardation: pathogenic or benign variants? Clin Genet 2011; 79:71-8. [PMID: 20486941 DOI: 10.1111/j.1399-0004.2010.01438.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Studies to identify copy number variants (CNVs) on the X-chromosome have revealed novel genes important in the causation of X-linked mental retardation (XLMR). Still, for many CNVs it is unclear whether they are associated with disease or are benign variants. We describe six different CNVs on the X-chromosome in five male patients with mental retardation that were identified by conventional karyotyping and single nucleotide polymorphism array analysis. One deletion and five duplications ranging in size from 325 kb to 12.5 Mb were observed. Five CNVs were maternally inherited and one occurred de novo. We discuss the involvement of potential candidate genes and focus on the complexity of X-chromosomal duplications in males inherited from healthy mothers with different X-inactivation patterns. Based on size and/or the presence of XLMR genes we were able to classify CNVs as pathogenic in two patients. However, it remains difficult to decide if the CNVs in the other three patients are pathogenic or benign.
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Affiliation(s)
- A C J Gijsbers
- Center for Human and Clinical Genetics, Leiden University Medical Center (LUMC), Einthovenweg 20, Leiden, The Netherlands.
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Yuan ZQ, Zhao BS, Zhang JY. Expression patterns of the STAG gene in intact and regenerating planarians (Dugesia japonica). GENETICS AND MOLECULAR RESEARCH 2011; 10:410-8. [PMID: 21425091 DOI: 10.4238/vol10-1gmr1042] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
We examined the spatial and temporal expression of the planarian Dugesia japonica STAG-related gene (DjStag), in both intact and regenerating planarians, by whole-mount in situ hybridization and relative quantitative real-time PCR. The first localized transcripts of DjStag were detected in the blastemas three days after amputation, in all regenerates including those from head, tail and trunk pieces. The maximum level of expression of DjStag transcripts occurred at five days after cutting. After regeneration for seven days, DjStag was weakly expressed. A similar decrease occurs regardless of the orientation of the cut. The expression pattern did not differ significantly in the different types of regeneration. Relative quantitative real-time PCR analysis of DjStag mRNA indicated that the expression of DjStag mRNA was increased after amputation compared to that in normal intact planarians, and the maximum level of expression of DjStag transcripts occurred at five days after amputation. All results suggest that DjStag, implicated in planarian regeneration, plays a role in maintaining the ability of pluripotent stem cells to regenerate lost tissue in planarians.
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Affiliation(s)
- Z Q Yuan
- Laboratory of Developmental and Evolutionary Biology, School of Life Sciences, Shandong University of Technology, Zibo, PR China
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Liu P, Erez A, Nagamani SCS, Bi W, Carvalho CMB, Simmons AD, Wiszniewska J, Fang P, Eng PA, Cooper ML, Sutton VR, Roeder ER, Bodensteiner JB, Delgado MR, Prakash SK, Belmont JW, Stankiewicz P, Berg JS, Shinawi M, Patel A, Cheung SW, Lupski JR. Copy number gain at Xp22.31 includes complex duplication rearrangements and recurrent triplications. Hum Mol Genet 2011; 20:1975-88. [PMID: 21355048 DOI: 10.1093/hmg/ddr078] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Genomic instability is a feature of the human Xp22.31 region wherein deletions are associated with X-linked ichthyosis, mental retardation and attention deficit hyperactivity disorder. A putative homologous recombination hotspot motif is enriched in low copy repeats that mediate recurrent deletion at this locus. To date, few efforts have focused on copy number gain at Xp22.31. However, clinical testing revealed a high incidence of duplication of Xp22.31 in subjects ascertained and referred with neurobehavioral phenotypes. We systematically studied 61 unrelated subjects with rearrangements revealing gain in copy number, using multiple molecular assays. We detected not only the anticipated recurrent and simple nonrecurrent duplications, but also unexpectedly identified recurrent triplications and other complex rearrangements. Breakpoint analyses enabled us to surmise the mechanisms for many of these rearrangements. The clinical significance of the recurrent duplications and triplications were assessed using different approaches. We cannot find any evidence to support pathogenicity of the Xp22.31 duplication. However, our data suggest that the Xp22.31 duplication may serve as a risk factor for abnormal phenotypes. Our findings highlight the need for more robust Xp22.31 triplication detection in that such further gain may be more penetrant than the duplications. Our findings reveal the distribution of different mechanisms for genomic duplication rearrangements at a given locus, and provide insights into aspects of strand exchange events between paralogous sequences in the human genome.
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Affiliation(s)
- Pengfei Liu
- Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Room 604B, Houston, TX 77030, USA
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Cañueto J, Ciria S, Hernández-Martín A, Unamuno P, González-Sarmiento R. Analysis of the STS gene in 40 patients with recessive X-linked ichthyosis: a high frequency of partial deletions in a Spanish population. J Eur Acad Dermatol Venereol 2011; 24:1226-9. [PMID: 20236202 DOI: 10.1111/j.1468-3083.2010.03612.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND Recessive X-linked ichthyosis (RXLI) (OMIM 308100) is a genodermatosis characterized by polygonal, dark, adherent and mild-to-moderate scales that normally improve during summer. RXLI is caused by a deficiency in steroid sulphatase (STS), whose gene has been located on the X chromosome (locus Xp22.3). Up to 90% of the mutations described in this gene are complete deletions. OBJECTIVES Previous reports of partial deletion of STS gene in cases of RXLI prompted us to determine the incidence of these abnormalities in a Spanish population. METHODS We have studied exons 1, 5 and 10 of the STS gene by polymerase chain reaction in 40 patients with clinical features of RXLI. RESULTS Our results revealed that 30 patients presented complete deletions (75%) while 10 patients had partial deletions (25%) a rate higher than that reported in the previous studies. CONCLUSIONS Amplification of exons 1, 5 and 10 is reliable in screening RXLI in the population studied here. No correlation was found between phenotype and the extent of the deletions.
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Affiliation(s)
- J Cañueto
- Department of Dermatology, University Hospital of Salamanca, Salamanca, Spain
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Mitochondrial dysfunction and organic aciduria in five patients carrying mutations in the Ras-MAPK pathway. Eur J Hum Genet 2010; 19:138-44. [PMID: 21063443 DOI: 10.1038/ejhg.2010.171] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Various syndromes of the Ras-mitogen-activated protein kinase (MAPK) pathway, including the Noonan, Cardio-Facio-Cutaneous, LEOPARD and Costello syndromes, share the common features of craniofacial dysmorphisms, heart defect and short stature. In a subgroup of patients, severe muscle hypotonia, central nervous system involvement and failure to thrive occur as well. In this study we report on five children diagnosed initially with classic metabolic and clinical symptoms of an oxidative phosphorylation disorder. Later in the course of the disease, the children presented with characteristic features of Ras-MAPK pathway-related syndromes, leading to the reevaluation of the initial diagnosis. In the five patients, in addition to the oxidative phosphorylation disorder, disease-causing mutations were detected in the Ras-MAPK pathway. Three of the patients also carried a second, mitochondrial genetic alteration, which was asymptomatically present in their healthy relatives. Did we miss the correct diagnosis in the first place or is mitochondrial dysfunction directly related to Ras-MAPK pathway defects? The Ras-MAPK pathway is known to have various targets, including proteins in the mitochondrial membrane influencing mitochondrial morphology and dynamics. Prospective screening of 18 patients with various Ras-MAPK pathway defects detected biochemical signs of disturbed oxidative phosphorylation in three additional children. We concluded that only a specific, metabolically vulnerable sub-population of patients with Ras-MAPK pathway mutations presents with mitochondrial dysfunction and a more severe, early-onset disease. We postulate that patients with Ras-MAPK mutations have an increased susceptibility, but a second metabolic hit is needed to cause the clinical manifestation of mitochondrial dysfunction.
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Abstract
Intellectual disability (ID) is the leading socio-economic problem of health care, but compared to autism and schizophrenia, it has received very little public attention. Important risk factors for ID are malnutrition, cultural deprivation, poor health care, and parental consanguinity. In the Western world, fetal alcohol exposure is the most common preventable cause. Most severe forms of ID have genetic causes. Cytogenetically detectable and submicroscopic chromosomal rearrangements account for approximately 25% of all cases. X-linked gene defects are responsible in 10-12% of males with ID; to date, 91 of these defects have been identified. In contrast, autosomal gene defects have been largely disregarded, but due to coordinated efforts and the advent of next-generation DNA sequencing, this is about to change. As shown for Fra(X) syndrome, this renewed focus on autosomal gene defects will pave the way for molecular diagnosis and prevention, shed more light on the pathogenesis of ID, and reveal new opportunities for therapy.
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Bukvic N, Carri VD, Di Cosola ML, Pustorino G, Cesarano C, Chetta M, Santacroce R, Sarno M, Sessa F, Longo V, Novelli A, Gentile M, Margaglione M. Familial X;Y translocation with distinct phenotypic consequences: Characterization using FISH and array CGH. Am J Med Genet A 2010; 152A:1730-4. [PMID: 20578256 DOI: 10.1002/ajmg.a.33437] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
X;Y translocation is a relatively rare event in humans. Analyzed cytogenetically, the majority of these aberrations have breakpoints at Xp22 and Yq11. Females with t(X;Y)(p22;q11) are phenotypically normal except for short stature, while the males may have abnormalities. Aberrations that lead to nullisomy of the deleted region and complete loss of the respective genes have been recognized as a cause of variable contiguous gene syndromes in males. The phenotype depends on the extent and position of the deletion showing the variable association of apparently unrelated clinical manifestations such as ichthyosis, chondrodysplasia punctata, hypogonadotropic hypogonadism with anosmia, ocular albinism, short stature, and mental retardation. In addition, some patients have been reported with symptoms of attention deficit hyperactivity disorder. The extent of terminal Xp deletions is limited by the presence of male lethal genes in Xp22.2 at about 10-11 Mb from the telomere. The deletions in the majority of viable reported male patients extend to the STS ( approximately 7.0 Mb) or to the KAL1 ( approximately 8.5 Mb) loci. We present a clinical, cytogenetic, FISH, and array CGH study of a family with an Xp;Yq translocation. The chromosomal status is also discussed in the light of their phenotypic traits. The final karyotypes of the patients were designated as: Patient 1: 46,Y,der(X),t(X;Y)(p22;q12).ish der(X)(Xpter-,DXZ1+,Xqter+)mat.arr cgh Xp22.31p22.33(RP11-60P14 --> RP13-391G2)x0;arr cgh Yq11.221qter (RP11-235I1 --> RP11-270H4)x2.Patient 2: 46,X,der(X),t(X;Y)(p22;q12).ish der(X)(Xpter-,DXZ1+,Xqter+)mat.arr cgh Xp22.31p22.33(RP11-60P14 --> RP13-391G2)x1;arr cgh Yq11.221qter (RP11-235I1 --> RP11-270H4)x1.
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Affiliation(s)
- N Bukvic
- Genetica Medica, Dipartimento di Scienze Biomediche, Università degli Studi di Foggia, Foggia, Italy.
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Ling SHM, Qamra R, Song H. Structural and functional insights into eukaryotic mRNA decapping. WILEY INTERDISCIPLINARY REVIEWS-RNA 2010; 2:193-208. [PMID: 21957006 DOI: 10.1002/wrna.44] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The control of messenger RNA (mRNA) translation and degradation is important in regulation of eukaryotic gene expression. In the general and specialized mRNA decay pathways which involve 5(') →3(') decay, decapping is the central step because it is the controlling gate preceding the actual degradation of mRNA and is a site of numerous control inputs. Removal of the cap structure is catalyzed by a decapping holoenzyme composed of the catalytic Dcp2 subunit and the coactivator Dcp1. Decapping is regulated by decapping activators and inhibitors. Recent structural and kinetics studies indicated that Dcp1 and the substrate RNA promote the closed form of the enzyme and the catalytic step of decapping is rate limiting and accelerated by Dcp1. The conformational change between the open and closed decapping enzyme is important for controlling decapping, and regulation of this transition has been proposed to be a checkpoint for determining the fate of mRNAs. Here we summarize the past and recent advances on the structural and functional studies of protein factors involved in regulating mRNA decapping.
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Affiliation(s)
- Sharon H M Ling
- Laboratory of Macromolecular Structure, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673
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Vazna A, Musova Z, Vlckova M, Novotna D, Dvorakova L, Hrdlicka M, Havlovicova M, Sedlacek Z. FMR1 gene expansion, large deletion of Xp, and skewed X-inactivation in a girl with mental retardation and autism. Am J Med Genet A 2010; 152A:1273-7. [PMID: 20425835 DOI: 10.1002/ajmg.a.33352] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
We describe a girl with mild facial anomalies, mild mental retardation, and atypical autism with a remarkable behavioral phenotype of persistent anger, aggression, and dysphoria. The occurrence of late-onset tremor and premature ovarian failure in the maternal branch of the family pointed to a possible defect in the FMR1 gene. Indeed, the patient carried a full FMR1 mutation. Unexpectedly, both alleles of the gene were almost completely methylated. Cytogenetic examination of the patient revealed in addition a large de novo deletion in band Xp22 on one of her X chromosomes. The deletion was fine mapped using oligonucleotide array CGH, and its breakpoints were localized using sequencing. The size of the deletion was about 17.4 Mb, and it contained more than 90 protein-coding genes. Microsatellite analysis indicated paternal origin of the aberrant chromosome. The large rearrangement was the most probable cause of the X-inactivation skewing, thus explaining the methylation of not only the expanded (maternal) but also the normal (paternal) FMR1 alleles. This pattern of skewed X-inactivation was confirmed using the analysis of methylation at the AR locus. The relatively mild phenotype of the patient resulted most likely from unmasking of the FMR1 defect. Although the deleted region contained many important genes, the phenotypic contribution of the rearranged X chromosome was probably limited by its almost complete inactivation. However, reduced dose of several genes escaping X-inactivation might also play a role in the phenotype of the patient.
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Affiliation(s)
- Alzbeta Vazna
- Department of Biology and Medical Genetics, Charles University, 2nd Faculty of Medicine and University Hospital Motol, Prague, Czech Republic
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