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Treccani M, Maggioni L, Di Giovanni C, Veschetti L, Cristofalo D, Patuzzo C, Lasalvia A, Ristic B, Kumar R, The PICOS-Veneto Group, Ruggeri M, Bonetto C, Malerba G, Tosato S. A Genome-Wide Association Study of First-Episode Psychosis: A Genetic Exploration in an Italian Cohort. Genes (Basel) 2025; 16:439. [PMID: 40282399 PMCID: PMC12026730 DOI: 10.3390/genes16040439] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2025] [Revised: 03/29/2025] [Accepted: 04/03/2025] [Indexed: 04/29/2025] Open
Abstract
BACKGROUND Psychosis, particularly schizophrenia (SZ), is influenced by genetic and environmental factors. The neurodevelopmental hypothesis suggests that genetic factors affect neuronal circuit connectivity during perinatal periods, hence causing the onset of the diseases. In this study, we performed a genome-wide association study (GWAS) in a sample of the first episode of psychosis (FEP). METHODS A sample of 147 individuals diagnosed with non-affective psychosis and 102 controls were recruited and assessed. After venous blood and DNA extraction, the samples were genotyped. Genetic data underwent quality controls, genotype imputation, and a case-control genome-wide association study (GWAS). After the GWAS, results were investigated using an in silico functional mapping and annotation approach. RESULTS Our GWAS showed the association of 27 variants across 13 chromosomes at genome-wide significance (p < 1 × 10-7) and a total of 1976 candidate variants across 188 genes at suggestive significance (p < 1 × 10-5), mostly mapping in non-coding or intergenic regions. Gene-based tests reported the association of the SUFU (p = 4.8 × 10-7) and NCAN (p = 1.6 × 10-5) genes. Gene-sets enrichment analyses showed associations in the early stages of life, spanning from 12 to 24 post-conception weeks (p < 1.4 × 10-3) and in the late prenatal period (p = 1.4 × 10-3), in favor of the neurodevelopmental hypothesis. Moreover, several matches with the GWAS Catalog reported associations with strictly related traits, such as SZ, as well as with autism spectrum disorder, which shares some genetic overlap, and risk factors, such as neuroticism and alcohol dependence. CONCLUSIONS The resulting genetic associations and the consequent functional analysis displayed common genetic liability between the non-affective psychosis, related traits, and risk factors. In sum, our investigation provided novel hints supporting the neurodevelopmental hypothesis in SZ and-in general-in non-affective psychoses.
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Affiliation(s)
- Mirko Treccani
- GM Lab, Department of Surgical Sciences, Dentistry, Gynaecology and Paediatrics, University of Verona, 37134 Verona, Italy; (M.T.); (G.M.)
| | - Lucia Maggioni
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
| | - Claudia Di Giovanni
- Department of Diagnostic and Public Health, University of Verona, 37134 Verona, Italy;
| | - Laura Veschetti
- Infections and Cystic Fibrosis Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, 20123 Milano, Italy;
- Vita-Salute San Raffaele University, 20123 Milano, Italy
| | - Doriana Cristofalo
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
| | - Cristina Patuzzo
- Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy;
| | - Antonio Lasalvia
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
| | - Branko Ristic
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
| | - Roushan Kumar
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
| | | | - Mirella Ruggeri
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
| | - Chiara Bonetto
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
| | - Giovanni Malerba
- GM Lab, Department of Surgical Sciences, Dentistry, Gynaecology and Paediatrics, University of Verona, 37134 Verona, Italy; (M.T.); (G.M.)
| | - Sarah Tosato
- Department of Neuroscience, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, 37134 Verona, Italy; (L.M.); (D.C.); (A.L.); (B.R.); (R.K.); (M.R.); (C.B.)
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Esmaeilzadeh E, Biglari S, Mosallaei M, Khorshid HRK, Vahidnezhad H, Tabatabaiefar MA. A Novel Homozygote Pathogenic Variant in the DIAPH1 Gene Associated With Seizures, Cortical Blindness, and Microcephaly Syndrome (SCBMS): Report of a Family and Literature Review. Mol Genet Genomic Med 2024; 12:e70031. [PMID: 39578953 PMCID: PMC11584415 DOI: 10.1002/mgg3.70031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2024] [Revised: 09/16/2024] [Accepted: 10/18/2024] [Indexed: 11/24/2024] Open
Abstract
OBJECTIVE Mammalian Diaphanous-Related Formin (mDia1), which is encoded by the DIAPH1 gene, serves as essential for the regulation of cell morphology and cytoskeletal organization. The role of DIAPH1 in brain development has been extensively established. This study aims to evaluate the clinical, neuroradiological, and genetic characteristics of patients with DIAPH1-related disease and determine probable genotype-phenotype relationships. METHODS In the current study, exome sequencing was performed to identify the genetic basis of the clinical presentation in an Iranian 7-year-old boy. Validation of the detected variant was done by Sanger sequencing. Furthermore, we performed a comprehensive review of the literature. RESULTS Here, we detected a novel homozygous c.1285C> T (p.Gln429*) pathogenic variant in the patient. In silico analysis with prediction software tools identified this variant as a probable source of damage. Twenty cases from seven studies were found after a review of the literature. The patients' main symptoms were a developmental delay, microcephaly, and seizures. The mean age of onset for patients in the group of 20 patients with a known age of onset was 2.3 months (SD = 1.6). Of the variants identified, c.2769del, c.684+1G>A, and c.2332C> T were identified in 72% of the patients. CONCLUSION Considering the variant's position in the gene and the encoding protein, a pathogenic effect is predicted for the variant. So, the patient's clinical manifestation is probably caused by this pathogenic variant. Moreover, by studying clinical manifestations in all molecularly confirmed reported cases, provided a comprehensive overview of clinical presentation, and attempted to find a genotype-phenotype correlation.
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Affiliation(s)
| | - Sajjad Biglari
- Department of Genetics and Molecular Biology, School of MedicineIsfahan University of Medical SciencesIsfahanIran
- Center for Applied GenomicsChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
- Department of Pediatrics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Meysam Mosallaei
- Fetal Health Research CenterHope Generation FoundationTehranIran
| | | | - Hassan Vahidnezhad
- Center for Applied GenomicsChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
- Department of Pediatrics, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Division of Human GeneticsChildren's Hospital of PhiladelphiaPhiladelphiaPennsylvaniaUSA
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of MedicineIsfahan University of Medical SciencesIsfahanIran
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3
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Dutta AK. Variable expressivity of Malan syndrome. BMJ Case Rep 2024; 17:e260787. [PMID: 39419602 DOI: 10.1136/bcr-2024-260787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024] Open
Abstract
We describe the family of a patient with developmental delay, macrocephaly, dysmorphic facial features and autism. His mother also shared similar facial features and macrocephaly but not his neurobehavioural issues. Subsequently, both the child and his mother were found to have a heterozygous frameshift variant NFIX: c.34_41dupGGGATACC. The child and his mother had many features consistent with a genetic diagnosis of Malan syndrome. Therefore, this family highlighted the variable expressivity of Malan syndrome.
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Affiliation(s)
- Atanu Kumar Dutta
- Biochemistry, All India Institute of Medical Sciences, Kalyani, Kalyani, West Bengal, India
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Al-Dewik N, Abuarja T, Younes S, Nasrallah G, Alsharshani M, Ibrahim FE, Samara M, Farrell T, Abdulrouf PV, Qoronfleh MW, Al Rifai H. Precision medicine activities and opportunities for shaping maternal and neonatal health in Qatar. Per Med 2024; 21:313-333. [PMID: 39347749 DOI: 10.1080/17410541.2024.2394397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2023] [Accepted: 08/16/2024] [Indexed: 10/01/2024]
Abstract
Precision Medicine (PM) is a transformative clinical medicine strategy that aims to revolutionize healthcare by leveraging biological information and biomarkers. In the context of maternal and neonatal health, PM enables personalized care from preconception through the postnatal period. Qatar has emerged as a key player in PM research, with dedicated programs driving advancements and translating cutting-edge research into clinical applications. This article delves into neonatal and maternal health in Qatar, emphasizing PM programs and initiatives that have been implemented. It also features noteworthy clinical cases that demonstrate the effectiveness of precision interventions. Furthermore, the article highlights the role of pharmacogenomics in addressing various maternal health conditions. The review further explores potential advancements in the application of PM in maternal and neonatal healthcare in Qatar.
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Affiliation(s)
- Nader Al-Dewik
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
- Department of Neonatology, Neonatal Intensive Care Unit, Newborn Screening Unit, Women's Wellness & Research Center, Hamad Medical Corporation, Doha, 3050, Qatar
- Translational Research Institute (TRI), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
- Genomics & Precision Medicine (GPM), College of Health & Life Science (CHLS), Hamad Bin Khalifa University (HBKU), Doha, 34110, Qatar
| | - Tala Abuarja
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Salma Younes
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University (QU), Doha, 2713, Qatar
| | - Gheyath Nasrallah
- Department of Biomedical Science, College of Health Sciences, Member of QU Health, Qatar University (QU), Doha, 2713, Qatar
| | - Mohamed Alsharshani
- Diagnostic Genetics Division (DGD), Department of Laboratory Medicine & Pathology (DLMP), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Faisal E Ibrahim
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Muthanna Samara
- Department of Psychology, Kingston University London, Kingston upon Thames, London, KT1 2EE, United Kingdom
| | - Thomas Farrell
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - Palli Valapila Abdulrouf
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
| | - M Walid Qoronfleh
- Q3 Research Institute (QRI), Healthcare Research & Policy Division, 7227 Rachel Drive, Ypsilanti, MI 48917, USA
| | - Hilal Al Rifai
- Department of Research & Translational & Precision Medicine Research Lab, Women's Wellness & Research Center (WWRC), Hamad Medical Corporation (HMC), Doha, 3050, Qatar
- Department of Neonatology, Neonatal Intensive Care Unit, Newborn Screening Unit, Women's Wellness & Research Center, Hamad Medical Corporation, Doha, 3050, Qatar
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Redeker KEM, Brockmöller J. Several orphan solute carriers functionally identified as organic cation transporters: Substrates specificity compared with known cation transporters. J Biol Chem 2024; 300:107629. [PMID: 39098524 PMCID: PMC11406361 DOI: 10.1016/j.jbc.2024.107629] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 07/10/2024] [Accepted: 07/25/2024] [Indexed: 08/06/2024] Open
Abstract
Organic cations comprise a significant part of medically relevant drugs and endogenous substances. Such substances need organic cation transporters for efficient transfer via cell membranes. However, the membrane transporters of most natural or synthetic organic cations are still unknown. To identify these transporters, genes of 10 known OCTs and 18 orphan solute carriers (SLC) were overexpressed in HEK293 cells and characterized concerning their transport activities with a broad spectrum of low molecular weight substances emphasizing organic cations. Several SLC35 transporters and SLC38A10 significantly enhanced the transport of numerous relatively hydrophobic organic cations. Significant organic cation transport activities have been found in gene families classified as transporters of other substance classes. For instance, SLC35G3 and SLC38A10 significantly accelerated the uptake of several cations, such as clonidine, 3,4-methylenedioxymethamphetamine, and nicotine, which are known as substrates of a thus far genetically unidentified proton/organic cation antiporter. The transporters SLC35G4 and SLC35F5 stood out by their significantly increased choline uptake, and several other SLC transported choline together with a broader spectrum of organic cations. Overall, there are many more polyspecific organic cation transporters than previously estimated. Several transporters had one predominant substrate but accepted some other cationic substrates, and others showed no particular preference for one substrate but transported several organic cations. The role of these transporters in biology and drug therapy remains to be elucidated.
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Affiliation(s)
- Kyra-Elisa Maria Redeker
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany.
| | - Jürgen Brockmöller
- Institute of Clinical Pharmacology, University Medical Center Göttingen, Georg-August-University Göttingen, Göttingen, Germany
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Khalaf T, Al Ojaimi M, Saleh DA, Sulaiman A, Sohal AP, Khan A, El-Hattab AW. The utility of exome sequencing in diagnosing pediatric neurodevelopmental disorders in a highly consanguineous population. Clin Genet 2024; 106:82-89. [PMID: 38438125 DOI: 10.1111/cge.14508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 02/07/2024] [Accepted: 02/08/2024] [Indexed: 03/06/2024]
Abstract
Exome sequencing (ES) has been utilized in diagnosing children with neurodevelopmental manifestations, this study aimed to investigate the utility of ES in children within a highly consanguineous population that presented with neurodevelopmental complaints. A retrospective chart review was performed for 405 children with neurodevelopmental complaints who have had ES and were evaluated in multiple centers in the United Arab Emirates over a four-year period. Within the cohort of 405 children, consanguinity was reported in 35% (144/405). The primary clinical presentations were developmental delay/cognitive impairment, distinctive facial features, hypotonia, seizures, and weakness. The diagnostic yield was 57% (231/405). Novel variants were identified in 54% (125/231) of positive cases. Within the positive cases, specific treatment was available in 6% (13/231) and copy number variants (CNV) were reported in 3% (8/231) of cases. In eight children, variants in genes that have not yet been linked to human disease that could potentially be the cause of the observed phenotype "candidate genes" were identified. ES was utilized effectively within this cohort with a high diagnostic yield and through the identification of novel gene variants, CNVs, candidate genes and secondary findings as well as the alteration of the treatment plan in cases where treatment was available.
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Affiliation(s)
- Tamam Khalaf
- Genetic Counseling Division, Igenomix, Dubai, UAE
| | - Mode Al Ojaimi
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE
- Department of Pediatrics, University Hospital Sharjah, Sharjah, UAE
| | - Dina Amin Saleh
- Pediatric Neurology Division, American Center for Psychiatry and Neurology, Abu Dhabi, UAE
- Department of Pediatrics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Alena Sulaiman
- Pediatric Division, KidsHeart Medical Center, Abu Dhabi, UAE
| | - Aman P Sohal
- Pediatric Neurology Division, Neuropedia Children's Neuroscience Center, Dubai, UAE
- Pediatric Neurology Division, Al Qassimi Women and Children's Hospital, Sharjah, UAE
| | - Arif Khan
- Pediatric Neurology Division, Neuropedia Children's Neuroscience Center, Dubai, UAE
- Pediatric Division, Kings College Hospital London, Dubai, UAE
- Pediatric Neurology Division, Kids Neuro Clinic and Rehab Center, Dubai, UAE
| | - Ayman W El-Hattab
- Department of Clinical Sciences, College of Medicine, University of Sharjah, Sharjah, UAE
- Department of Pediatrics, University Hospital Sharjah, Sharjah, UAE
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Romano F, Haanpää MK, Pomianowski P, Peraino AR, Pollard JR, Di Feo MF, Traverso M, Severino M, Derchi M, Henzen E, Zara F, Faravelli F, Capra V, Scala M. Expanding the phenotype of UPF3B-related disorder: Case reports and literature review. Am J Med Genet A 2024; 194:e63534. [PMID: 38318947 DOI: 10.1002/ajmg.a.63534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 12/13/2023] [Accepted: 12/22/2023] [Indexed: 02/07/2024]
Abstract
UPF3B encodes the Regulator of nonsense transcripts 3B protein, a core-member of the nonsense-mediated mRNA decay pathway, protecting the cells from the potentially deleterious actions of transcripts with premature termination codons. Hemizygous variants in the UPF3B gene cause a spectrum of neuropsychiatric issues including intellectual disability, autism spectrum disorder, attention deficit hyperactivity disorder, and schizophrenia/childhood-onset schizophrenia (COS). The number of patients reported to date is very limited, often lacking an extensive phenotypical and neuroradiological description of this ultra-rare syndrome. Here we report three subjects harboring UPF3B variants, presenting with variable clinical pictures, including cognitive impairment, central hypotonia, and syndromic features. Patients 1 and 2 harbored novel UPF3B variants-the p.(Lys207*) and p.(Asp429Serfs*27) ones, respectively-while the p.(Arg225Lysfs*229) variant, identified in Patient 3, was already reported in the literature. Novel features in our patients are represented by microcephaly, midface hypoplasia, and brain malformations. Then, we reviewed pertinent literature and compared previously reported subjects to our cases, providing possible insights into genotype-phenotype correlations in this emerging condition. Overall, the detailed phenotypic description of three patients carrying UPF3B variants is useful not only to expand the genotypic and phenotypic spectrum of UPF3B-related disorders, but also to ameliorate the clinical management of affected individuals.
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Affiliation(s)
- Ferruccio Romano
- Clinical Genomics and Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Maria K Haanpää
- Department of Genomics and Clinical Genetics, Turku University Hospital, Turku, Finland
| | - Pawel Pomianowski
- Center for Medical Genetics and Genomics, Christiana Care Health System, Newark, Delaware, USA
| | - Amanda Rose Peraino
- Center for Medical Genetics and Genomics, Christiana Care Health System, Newark, Delaware, USA
| | - John R Pollard
- Epilepsy Center, Christiana Care Health System, Newark, Delaware, USA
| | - Maria Francesca Di Feo
- Clinical Genomics and Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Genomics and Clinical Genetics, Turku University Hospital, Turku, Finland
- Center for Medical Genetics and Genomics, Christiana Care Health System, Newark, Delaware, USA
- Epilepsy Center, Christiana Care Health System, Newark, Delaware, USA
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Monica Traverso
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | | | - Maria Derchi
- Cardiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Edoardo Henzen
- Genomics Facility, Italian Institute of Technology (IIT), Genoa, Italy
| | - Federico Zara
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
| | - Francesca Faravelli
- Clinical Genomics and Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Valeria Capra
- Clinical Genomics and Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marcello Scala
- Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
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Jolfayi AG, Kohansal E, Ghasemi S, Naderi N, Hesami M, MozafaryBazargany M, Moghadam MH, Fazelifar AF, Maleki M, Kalayinia S. Exploring TTN variants as genetic insights into cardiomyopathy pathogenesis and potential emerging clues to molecular mechanisms in cardiomyopathies. Sci Rep 2024; 14:5313. [PMID: 38438525 PMCID: PMC10912352 DOI: 10.1038/s41598-024-56154-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 03/01/2024] [Indexed: 03/06/2024] Open
Abstract
The giant protein titin (TTN) is a sarcomeric protein that forms the myofibrillar backbone for the components of the contractile machinery which plays a crucial role in muscle disorders and cardiomyopathies. Diagnosing TTN pathogenic variants has important implications for patient management and genetic counseling. Genetic testing for TTN variants can help identify individuals at risk for developing cardiomyopathies, allowing for early intervention and personalized treatment strategies. Furthermore, identifying TTN variants can inform prognosis and guide therapeutic decisions. Deciphering the intricate genotype-phenotype correlations between TTN variants and their pathologic traits in cardiomyopathies is imperative for gene-based diagnosis, risk assessment, and personalized clinical management. With the increasing use of next-generation sequencing (NGS), a high number of variants in the TTN gene have been detected in patients with cardiomyopathies. However, not all TTN variants detected in cardiomyopathy cohorts can be assumed to be disease-causing. The interpretation of TTN variants remains challenging due to high background population variation. This narrative review aimed to comprehensively summarize current evidence on TTN variants identified in published cardiomyopathy studies and determine which specific variants are likely pathogenic contributors to cardiomyopathy development.
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Affiliation(s)
- Amir Ghaffari Jolfayi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Erfan Kohansal
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Serwa Ghasemi
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Naderi
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahshid Hesami
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Maryam Hosseini Moghadam
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Amir Farjam Fazelifar
- Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Majid Maleki
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Samira Kalayinia
- Cardiogenetic Research Center, Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran.
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Alkhidir S, El-Akouri K, Al-Dewik N, Khodjet-El-Khil H, Okashah S, Islam N, Ben-Omran T, Al-Shafai M. The genetic basis and the diagnostic yield of genetic testing related to nonsyndromic hearing loss in Qatar. Sci Rep 2024; 14:4202. [PMID: 38378725 PMCID: PMC10879212 DOI: 10.1038/s41598-024-52784-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 01/23/2024] [Indexed: 02/22/2024] Open
Abstract
Hearing loss is the most predominant sensory defect occurring in pediatrics, of which, 66% cases are attributed to genetic factors. The prevalence of hereditary hearing loss increases in consanguineous populations, and the prevalence of hearing loss in Qatar is 5.2%. We aimed to investigate the genetic basis of nonsyndromic hearing loss (NSHL) in Qatar and to evaluate the diagnostic yield of different genetic tests available. A retrospective chart review was conducted for 59 pediatric patients with NSHL referred to the Department of Adult and Pediatric Medical Genetics at Hamad Medical Corporation in Qatar, and who underwent at least one genetic test. Out of the 59 patients, 39 were solved cases due to 19 variants in 11 genes and two copy number variants that explained the NSHL phenotype. Of them 2 cases were initially uncertain and were reclassified using familial segregation. Around 36.8% of the single variants were in GJB2 gene and c.35delG was the most common recurrent variant seen in solved cases. We detected the c.283C > T variant in FGF3 that was seen in a Qatari patient and found to be associated with NSHL for the first time. The overall diagnostic yield was 30.7%, and the diagnostic yield was significantly associated with genetic testing using GJB2 sequencing and using the hearing loss (HL) gene panel. The diagnostic yield for targeted familial testing was 60% (n = 3 patients) and for gene panel was 50% (n = 5). Thus, we recommend using GJB2 gene sequencing as a first-tier genetic test and HL gene panel as a second-tier genetic test for NSHL. Our work provided new insights into the genetic pool of NSHL among Arabs and highlights its unique diversity, this is believed to help further in the diagnostic and management options for NSHL Arab patients.
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Affiliation(s)
- Shaza Alkhidir
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
- Department of Adult and Pediatric Medical Genetics, Hamad Medical Corporation, Doha, Qatar
| | - Karen El-Akouri
- Department of Adult and Pediatric Medical Genetics, Hamad Medical Corporation, Doha, Qatar
- Division of Genetic and Genomic Medicine, Sidra Medicine, Doha, Qatar
| | - Nader Al-Dewik
- Department of Adult and Pediatric Medical Genetics, Hamad Medical Corporation, Doha, Qatar
| | - Houssein Khodjet-El-Khil
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Sarah Okashah
- Department of Adult and Pediatric Medical Genetics, Hamad Medical Corporation, Doha, Qatar
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
| | - Nazmul Islam
- Department of Public Health, College of Health Sciences, QU Health, Qatar University, Doha, Qatar
- Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Tawfeg Ben-Omran
- Department of Adult and Pediatric Medical Genetics, Hamad Medical Corporation, Doha, Qatar.
- Division of Genetic and Genomic Medicine, Sidra Medicine, Doha, Qatar.
| | - Mashael Al-Shafai
- Department of Biomedical Sciences, College of Health Sciences, QU Health, Qatar University, Doha, Qatar.
- Biomedical Research Center, Qatar University, Doha, Qatar.
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10
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Racine C, Denommé-Pichon AS, Engel C, Tran Mau-Them F, Bruel AL, Vitobello A, Safraou H, Sorlin A, Nambot S, Delanne J, Garde A, Colin E, Moutton S, Thevenon J, Jean-Marçais N, Willems M, Geneviève D, Pinson L, Perrin L, Laffargue F, Lespinasse J, Lacaze E, Molin A, Gerard M, Lambert L, Benigni C, Patat O, Bourgeois V, Poe C, Chevarin M, Couturier V, Garret P, Philippe C, Duffourd Y, Faivre L, Thauvin-Robinet C. Multiple molecular diagnoses in the field of intellectual disability and congenital anomalies: 3.5% of all positive cases. J Med Genet 2023; 61:36-46. [PMID: 37586840 DOI: 10.1136/jmg-2023-109170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2023] [Accepted: 07/27/2023] [Indexed: 08/18/2023]
Abstract
PURPOSE Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID). METHODS From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018). RESULTS MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%). CONCLUSION MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.
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Affiliation(s)
- Caroline Racine
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
| | - Anne-Sophie Denommé-Pichon
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Camille Engel
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
| | - Frederic Tran Mau-Them
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Ange-Line Bruel
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Antonio Vitobello
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Hana Safraou
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Arthur Sorlin
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
| | - Sophie Nambot
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Julian Delanne
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
| | - Aurore Garde
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
| | - Estelle Colin
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
| | - Sébastien Moutton
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
| | - Julien Thevenon
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
| | - Nolwenn Jean-Marçais
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
| | - Marjolaine Willems
- Centre de Référence "Anomalies du Développement syndromes malformatifs" Occitanie, Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier, France
| | - David Geneviève
- Centre de Référence "Anomalies du Développement syndromes malformatifs" Occitanie, Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier, France
- INSERM U1183, Université de Montpellier, Montpellier, France
| | - Lucile Pinson
- Centre de Référence "Anomalies du Développement syndromes malformatifs" Occitanie, Service de Génétique Médicale, Hôpital Arnaud de Villeneuve, Montpellier, France
| | - Laurence Perrin
- Genetic Department, Robert-Debré Hospital Department of Genetics, Paris, France
| | - Fanny Laffargue
- Service de Génétique médicale, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - James Lespinasse
- Unité de Génétique médicale, Centre Hospitalier Métropole Savoie, Chambery, France
| | - Elodie Lacaze
- Department of Medical Genetics, Hospital Group Le Havre, Le Havre, France
| | - Arnaud Molin
- Service de Génétique, University Hospital Centre Caen, Caen, France
| | - Marion Gerard
- Service de Génétique, University Hospital Centre Caen, Caen, France
| | | | | | - Olivier Patat
- Department of Medical Genetics, University Hospital Centre Toulouse, Toulouse, France
| | - Valentin Bourgeois
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Charlotte Poe
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Martin Chevarin
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Victor Couturier
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Philippine Garret
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Christophe Philippe
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Yannis Duffourd
- Functional Unity of Innovative Diagnosis for Rare Diseases, University of Burgundy, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Laurence Faivre
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
| | - Christel Thauvin-Robinet
- Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'interrégion Est et FHU TRANSLAD, Centre Hospitalier Universitaire de Dijon Centre de Genetique, Dijon, France
- Inserm UMR1231 team GAD, University of Burgundy, Dijon, France
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11
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Muthaffar OY, Abdulkareem AA, Ashi A, Naseer MI. A novel homozygous splice donor variant in the LRPPRC gene causing Leigh syndrome with epilepsy, a French-Canadian disorder in a Saudi family: case report. Front Pediatr 2023; 11:1288542. [PMID: 38046674 PMCID: PMC10690952 DOI: 10.3389/fped.2023.1288542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 10/24/2023] [Indexed: 12/05/2023] Open
Abstract
Background The mitochondria are a cellular power house. Tissues are involved in frequent energy consumption, and any failure or irregularity in the continuous energy production could lead to abnormalities. The leucine-rich pentatricopeptide repeat (LRPPRC) gene is one of the mitochondrial-related functions genes; variations in these genes are responsible for complex phenotypes that affect many organs such as the brain, liver, and muscles. Materials and methods This study enrolled a family with Leigh syndrome-like phenotype. The molecular diagnosis was conducted by first performing whole exome sequencing (WES), followed by Sanger sequencing. Results A novel splice-site variant (c.469 + 2T > A) at the exon-intron boundary in the LRPPRC gene was identified using the WES data analysis. Sanger validation confirmed the autosomal recessive inheritance of the identified variant. Based on the ACMG criteria for variant classification, PVS1 and PM2 suggest that the identified variant in the LRPPRC gene is likely to be pathogenic. Conclusion To the best of our knowledge, there have been no previous reports of this variant in the LRPPRC gene. Our research not only identifies a novel variant in the LRPPRC gene, but also confirms the unresolved molecular diagnosis of the family. WES can be used as a first-line diagnostic tool in familial cases, particularly in those cases when detailed clinical phenotyping is not possible. Once the molecular diagnosis is confirmed in a family, it is necessary to conduct a thorough re-evaluation of the patients' specific clinical phenotypes in order to establish a clear genotype-phenotype correlation.
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Affiliation(s)
- Osama Y. Muthaffar
- Department of Pediatrics, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Angham Abdulrhman Abdulkareem
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Abrar Ashi
- King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Muhammad Imran Naseer
- Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah, Saudi Arabia
- Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
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12
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Fong S, Carollo A, Ashour R, Dimitriou D, Gianluca Esposito. Identifying major research themes in the literature on developmental disabilities in Middle Eastern countries: A scientometric review from 1962 to 2023. RESEARCH IN DEVELOPMENTAL DISABILITIES 2023; 140:104551. [PMID: 37473627 DOI: 10.1016/j.ridd.2023.104551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Revised: 05/05/2023] [Accepted: 06/02/2023] [Indexed: 07/22/2023]
Abstract
Developmental disabilities have been widely studied in higher-income countries. However, most individuals with these conditions live in low- and middle-income countries and they are reportedly under-represented in the scientific literature. To tackle this issue, previous research has provided insight into the thematic developments in the research on developmental disabilities in Africa by means of a scientometric approach to reviews. The current work aims to extend the scientometric approach to investigate the main interests in the literature on developmental disabilities conducted in Middle Eastern countries. A total of 1110 documents were retrieved from Scopus and their patterns of co-citation were analysed with the CiteSpace software. Research in Developmental Disabilities emerged to be the main source in the sample of downloaded documents. Furthermore, a total of six main thematic domains and the four most impactful documents in the literature were identified. Results showed that research on developmental disabilities in the Middle East has been mainly focused on uncovering the genetic basis of this group of conditions. The study of clinical profiles, diagnosis, management, and treatment of individuals with developmental disabilities have been so far under-investigated and represents material for future studies.
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Affiliation(s)
- Seraphina Fong
- Department of Psychology and Cognitive Science, University of Trento, 38068 Rovereto, Italy
| | - Alessandro Carollo
- Department of Psychology and Cognitive Science, University of Trento, 38068 Rovereto, Italy
| | - Rola Ashour
- Sleep Education and Research Laboratory, UCL Institute of Education, London WC1H 0AA, England, UK
| | - Dagmara Dimitriou
- Sleep Education and Research Laboratory, UCL Institute of Education, London WC1H 0AA, England, UK
| | - Gianluca Esposito
- Department of Psychology and Cognitive Science, University of Trento, 38068 Rovereto, Italy.
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13
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Chung CCY, Hue SPY, Ng NYT, Doong PHL, Chu ATW, Chung BHY. Meta-analysis of the diagnostic and clinical utility of exome and genome sequencing in pediatric and adult patients with rare diseases across diverse populations. Genet Med 2023; 25:100896. [PMID: 37191093 DOI: 10.1016/j.gim.2023.100896] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 05/07/2023] [Accepted: 05/10/2023] [Indexed: 05/17/2023] Open
Abstract
PURPOSE This meta-analysis aims to compare the diagnostic and clinical utility of exome sequencing (ES) vs genome sequencing (GS) in pediatric and adult patients with rare diseases across diverse populations. METHODS A meta-analysis was conducted to identify studies from 2011 to 2021. RESULTS One hundred sixty-one studies across 31 countries/regions were eligible, featuring 50,417 probands of diverse populations. Diagnostic rates of ES (0.38, 95% CI 0.36-0.40) and GS (0.34, 95% CI 0.30-0.38) were similar (P = .1). Within-cohort comparison illustrated 1.2-times odds of diagnosis by GS over ES (95% CI 0.79-1.83, P = .38). GS studies discovered a higher range of novel genes than ES studies; yet, the rate of variant of unknown significance did not differ (P = .78). Among high-quality studies, clinical utility of GS (0.77, 95% CI 0.64-0.90) was higher than that of ES (0.44, 95% CI 0.30-0.58) (P < .01). CONCLUSION This meta-analysis provides an important update to demonstrate the similar diagnostic rates between ES and GS and the higher clinical utility of GS over ES. With the newly published recommendations for clinical interpretation of variants found in noncoding regions of the genome and the trend of decreasing variant of unknown significance and GS cost, it is expected that GS will be more widely used in clinical settings.
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Affiliation(s)
| | - Shirley P Y Hue
- Hong Kong Genome Institute, Hong Kong Special Administrative Region
| | - Nicole Y T Ng
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Phoenix H L Doong
- Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region
| | - Annie T W Chu
- Hong Kong Genome Institute, Hong Kong Special Administrative Region.
| | - Brian H Y Chung
- Hong Kong Genome Institute, Hong Kong Special Administrative Region; Department of Paediatrics and Adolescent Medicine, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region.
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14
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Pakarinen E, Lindholm P. CDNF and MANF in the brain dopamine system and their potential as treatment for Parkinson's disease. Front Psychiatry 2023; 14:1188697. [PMID: 37555005 PMCID: PMC10405524 DOI: 10.3389/fpsyt.2023.1188697] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 05/23/2023] [Indexed: 08/10/2023] Open
Abstract
Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by gradual loss of midbrain dopamine neurons, leading to impaired motor function. Preclinical studies have indicated cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) to be potential therapeutic molecules for the treatment of PD. CDNF was proven to be safe and well tolerated when tested in Phase I-II clinical trials in PD patients. Neuroprotective and neurorestorative effects of CDNF and MANF were demonstrated in animal models of PD, where they promoted the survival of dopamine neurons and improved motor function. However, biological roles of endogenous CDNF and MANF proteins in the midbrain dopamine system have been less clear. In addition to extracellular trophic activities, CDNF/MANF proteins function intracellularly in the endoplasmic reticulum (ER), where they modulate protein homeostasis and protect cells against ER stress by regulating the unfolded protein response (UPR). Here, our aim is to give an overview of the biology of endogenous CDNF and MANF in the brain dopamine system. We will discuss recent studies on CDNF and MANF knockout animal models, and effects of CDNF and MANF in preclinical models of PD. To elucidate possible roles of CDNF and MANF in human biology, we will review CDNF and MANF tissue expression patterns and regulation of CDNF/MANF levels in human diseases. Finally, we will discuss novel findings related to the molecular mechanism of CDNF and MANF action in ER stress, UPR, and inflammation, all of which are mechanisms potentially involved in the pathophysiology of PD.
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Affiliation(s)
| | - Päivi Lindholm
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland
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15
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Masri AT, Oweis L, Ali M, Hamamy H. Global developmental delay and intellectual disability in the era of genomics: Diagnosis and challenges in resource limited areas. Clin Neurol Neurosurg 2023; 230:107799. [PMID: 37236004 DOI: 10.1016/j.clineuro.2023.107799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 05/12/2023] [Accepted: 05/22/2023] [Indexed: 05/28/2023]
Abstract
AIMS To report the diagnostic yield of clinical singleton whole exome sequencing (WES) performed among a group of Jordanian children presenting with global developmental delay /intellectual disability (GDD/ID), discuss the underlying identified genetic disorders and the challenges encountered. PATIENTS AND METHODS This retrospective medical record review study included 154 children who were diagnosed with GDD/ID at our clinic at Jordan University Hospital between 2016 and 2021, and whose diagnostic work up included WES. RESULTS Consanguinity among parents was reported in 94/154 (61.0%) patients and history of other affected siblings in 35/154 (22.7%) patients. Pathogenic and likely pathogenic variants (solved cases) were reported in 69/154 (44.8%) patients, a variant of uncertain significance was reported in 54/154 (35.0%) and a negative result was reported in 31/154 (20.1%) cases. In the solved cases, autosomal recessive diseases were the most common (33/69; 47.8%). Metabolic disorders were identified in 20/69 (28.9%) patients, followed by developmental and epileptic encephalopathies (9/69; 13.0%) and MECP2 related disorders (7/69; 10.1%). Other single gene disorders were identified in 33/69; 47.8%) patients. CONCLUSION This study had several limitations, as it was hospital-based and only including patients who were able to afford the test. Nevertheless, it yielded several important findings. In resource-limited countries, WES may be a reasonable approach. We discussed the challenges that clinicians meet in the context of shortage of resources.
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Affiliation(s)
- Amira T Masri
- Faculty of Medicine, Paediatric Department, Division of Child Neurology, The University of Jordan, Jordan.
| | - Liyana Oweis
- Faculty of Medicine, The University of Jordan, Jordan
| | - Majd Ali
- Faculty of Medicine, The University of Jordan, Jordan
| | - Hanan Hamamy
- Department of Genetic Medicine and Development, University of Geneva, Geneva, Switzerland
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16
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Sapuppo A, Portale L, Massimino CR, Presti S, Tardino L, Marino S, Polizzi A, Falsaperla R, Praticò AD. GRIN2A and GRIN2B and Their Related Phenotypes. JOURNAL OF PEDIATRIC NEUROLOGY 2023; 21:212-223. [DOI: 10.1055/s-0041-1727146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
AbstractGlutamate is the most relevant excitatory neurotransmitter of the central nervous system; it binds with several receptors, including N-methyl-D-aspartate receptors (NMDARs), a subtype of ionotropic glutamate receptor that displays voltage-dependent block by Mg2+ and a high permeability to Ca2+. GRIN2A and GRIN2B genes encode the GluN2A and GluN2B subunits of the NMDARs, which play important roles in synaptogenesis, synaptic transmission, and synaptic plasticity, as well as contributing to neuronal loss and dysfunction in several neurological disorders. Recently, individuals with a range of childhood-onset drug-resistant epilepsies, such as Landau–Kleffner or Lennox–Gastaut syndrome, intellectual disability (ID), and other neurodevelopmental abnormalities have been found to carry mutations in GRIN2A and GRIN2B, with high variable expressivity in phenotype. The first one is found mainly in epilepsy-aphasia syndromes, while the second one mainly in autism, schizophrenia, and ID, such as autism spectrum disorders. Brain magnetic resonance imaging alterations are found in some patients, even if without a clear clinical correlation. At the same time, increasing data on genotype–phenotype correlation have been found, but this is still not fully demonstrated. There are no specific therapies for the treatment of correlated NMDARs epilepsy, although some evidence with memantine, an antagonist of glutamate receptor, is reported in the literature in selected cases with mutation determining a gain of function.
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Affiliation(s)
- Annamaria Sapuppo
- Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Laura Portale
- Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Carmela R. Massimino
- Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Santiago Presti
- Pediatrics Postgraduate Residency Program, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Lucia Tardino
- Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
| | - Simona Marino
- Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
| | - Agata Polizzi
- Chair of Pediatrics, Department of Educational Sciences, University of Catania, Catania, Italy
| | - Raffaele Falsaperla
- Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
- Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy
| | - Andrea D. Praticò
- Unit of Rare Diseases of the Nervous Systemin Childhood, Section of Pediatrics and Child Neuropsychiatry, Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
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17
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Lorenzo DN, Edwards RJ, Slavutsky AL. Spectrins: molecular organizers and targets of neurological disorders. Nat Rev Neurosci 2023; 24:195-212. [PMID: 36697767 PMCID: PMC10598481 DOI: 10.1038/s41583-022-00674-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2022] [Indexed: 01/26/2023]
Abstract
Spectrins are cytoskeletal proteins that are expressed ubiquitously in the mammalian nervous system. Pathogenic variants in SPTAN1, SPTBN1, SPTBN2 and SPTBN4, four of the six genes encoding neuronal spectrins, cause neurological disorders. Despite their structural similarity and shared role as molecular organizers at the cell membrane, spectrins vary in expression, subcellular localization and specialization in neurons, and this variation partly underlies non-overlapping disease presentations across spectrinopathies. Here, we summarize recent progress in discerning the local and long-range organization and diverse functions of neuronal spectrins. We provide an overview of functional studies using mouse models, which, together with growing human genetic and clinical data, are helping to illuminate the aetiology of neurological spectrinopathies. These approaches are all critical on the path to plausible therapeutic solutions.
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Affiliation(s)
- Damaris N Lorenzo
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Reginald J Edwards
- Department of Cell Biology and Physiology, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Anastasia L Slavutsky
- Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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18
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Gorukmez O, Gorukmez O, Topak A. Clinical exome sequencing findings in 1589 patients. Am J Med Genet A 2023; 191:1557-1564. [PMID: 36964972 DOI: 10.1002/ajmg.a.63190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 01/31/2023] [Accepted: 03/15/2023] [Indexed: 03/27/2023]
Abstract
Clinical exome sequencing (CES) is important for the diagnosis of Mendelian diseases, which are clinically and etiologically heterogeneous. Sharing of large amounts of CES data associated with clinical findings will increase the accuracy of variant interpretation. We performed a retrospective study to state the diagnostic yield of CES in 1589 patients with a wide phenotypic spectrum. CES was performed using the Sophia Clinical Exome Sequencing Kit with 4493 genes, followed by sequencing on a NextSeq 500 system. The diagnosis rate was 36.8% when only pathogenic and likely pathogenic variants were included. Consanguineous unions and positive family history were associated with a high diagnostic yield. The neurological disease group had the highest number of patients. The groups with high diagnosis rates were ear, eye, and muscle disease groups. Seven candidate genes (EFHC2, HSPB3, FAAH2, ITGB1, GYG2, CD177, and CSTF2T) that are not yet associated with human diseases were identified. Owing to the high diagnostic yield of CES compared with that of other genetic tests, it can be used as a standard diagnostic test in patients with rare genetic disorders that require a wide differential diagnosis, especially in laboratories with limited resources.
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Affiliation(s)
- Ozlem Gorukmez
- Department of Medical Genetics, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
| | - Orhan Gorukmez
- Department of Medical Genetics, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
| | - Ali Topak
- Department of Medical Genetics, Bursa Yüksek İhtisas Training and Research Hospital, Bursa, Turkey
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Sheth F, Shah J, Patel K, Patel D, Jain D, Sheth J, Sheth H. A novel case of two siblings harbouring homozygous variant in the NEUROG1 gene with autism as an additional phenotype: a case report. BMC Neurol 2023; 23:20. [PMID: 36647078 PMCID: PMC9841689 DOI: 10.1186/s12883-023-03065-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Accepted: 01/11/2023] [Indexed: 01/18/2023] Open
Abstract
INTRODUCTION NEUROG1 gene is yet to be associated with a set of human phenotypes in the OMIM database. Three cases have previously been diagnosed with cranial dysinnervation due to biallelic variants in the NEUROG1 gene. This is the fourth and a novel report of a sibling pair harboring a homozygous variant in the NEUROG1 gene with autism as an additional phenotype. A brief review of the literature in conjunction with a genotype-phenotype correlation has been described. A potential hypothesis for the presence of the autistic phenotype in the present case has also been elucidated. CASE PRESENTATION A female aged 6 years and 9 months born to endogamous and phenotypically healthy parents was diagnosed with global developmental delay, autism spectrum disorder, hearing loss, corneal opacity and no eye blinking. Her MRI of the brain revealed mild peritrigonal white matter hyperintensity, and MRI and CT scan of the temporal bones showed abnormal cranial nerves. The proband's younger sister, aged 4-years, was similarly affected. Whole exome sequencing was performed in the proband, which revealed a novel homozygous, likely pathogenic, truncating frameshift variant, c.228_231dup (p.Thr78ProfsTer122) in exon 1 of the NEUROG1 gene (ENST00000314744.4). Segregation analysis by Sanger sequencing showed the proband and her younger sister to be homozygotes and their parents to be heterozygous carriers. CONCLUSION This is the fourth report across the globe with a variant identified in the NEUROG1 gene to be associated with cranial dysinnervation phenotype. An additional phenotype of autism in two female siblings was a novel observation. We provide a hypothetical framework which could explain the pleiotropic effect of a dysfunctional NEUROG1 protein leading to autism and posit it as a candidate for diagnosis of autism spectrum disorder with congenital cranial dysinnervation disorder.
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Affiliation(s)
- Frenny Sheth
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, 380015, Satellite, Ahmedabad, India.
| | - Jhanvi Shah
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, 380015, Satellite, Ahmedabad, India
| | - Ketan Patel
- Speciality Homeopathy Clinic, Ahmedabad, India
| | - Darshan Patel
- Charotar Institute of Paramedical Sciences, Charotar University of Science and Technology, Changa, Gujarat, India
| | - Deepika Jain
- Shishu Child Development and Early Intervention Centre, Ahmedabad, India
| | - Jayesh Sheth
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, 380015, Satellite, Ahmedabad, India
| | - Harsh Sheth
- FRIGE's Institute of Human Genetics, FRIGE House, Jodhpur Gam Road, 380015, Satellite, Ahmedabad, India.
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20
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Lieberwirth JK, Büttner B, Klöckner C, Platzer K, Popp B, Abou Jamra R. AutoCaSc: Prioritizing candidate genes for neurodevelopmental disorders. Hum Mutat 2022; 43:1795-1807. [PMID: 35998261 DOI: 10.1002/humu.24451] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2022] [Revised: 07/24/2022] [Accepted: 08/18/2022] [Indexed: 01/24/2023]
Abstract
Routine exome sequencing (ES) in individuals with neurodevelopmental disorders (NDD) remains inconclusive in >50% of the cases. Research analysis of unsolved cases can identify novel candidate genes but is time-consuming, subjective, and hard to compare between labs. The field, therefore, requires automated and standardized assessment methods to prioritize candidates for matchmaking. We developed AutoCaSc (https://autocasc.uni-leipzig.de) based on our candidate scoring scheme. We validated our approach using synthetic trios and real in-house trio ES data. AutoCaSc consistently (94.5% of all cases) scored the relevant variants in valid novel NDD genes in the top three ranks. In 93 real trio exomes, AutoCaSc identified most (97.5%) previously manually scored variants while evaluating additional high-scoring variants missed in manual evaluation. It identified candidate variants in previously undescribed NDD candidate genes (CNTN2, DLGAP1, SMURF1, NRXN3, and PRICKLE1). AutoCaSc enables anybody to quickly screen a variant for its plausibility in NDD. After contributing >40 descriptions of NDD-associated genes, we provide usage recommendations based on our extensive experience. Our implementation is capable of pipeline integration and therefore allows the screening of large cohorts for candidate genes. AutoCaSc empowers even small labs to a standardized matchmaking collaboration and to contribute to the ongoing identification of novel NDD entities.
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Affiliation(s)
| | - Benjamin Büttner
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Chiara Klöckner
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Konrad Platzer
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
| | - Bernt Popp
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.,Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Center of Functional Genomics, Berlin, Germany
| | - Rami Abou Jamra
- Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
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21
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Salman DO, Mahfouz R, Bitar ER, Samaha J, Karam PE. Challenges of genetic diagnosis of inborn errors of metabolism in a major tertiary care center in Lebanon. Front Genet 2022; 13:1029947. [PMID: 36468010 PMCID: PMC9715967 DOI: 10.3389/fgene.2022.1029947] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 11/08/2022] [Indexed: 01/25/2023] Open
Abstract
Background: Inborn errors of metabolism are rare genetic disorders; however, these are prevalent in countries with high consanguinity rates, like Lebanon. Patients are suspected, based on a combination of clinical and biochemical features; however, the final confirmation relies on genetic testing. Using next generation sequencing, as a new genetic investigational tool, carries several challenges for the physician, the geneticist, and the families. Methods: In this retrospective study, we analyzed the clinical, biochemical, and genetic profile of inborn errors of metabolism suspected patients, seen at a major tertiary care center in Lebanon, between 2015 and 2018. Genetic testing was performed using next generation sequencing. Genotype-phenotype correlation and diagnostic yield of each testing modality were studied. Results: Out of 211 patients genetically tested, 126 were suspected to have an inborn error of metabolism. The diagnostic yield of next generation sequencing reached 64.3%. Single gene testing was requested in 53%, whole exome sequencing in 36% and gene panels in 10%. Aminoacid disorders were mostly diagnosed followed by storage disorders, organic acidemias and mitochondrial diseases. Targeted testing was performed in 77% of aminoacid and organic acid disorders and half of suspected storage disorders. Single gene sequencing was positive in 75%, whereas whole exome sequencing diagnostic yield for complex cases, like mitochondrial disorders, reached 49%. Good clinical and biochemical correlation allowed the interpretation of variants of unknown significance and negative mutations as well as therapeutic management of most patients. Conclusion: Tailoring the choice of test modality, by next generation sequencing, to the category of suspected inborn errors of metabolism may lead to rapid diagnosis, shortcutting the cost of repeated testing. Whole exome sequencing as a first-tier investigation may be considered mainly for suspected mitochondrial diseases, whereas targeted sequencing can be offered upon suspicion of a specific enzyme deficiency. Timing and modality of gene test remain challenging, in view of the cost incurred by families.
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Affiliation(s)
- Doaa O. Salman
- Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon
| | - Rami Mahfouz
- Department of Pathology and Laboratory Medicine, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Elio R. Bitar
- Faculty of Medicine, American University of Beirut, Beirut, Lebanon
| | - Jinane Samaha
- Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon,Inherited Metabolic Diseases Program, American University of Beirut Medical Center, Beirut, Lebanon
| | - Pascale E. Karam
- Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon,Inherited Metabolic Diseases Program, American University of Beirut Medical Center, Beirut, Lebanon,*Correspondence: Pascale E. Karam,
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22
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The diagnostic yield, candidate genes, and pitfalls for a genetic study of intellectual disability in 118 middle eastern families. Sci Rep 2022; 12:18862. [PMID: 36344539 PMCID: PMC9640568 DOI: 10.1038/s41598-022-22036-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 10/07/2022] [Indexed: 11/09/2022] Open
Abstract
Global Developmental Delay/Intellectual disability (ID) is the term used to describe various disorders caused by abnormal brain development and characterized by impairments in cognition, communication, behavior, or motor skills. In the past few years, whole-exome sequencing (WES) has been proven to be a powerful, robust, and scalable approach for candidate gene discoveries in consanguineous populations. In this study, we recruited 215 patients affected with ID from 118 Middle Eastern families. Whole-exome sequencing was completed for 188 individuals. The average age at which WES was completed was 8.5 years. Pathogenic or likely pathogenic variants were detected in 32/118 families (27%). Variants of uncertain significance were seen in 33/118 families (28%). The candidate genes with a possible association with ID were detected in 32/118 (27%) with a total number of 64 affected individuals. These genes are novel, were previously reported in a single family, or cause strikingly different phenotypes with a different mode of inheritance. These genes included: AATK, AP1G2, CAMSAP1, CCDC9B, CNTROB, DNAH14, DNAJB4, DRG1, DTNBP1, EDRF1, EEF1D, EXOC8, EXOSC4, FARSB, FBXO22, FILIP1, INPP4A, P2RX7, PRDM13, PTRHD1, SCN10A, SCYL2, SMG8, SUPV3L1, TACC2, THUMPD1, XPR1, ZFYVE28. During the 5 years of the study and through gene matching databases, several of these genes have now been confirmed as causative of ID. In conclusion, understanding the causes of ID will help understand biological mechanisms, provide precise counseling for affected families, and aid in primary prevention.
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23
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Alhaidari AI, Albakri AS, Alhumaidi SS. A Novel PGAP3 Gene Mutation-Related Megalocornea Can Be Misdiagnosed as Primary Congenital Glaucoma. Cureus 2022; 14:e29387. [PMID: 36304370 PMCID: PMC9585391 DOI: 10.7759/cureus.29387] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/20/2022] [Indexed: 11/17/2022] Open
Abstract
Hyperphosphatasia with mental retardation syndrome 4 (HPMRS4) is a rare autosomal recessive disorder caused by glycosylphosphatidylinositol (GPI) deficiency. GPI deficiency results from a mutation in one of six known genes. Mutation in post-GPI attachment to protein phospholipase 3 gene (PGAP3) is linked to HPMRS4. Patients usually present with dysmorphic features, developmental delay, central hypotonia, and seizure. However, in our case, we report a novel homozygous missense mutation of PGAP3 gene in a female child who presented with megalocornea, which is an unusual clinical presentation for HPMRS4. Megalocornea, in her first days of life, led to a misdiagnosis of primary congenital glaucoma. Later, other common clinical features of HPMRS4 became apparent.
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24
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Benske TM, Mu TW, Wang YJ. Protein quality control of N-methyl-D-aspartate receptors. Front Cell Neurosci 2022; 16:907560. [PMID: 35936491 PMCID: PMC9352929 DOI: 10.3389/fncel.2022.907560] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Accepted: 06/29/2022] [Indexed: 12/23/2022] Open
Abstract
N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated cation channels that mediate excitatory neurotransmission and are critical for synaptic development and plasticity in the mammalian central nervous system (CNS). Functional NMDARs typically form via the heterotetrameric assembly of GluN1 and GluN2 subunits. Variants within GRIN genes are implicated in various neurodevelopmental and neuropsychiatric disorders. Due to the significance of NMDAR subunit composition for regional and developmental signaling at synapses, properly folded receptors must reach the plasma membrane for their function. This review focuses on the protein quality control of NMDARs. Specifically, we review the quality control mechanisms that ensure receptors are correctly folded and assembled within the endoplasmic reticulum (ER) and trafficked to the plasma membrane. Further, we discuss disease-associated variants that have shown disrupted NMDAR surface expression and function. Finally, we discuss potential targeted pharmacological and therapeutic approaches to ameliorate disease phenotypes by enhancing the expression and surface trafficking of subunits harboring disease-associated variants, thereby increasing their incorporation into functional receptors.
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Affiliation(s)
| | - Ting-Wei Mu
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Ya-Juan Wang
- Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH, United States
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25
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Lõhelaid H, Anttila JE, Liew HK, Tseng KY, Teppo J, Stratoulias V, Airavaara M. UPR Responsive Genes Manf and Xbp1 in Stroke. Front Cell Neurosci 2022; 16:900725. [PMID: 35783104 PMCID: PMC9240287 DOI: 10.3389/fncel.2022.900725] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 05/02/2022] [Indexed: 11/13/2022] Open
Abstract
Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF’s function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.
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Affiliation(s)
- Helike Lõhelaid
- HiLIFE – Neuroscience Center, University of Helsinki, Helsinki, Finland
- *Correspondence: Helike Lõhelaid,
| | - Jenni E. Anttila
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Individualized Drug Therapy Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hock-Kean Liew
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien City, Taiwan
| | - Kuan-Yin Tseng
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Jaakko Teppo
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | | | - Mikko Airavaara
- HiLIFE – Neuroscience Center, University of Helsinki, Helsinki, Finland
- Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- Mikko Airavaara,
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26
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Pitfalls in Genetic Testing for Consanguineous Pediatric Populations. Case Rep Genet 2022; 2022:9393042. [PMID: 35663206 PMCID: PMC9159873 DOI: 10.1155/2022/9393042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/12/2022] [Accepted: 04/28/2022] [Indexed: 11/18/2022] Open
Abstract
We describe the diagnostic odyssey of an eight-year-old female born to consanguineous parents. Our patient presented with global developmental delay, regression, microcephaly, spastic diplegia, and leukodystrophy confirmed on brain magnetic resonance imaging (MRI). She was found on whole exome sequencing (WES) to have dual genetic diagnoses. The first was a homozygous pathogenic HERC2 gene partial deletion of exons 43–45 that causes HERC2-related disorder. The second was a homozygous pathogenic variant (c.836 C > T, p.A279 V) in the SUMF1 gene responsible for multiple sulfatase deficiency. This case highlights some of the challenges in diagnosing consanguineous pediatric populations where standard genetic and metabolic testing may not provide answers. Our case further supports the recent American College of Medical Genetics and Genomics (ACMG) recommendation of WES as a first or second-tier test for patients with developmental delay, particularly in a population where the chances of dual diagnosis is high.
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27
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Wen W, Li H, Luo J. Potential Role of MANF, an ER Stress Responsive Neurotrophic Factor, in Protecting Against Alcohol Neurotoxicity. Mol Neurobiol 2022; 59:2992-3015. [PMID: 35254650 PMCID: PMC10928853 DOI: 10.1007/s12035-022-02786-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Accepted: 02/26/2022] [Indexed: 10/18/2022]
Abstract
Alcohol exposure during pregnancy is harmful to the fetus and causes a wide range of long-lasting physiological and neurocognitive impairments, collectively referred to as fetal alcohol spectrum disorders (FASD). The neurobehavioral deficits observed in FASD result from structural and functional damages in the brain, with neurodegeneration being the most destructive consequence. Currently, there are no therapies for FASD. It is exigent to delineate the underlying mechanisms of alcohol neurotoxicity and develop an effective strategy of treatment. ER stress, caused by the accumulation of unfolded/misfolded proteins in the ER, is the hallmark of many neurodegenerative diseases, including alcohol-induced neurodegeneration. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a newly discovered endoplasmic reticulum (ER) stress responsive neurotrophic factor that regulates diverse neuronal functions. This review summarizes the recent findings revealing the effects of MANF on the CNS and its protective role against neurodegeneration. Particularly, we focus the role of MANF on alcohol-induced ER stress and neurodegeneration and discuss the therapeutic potential of MANF in treating alcohol neurotoxicity such as FASD.
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Affiliation(s)
- Wen Wen
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Hui Li
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Jia Luo
- Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA.
- Iowa City VA Health Care System, Iowa City, IA, 52246, USA.
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28
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Tang Q, Li Y, He J. MANF: an emerging therapeutic target for metabolic diseases. Trends Endocrinol Metab 2022; 33:236-246. [PMID: 35135706 DOI: 10.1016/j.tem.2022.01.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 02/08/2023]
Abstract
Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum-resident protein and a secretory factor and has beneficial effects in multiple diseases. Recent evidence shows that its circulating levels in humans are dynamically regulated under various metabolic diseases, including diabetes, obesity, fatty liver, and cardiovascular diseases, suggesting that MANF may play a role in these pathological states. Also, its downregulation in mice impairs glucose homeostasis, promotes lipid accumulation in the liver, reduces energy expenditure, and induces inflammation. Conversely, MANF overexpression prevents or mitigates some of these metabolic disturbances. In particular, systemic MANF administration alleviates dietary obesity and related metabolic disorders in obese mice. We therefore propose that MANF might be a promising target for treating chronic metabolic diseases.
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Affiliation(s)
- Qin Tang
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Yanping Li
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
| | - Jinhan He
- Laboratory of Clinical Pharmacy and Adverse Drug Reaction, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China; Department of Pharmacy, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
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29
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Kysilov B, Hrcka Krausova B, Vyklicky V, Smejkalova T, Korinek M, Horak M, Chodounska H, Kudova E, Cerny J, Vyklicky L. Pregnane-based steroids are novel positive NMDA receptor modulators that may compensate for the effect of loss-of-function disease-associated GRIN mutations. Br J Pharmacol 2022; 179:3970-3990. [PMID: 35318645 DOI: 10.1111/bph.15841] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Revised: 02/24/2022] [Accepted: 03/04/2022] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND AND PURPOSE N-methyl-D-aspartate receptors (NMDARs) play a critical role in synaptic plasticity, and mutations in human genes encoding NMDAR subunits have been described in individuals with various neuropsychiatric disorders. Compounds with a positive allosteric effect are thought to compensate for reduced receptor function. EXPERIMENTAL APPROACH We have used whole-cell patch-clamp electrophysiology on recombinant rat NMDARs and human variants found in individuals with neuropsychiatric disorders, in combination with in silico modelling, to explore the site of action of novel epipregnanolone-based NMDAR modulators. KEY RESULTS Analysis of the action of 4-(20-oxo-5β-pregnan-3β-yl) butanoic acid (EPA-But) at the NMDAR indicates that the effect of this steroid with a "bent" structure is different from that of cholesterol and oxysterols and shares a disuse-dependent mechanism of NMDAR potentiation with the "planar" steroid 20-oxo-pregn-5-en-3β-yl sulfate (PE-S). The potentiating effects of EPA-But and PE-S are additive. Alanine scan mutagenesis identified residues that reduce the potentiating effect of EPA-But. No correlation was found between the effects of EPA-But and PE-S at mutated receptors that were less sensitive to either steroid. The relative degree of potentiation induced by the two steroids also differed in human NMDARs carrying rare variants of hGluN1 or hGluN2B subunits found in individuals with neuropsychiatric disorders, including intellectual disability, epilepsy, developmental delay, and autism spectrum disorder. CONCLUSION AND IMPLICATIONS Our results show novel sites of action for pregnanolones at the NMDAR and provide an opportunity for the development of new therapeutic neurosteroid-based ligands to treat diseases associated with glutamatergic system hypofunction.
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Affiliation(s)
- Bohdan Kysilov
- Institute of Physiology CAS, Prague 4, Czech Republic.,Third Faculty of Medicine, Charles University in Prague, Prague 10, Czech Republic
| | | | | | | | | | - Martin Horak
- Institute of Physiology CAS, Prague 4, Czech Republic
| | - Hana Chodounska
- Institute of Organic Chemistry and Biochemistry CAS, Prague 6, Czech Republic
| | - Eva Kudova
- Institute of Organic Chemistry and Biochemistry CAS, Prague 6, Czech Republic
| | - Jiri Cerny
- Institute of Physiology CAS, Prague 4, Czech Republic
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30
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Van de Vondel L, De Winter J, Beijer D, Coarelli G, Wayand M, Palvadeau R, Pauly MG, Klein K, Rautenberg M, Guillot-Noël L, Deconinck T, Vural A, Ertan S, Dogu O, Uysal H, Brankovic V, Herzog R, Brice A, Durr A, Klebe S, Stock F, Bischoff AT, Rattay TW, Sobrido MJ, De Michele G, De Jonghe P, Klopstock T, Lohmann K, Zanni G, Santorelli FM, Timmerman V, Haack TB, Züchner S, Schüle R, Stevanin G, Synofzik M, Basak AN, Baets J. De Novo and Dominantly Inherited SPTAN1 Mutations Cause Spastic Paraplegia and Cerebellar Ataxia. Mov Disord 2022; 37:1175-1186. [PMID: 35150594 DOI: 10.1002/mds.28959] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. OBJECTIVES We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. METHODS We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. RESULTS We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. CONCLUSIONS We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society.
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Affiliation(s)
- Liedewei Van de Vondel
- Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
| | - Jonathan De Winter
- Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.,Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
| | - Danique Beijer
- Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.,Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Giulia Coarelli
- Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France
| | - Melanie Wayand
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
| | - Robin Palvadeau
- Koc University, School of Medicine, Suna and Inan Kirac Foundation, Istanbul, Turkey
| | - Martje G Pauly
- Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany.,Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Katrin Klein
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany
| | - Maren Rautenberg
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany
| | - Léna Guillot-Noël
- Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France
| | - Tine Deconinck
- Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Edegem, Belgium
| | - Atay Vural
- School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey
| | - Sibel Ertan
- School of Medicine, Department of Neurology, Koc University, Istanbul, Turkey
| | - Okan Dogu
- Department of Neurology, School of Medicine, Mersin University, Mersin, Turkey
| | - Hilmi Uysal
- Department of Neurology, School of Medicine, Akdeniz University, Antalya, Turkey
| | - Vesna Brankovic
- Clinic for Child Neurology and Psychiatry, University of Belgrade, Belgrade, Serbia
| | - Rebecca Herzog
- Department of Neurology, University Hospital Schleswig Holstein, Lübeck, Germany
| | - Alexis Brice
- Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France
| | - Alexandra Durr
- Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France
| | - Stephan Klebe
- Department of Neurology, University Hospital Essen, Essen, Germany
| | - Friedrich Stock
- Institute of Human Genetics, University Hospital Essen, Essen, Germany
| | | | - Tim W Rattay
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
| | - María-Jesús Sobrido
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain.,Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain
| | - Giovanna De Michele
- Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
| | - Peter De Jonghe
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.,Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
| | - Thomas Klopstock
- Department of Neurology, Friedrich-Baur-Institute, LMU Munich, Munich, Germany.,German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.,Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
| | - Katja Lohmann
- Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
| | - Ginevra Zanni
- Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy
| | | | - Vincent Timmerman
- Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.,Peripheral Neuropathy Research Group, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium
| | - Tobias B Haack
- Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tübingen, Germany.,Centre for Rare Diseases, University of Tübingen, Tübingen, Germany
| | - Stephan Züchner
- Dr John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Rebecca Schüle
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
| | - Giovanni Stevanin
- Sorbonne University, ICM-Paris Brain Institute, INSERM, CNRS, APHP, Pitié Salpêtrière Hospital, Paris, France.,Paris Sciences Lettres Research University, Ecole Pratique des Hautes Etudes, Paris, France
| | - Matthis Synofzik
- Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research (HIH), Center of Neurology, University of Tübingen, Tübingen, Germany.,German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany
| | - A Nazli Basak
- Koc University, School of Medicine, Suna and Inan Kirac Foundation, Istanbul, Turkey
| | - Jonathan Baets
- Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium.,Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.,Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium
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Insights into National Laboratory Newborn Screening and Future Prospects. Medicina (B Aires) 2022; 58:medicina58020272. [PMID: 35208595 PMCID: PMC8879506 DOI: 10.3390/medicina58020272] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 01/26/2022] [Accepted: 02/09/2022] [Indexed: 11/17/2022] Open
Abstract
Newborn screening (NBS) is a group of tests that check all newborns for certain rare conditions, covering several genetic or metabolic disorders. The laboratory NBS is performed through blood testing. However, the conditions that newborn babies are screened for vary from one country to another. Since NBS began in the 1960s, technological advances have enabled its expansion to include an increasing number of disorders, and there is a national trend to further expand the NBS program. The use of mass spectrometry (MS) for the diagnosis of inborn errors of metabolism (IEM) obviously helps in the expansion of the screening panels. This technology allows the detection of different metabolic disorders at one run, replacing the use of traditional techniques. Analysis of the targeted pathogenic gene variant is a routine application in the molecular techniques for the NBS program as a confirmatory testing to the positive laboratory screening results. Recently, a lot of molecular investigations, such as next generation sequencing (NGS), have been introduced in the routine NBS program. Nowadays, NGS techniques are widely used in the diagnosis of IMD where its results are rapid, confirmed and reliable, but, due to its uncertainties and the nature of IEM, it necessitates a holistic approach for diagnosis. However, various characteristics found in NGS make it a potentially powerful tool for NBS. A range of disorders can be analyzed with a single assay directly, and samples can reduce costs and can largely be automated. For the implementation of a robust technology such as NGS in a mass NBS program, the main focus should not be just technologically biased; it should also be tested for its long- and short-term impact on the family and the child. The crucial question here is whether large-scale genomic sequencing can provide useful medical information beyond what current NBS is already providing and at what economical and emotional cost? Currently, the topic of newborn genome sequencing as a public health initiative remains argumentative. Thus, this article seeks the answer to the question: NGS for newborn screening- are we there yet?
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Pakarinen E, Lindholm P, Saarma M, Lindahl M. CDNF and MANF regulate ER stress in a tissue-specific manner. Cell Mol Life Sci 2022; 79:124. [PMID: 35129674 PMCID: PMC8821067 DOI: 10.1007/s00018-022-04157-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 01/11/2022] [Accepted: 01/19/2022] [Indexed: 12/19/2022]
Abstract
Cerebral dopamine neurotrophic factor (CDNF) and mesencephalic astrocyte-derived neurotrophic factor (MANF) display cytoprotective effects in animal models of neurodegenerative diseases. These endoplasmic reticulum (ER)-resident proteins belong to the same protein family and function as ER stress regulators. The relationship between CDNF and MANF function, as well as their capability for functional compensation, is unknown. We aimed to investigate these questions by generating mice lacking both CDNF and MANF. Results showed that CDNF-deficient Manf−/− mice presented the same phenotypes of growth defect and diabetes as Manf−/− mice. In the muscle, CDNF deficiency resulted in increased activation of unfolded protein response (UPR), which was aggravated when MANF was ablated. In the brain, the combined loss of CDNF and MANF did not exacerbate UPR activation caused by the loss of MANF alone. Consequently, CDNF and MANF deficiency in the brain did not cause degeneration of dopamine neurons. In conclusion, CDNF and MANF present functional redundancy in the muscle, but not in the other tissues examined here. Thus, they regulate the UPR in a tissue-specific manner.
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Affiliation(s)
- Emmi Pakarinen
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland
| | - Päivi Lindholm
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, HiLIFE Unit, University of Helsinki, 00014, Helsinki, Finland.
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33
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Dai D, Mei M, Hu L, Cao Y, Wang X, Wang L, Lu Y, Yang L, Dong X, Wang H, Wu B, Qian L. Prevalence of monogenic disease in paediatric patients with a predominant respiratory phenotype. Arch Dis Child 2022; 107:141-147. [PMID: 34134972 PMCID: PMC8785068 DOI: 10.1136/archdischild-2021-322058] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/03/2021] [Indexed: 11/11/2022]
Abstract
OBJECTIVE This study aimed to investigate the prevalence and clinical characteristics of monogenic disease in paediatric patients with a predominant respiratory phenotype. METHODS Exome sequencing was performed in a cohort of 971 children with a predominant respiratory phenotype and suspected genetic aetiology. A total of 140 positive cases were divided into subgroups based on recruitment age and the primary biological system(s) involved. RESULTS There were 140 (14.4%) patients with a positive molecular diagnosis, and their primary clinical manifestations were respiratory distress (12.9%, 18 of 140), respiratory failure (12.9%, 18 of 140) and recurrent/persistent lower respiratory infections (66.4%, 93 of 140). Primary immunodeficiency (49.3%), multisystem malformations/syndromes (17.9%), and genetic lung disease (16.4%) were the three most common genetic causes in the cohort, and they varied among the age subgroups. A total of 72 (51.4%) patients had changes in medical management strategies after genetic diagnosis, and the rate in those with genetic lung disease (82.6%, 19 of 23) was far higher than that in patients with genetic disease with lung involvement (45.3%, 53 of 117) (p=0.001). CONCLUSION Our findings demonstrate that exome sequencing is a valuable diagnostic tool for monogenic diseases in children with a predominant respiratory phenotype, and the genetic spectrum varies with age. Taken together, genetic diagnoses provide invaluable clinical and prognostic information that may also facilitate the development of precision medicine for paediatric patients.
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Affiliation(s)
- Dan Dai
- Division of Pulmonary Medicine, Children's Hospital of Fudan University, Shanghai, China
| | - Mei Mei
- Division of Pulmonary Medicine, Children's Hospital of Fudan University, Shanghai, China
| | - Liyuan Hu
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Yun Cao
- Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China
| | - Xiaochuan Wang
- Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai, China
| | - Libo Wang
- Division of Pulmonary Medicine, Children's Hospital of Fudan University, Shanghai, China
| | - Yulan Lu
- Molecular Medical Center, Children's Hospital of Fudan University, Shanghai, China
| | - Lin Yang
- Molecular Medical Center, Children's Hospital of Fudan University, Shanghai, China,Shanghai Key Laboratory of Birth Defects, Shanghai, China
| | - Xinran Dong
- Molecular Medical Center, Children's Hospital of Fudan University, Shanghai, China
| | - Huijun Wang
- Molecular Medical Center, Children's Hospital of Fudan University, Shanghai, China
| | - Bingbing Wu
- Molecular Medical Center, Children's Hospital of Fudan University, Shanghai, China
| | - Liling Qian
- Division of Pulmonary Medicine, Children's Hospital of Fudan University, Shanghai, China .,Shanghai Key Laboratory of Birth Defects, Shanghai, China
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34
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Sukenik‐Halevy R, Perlman S, Ruhrman‐Shahar N, Engel O, Orenstein N, Gonzaga‐Jauregui C, Shuldiner AR, Magal N, Hagari O, Azulay N, Lidzbarsky GA, Bazak L, Basel‐Salmon L. The prevalence of prenatal sonographic findings in postnatal diagnostic exome sequencing performed for neurocognitive phenotypes: a cohort study. Prenat Diagn 2022; 42:717-724. [PMID: 35032046 PMCID: PMC9303252 DOI: 10.1002/pd.6095] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 01/01/2022] [Accepted: 01/09/2022] [Indexed: 11/24/2022]
Abstract
Objective Prenatal exome sequencing (ES) is currently indicated for fetal malformations. Some neurocognitive genetic disorders may not have a prenatal phenotype. We assessed the prevalence of prenatally detectable phenotypes among patients with neurocognitive syndromes diagnosed postnatally by ES. Methods The medical files of a cohort of 138 patients diagnosed postnatally with a neurocognitive disorder using ES were reviewed for prenatal sonographic data. The Online Mendelian Inheritance in Man (OMIM) database was searched for prenatally detectable phenotypes for all genes identified. Results Prenatal imaging data were available for 122 cases. Of these, 29 (23.75%) had fetal structural abnormalities and another 29 had other ultrasound abnormalities (fetal growth restriction, polyhydramnios, elevated nuchal translucency). In 30 patients, structural aberrations that were not diagnosed prenatally were detected at birth; in 21 (17.2%), the abnormalities could theoretically be detected prenatally by third‐trimester/targeted scans. According to OMIM, 55.9% of the diagnosed genes were not associated with structural anomalies. Conclusions Most patients (52.5%) with postnatally diagnosed neurocognitive disorders did not have prenatal sonographic findings indicating prenatal ES should be considered. The prevalence of specific prenatal phenotypes such as fetal growth restriction and polyhydramnios in our cohort suggests that additional prenatal findings should be assessed as possible indications for prenatal ES.
What's already known about this topic?
Prenatal exome sequencing (ES) is currently indicated for fetal malformations. Some neurocognitive genetic disorders may not have prenatal phenotypes.
What does this study add?
We assessed the prevalence of prenatally detectable phenotypes among 138 patients with neurocognitive syndromes diagnosed postnatally by ES. Fetal structural abnormalities were present in 23.75%. Other ultrasound abnormalities (such as fetal growth restriction, polyhydramnios) were reported in 23.75%. Most patients diagnosed with neurocognitive disorders did not have an indication for prenatal ES.
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Affiliation(s)
- Rivka Sukenik‐Halevy
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
| | - Sharon Perlman
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Ultrasound Unit Helen Schneider Women’s Hospital Rabin Medical Center Petach Tikva Israel
| | - Noa Ruhrman‐Shahar
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
| | - Offra Engel
- Department of Obstetrics and Gynecology Meir Medical Center Kfar Saba Israel
| | - Naama Orenstein
- Pediatric Genetics Clinic Schneider Children's Medical Center of Israel Petach Tikva Israel
| | | | | | - Nurit Magal
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
| | - Ofir Hagari
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
| | - Noy Azulay
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
| | - Gabriel Arie Lidzbarsky
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
| | - Lily Bazak
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
| | - Lina Basel‐Salmon
- Raphael Recanati Genetic Institute Rabin Medical Center – Beilinson Hospital Petach Tikva Israel
- Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
- Pediatric Genetics Clinic Schneider Children's Medical Center of Israel Petach Tikva Israel
- Felsenstein Medical Research Center Petach Tikva Israel
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35
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Ranganathan Ganakammal S, Huang K, Walkiewicz M, Xirasagar S. Genomics technologies and bioinformatics in allergy and immunology. ALLERGIC AND IMMUNOLOGIC DISEASES 2022:221-260. [DOI: 10.1016/b978-0-323-95061-9.00008-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Lindholm P, Saarma M. Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism. Mol Psychiatry 2022; 27:1310-1321. [PMID: 34907395 PMCID: PMC9095478 DOI: 10.1038/s41380-021-01394-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 11/09/2021] [Accepted: 11/15/2021] [Indexed: 12/20/2022]
Abstract
Midbrain dopamine neurons deteriorate in Parkinson's disease (PD) that is a progressive neurodegenerative movement disorder. No cure is available that would stop the dopaminergic decline or restore function of injured neurons in PD. Neurotrophic factors (NTFs), e.g., glial cell line-derived neurotrophic factor (GDNF) are small, secreted proteins that promote neuron survival during mammalian development and regulate adult neuronal plasticity, and they are studied as potential therapeutic agents for the treatment of neurodegenerative diseases. However, results from clinical trials of GDNF and related NTF neurturin (NRTN) in PD have been modest so far. In this review, we focus on cerebral dopamine neurotrophic factor (CDNF), an unconventional neurotrophic protein. CDNF delivered to the brain parenchyma protects and restores dopamine neurons in animal models of PD. In a recent Phase I-II clinical trial CDNF was found safe and well tolerated. CDNF deletion in mice led to age-dependent functional changes in the brain dopaminergic system and loss of enteric neurons resulting in slower gastrointestinal motility. These defects in Cdnf-/- mice intriguingly resemble deficiencies observed in early stage PD. Different from classical NTFs, CDNF can function both as an extracellular trophic factor and as an intracellular, endoplasmic reticulum (ER) luminal protein that protects neurons and other cell types against ER stress. Similarly to the homologous mesencephalic astrocyte-derived neurotrophic factor (MANF), CDNF is able to regulate ER stress-induced unfolded protein response (UPR) signaling and promote protein homeostasis in the ER. Since ER stress is thought to be one of the pathophysiological mechanisms contributing to the dopaminergic degeneration in PD, CDNF, and its small-molecule derivatives that are under development may provide useful tools for experimental medicine and future therapies for the treatment of PD and other neurodegenerative protein-misfolding diseases.
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Affiliation(s)
- Päivi Lindholm
- grid.7737.40000 0004 0410 2071Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014 Helsinki, Finland
| | - Mart Saarma
- Institute of Biotechnology, Helsinki Institute of Life Science, University of Helsinki, FI-00014, Helsinki, Finland.
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Abstract
PURPOSE OF REVIEW A single genetic diagnosis, especially from the analysis of a limited number of genes, may not signal the end of a diagnostic odyssey. When a patient with a genetic syndrome presents with symptoms that are not usually associated with their disease phenotype, additional genetic testing is warranted. RECENT FINDINGS Although multiple co-existing genetic diagnoses may sound unlikely, many recent studies and case reports have demonstrated that this scenario is more common than expected. Studies involving whole exome and genome sequencing have identified a frequency of multiple genetic diagnoses and have identified clinical findings that make a second diagnosis more likely, which we have seen reflected in recent cases from our own clinic and consult service. These include multisystem disease, consanguinity, well described aneuploidies with rare or new symptoms, and complex structural chromosomal anomalies which may include multiple chromosomes and breakpoints that disrupt gene function. SUMMARY Identifying a second diagnosis can have vast implications for patient management and counseling. Patients can be followed with appropriate medical screening and early interventions to support optimal child development. Furthermore, the patient's family can be impacted by ending the diagnostic odyssey, providing testing for other at-risk family members, and offering prenatal options.
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Affiliation(s)
- Kristin B Linscott
- Department of Genetics
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jennifer A Cassady
- Department of Genetics
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Nathaniel H Robin
- Department of Genetics
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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38
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Ikäheimo K, Herranen A, Iivanainen V, Lankinen T, Aarnisalo AA, Sivonen V, Patel KA, Demir K, Saarma M, Lindahl M, Pirvola U. MANF supports the inner hair cell synapse and the outer hair cell stereocilia bundle in the cochlea. Life Sci Alliance 2021; 5:5/2/e202101068. [PMID: 34815294 PMCID: PMC8616558 DOI: 10.26508/lsa.202101068] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 11/08/2021] [Accepted: 11/08/2021] [Indexed: 11/29/2022] Open
Abstract
The authors show in the mouse how the auditory hair cell structural maintenance is perturbed by the inactivation of Manf and the concomitant ER stress, causing early-onset, progressive hearing loss. Failure in the structural maintenance of the hair cell stereocilia bundle and ribbon synapse causes hearing loss. Here, we have studied how ER stress elicits hair cell pathology, using mouse models with inactivation of Manf (mesencephalic astrocyte-derived neurotrophic factor), encoding an ER-homeostasis-promoting protein. From hearing onset, Manf deficiency caused disarray of the outer hair cell stereocilia bundle and reduced cochlear sound amplification capability throughout the tonotopic axis. In high-frequency outer hair cells, the pathology ended in molecular changes in the stereocilia taper region and in strong stereocilia fusion. In high-frequency inner hair cells, Manf deficiency degraded ribbon synapses. The altered phenotype strongly depended on the mouse genetic background. Altogether, the failure in the ER homeostasis maintenance induced early-onset stereociliopathy and synaptopathy and accelerated the effect of genetic causes driving age-related hearing loss. Correspondingly, MANF mutation in a human patient induced severe sensorineural hearing loss from a young age onward. Thus, we present MANF as a novel protein and ER stress as a mechanism that regulate auditory hair cell maintenance in both mice and humans.
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Affiliation(s)
- Kuu Ikäheimo
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
| | - Anni Herranen
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
| | - Vilma Iivanainen
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
| | - Tuuli Lankinen
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
| | - Antti A Aarnisalo
- Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Ville Sivonen
- Department of Otorhinolaryngology-Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Kashyap A Patel
- Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK
| | - Korcan Demir
- Department of Paediatric Endocrinology, Dokuz Eylul University, Izmir, Turkey
| | - Mart Saarma
- Institute of Biotechnology, HILIFE Unit, University of Helsinki, Helsinki, Finland
| | - Maria Lindahl
- Institute of Biotechnology, HILIFE Unit, University of Helsinki, Helsinki, Finland
| | - Ulla Pirvola
- Molecular and Integrative Biosciences Research Programme, University of Helsinki, Helsinki, Finland
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Parenti I, Kaiser FJ. Cornelia de Lange Syndrome as Paradigm of Chromatinopathies. Front Neurosci 2021; 15:774950. [PMID: 34803598 PMCID: PMC8603810 DOI: 10.3389/fnins.2021.774950] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Accepted: 10/18/2021] [Indexed: 12/18/2022] Open
Abstract
Chromatinopathies can be defined as a class of neurodevelopmental disorders caused by mutations affecting proteins responsible for chromatin remodeling and transcriptional regulation. The resulting dysregulation of gene expression favors the onset of a series of clinical features such as developmental delay, intellectual disability, facial dysmorphism, and behavioral disturbances. Cornelia de Lange syndrome (CdLS) is a prime example of a chromatinopathy. It is caused by mutations affecting subunits or regulators of the cohesin complex, a multisubunit protein complex involved in various molecular mechanisms such as sister chromatid cohesion, transcriptional regulation and formation of topologically associated domains. However, disease-causing variants in non-cohesin genes with overlapping functions have also been described in association with CdLS. Notably, the majority of these genes had been previously found responsible for distinct neurodevelopmental disorders that also fall within the category of chromatinopathies and are frequently considered as differential diagnosis for CdLS. In this review, we provide a systematic overview of the current literature to summarize all mutations in non-cohesin genes identified in association with CdLS phenotypes and discuss about the interconnection of proteins belonging to the chromatinopathies network.
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Affiliation(s)
- Ilaria Parenti
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany
| | - Frank J Kaiser
- Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.,Essener Zentrum für Seltene Erkrankungen (EZSE), Universitätsklinikum Essen, Essen, Germany
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40
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Calame DG, Fatih JM, Herman I, Coban‐Akdemir Z, Du H, Mitani T, Jhangiani SN, Marafi D, Gibbs RA, Posey JE, Mehta VP, Mohila CA, Abid F, Lotze TE, Pehlivan D, Adesina AM, Lupski JR. Deep clinicopathological phenotyping identifies a previously unrecognized pathogenic EMD splice variant. Ann Clin Transl Neurol 2021; 8:2052-2058. [PMID: 34524739 PMCID: PMC8528454 DOI: 10.1002/acn3.51454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2021] [Revised: 08/12/2021] [Accepted: 09/02/2021] [Indexed: 12/05/2022] Open
Abstract
Exome sequencing (ES) has revolutionized rare disease management, yet only ~25%-30% of patients receive a molecular diagnosis. A limiting factor is the quality of available phenotypic data. Here, we describe how deep clinicopathological phenotyping yielded a molecular diagnosis for a 19-year-old proband with muscular dystrophy and negative clinical ES. Deep phenotypic analysis identified two critical data points: (1) the absence of emerin protein in muscle biopsy and (2) clinical features consistent with Emery-Dreifuss muscular dystrophy. Sequencing data analysis uncovered an ultra-rare, intronic variant in EMD, the gene encoding emerin. The variant, NM_000117.3: c.188-6A > G, is predicted to impact splicing by in silico tools. This case thus illustrates how better integration of clinicopathologic data into ES analysis can enhance diagnostic yield with implications for clinical practice.
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Affiliation(s)
- Daniel G. Calame
- Division of Neurology and Developmental NeuroscienceDepartment of PediatricsBaylor College of MedicineHoustonTexas77030USA
- Texas Children’s HospitalHoustonTexas77030USA
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | - Jawid M. Fatih
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | - Isabella Herman
- Division of Neurology and Developmental NeuroscienceDepartment of PediatricsBaylor College of MedicineHoustonTexas77030USA
- Texas Children’s HospitalHoustonTexas77030USA
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | - Zeynep Coban‐Akdemir
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | - Haowei Du
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | - Tadahiro Mitani
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | | | - Dana Marafi
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
- Department of PediatricsFaculty of MedicineKuwait UniversitySafat13110Kuwait
| | - Richard A. Gibbs
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
- Human Genome Sequencing CenterBaylor College of MedicineHoustonTexas77030USA
| | - Jennifer E. Posey
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | - Vidya P. Mehta
- Department of PathologyTexas Children's HospitalBaylor College of MedicineHoustonTexas77030USA
| | - Carrie A. Mohila
- Department of PathologyTexas Children's HospitalBaylor College of MedicineHoustonTexas77030USA
| | - Farida Abid
- Division of Neurology and Developmental NeuroscienceDepartment of PediatricsBaylor College of MedicineHoustonTexas77030USA
- Texas Children’s HospitalHoustonTexas77030USA
| | - Timothy E. Lotze
- Division of Neurology and Developmental NeuroscienceDepartment of PediatricsBaylor College of MedicineHoustonTexas77030USA
- Texas Children’s HospitalHoustonTexas77030USA
| | - Davut Pehlivan
- Division of Neurology and Developmental NeuroscienceDepartment of PediatricsBaylor College of MedicineHoustonTexas77030USA
- Texas Children’s HospitalHoustonTexas77030USA
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
| | - Adekunle M. Adesina
- Department of PathologyTexas Children's HospitalBaylor College of MedicineHoustonTexas77030USA
| | - James R. Lupski
- Texas Children’s HospitalHoustonTexas77030USA
- Department of Molecular and Human GeneticsBaylor College of MedicineHoustonTexas77030USA
- Human Genome Sequencing CenterBaylor College of MedicineHoustonTexas77030USA
- Department of PediatricsBaylor College of MedicineHoustonTexas77030USA
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41
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Marco Hernández AV, Caro A, Montoya Filardi A, Tomás Vila M, Monfort S, Beseler Soto B, Nieto-Barceló JJ, Martínez F. Extending the clinical phenotype of SPTAN1: From DEE5 to migraine, epilepsy, and subependymal heterotopias without intellectual disability. Am J Med Genet A 2021; 188:147-159. [PMID: 34590414 DOI: 10.1002/ajmg.a.62507] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/23/2021] [Accepted: 08/26/2021] [Indexed: 11/08/2022]
Abstract
Mutations in SPTAN1 gene, encoding the nonerythrocyte αII-spectrin, are responsible for a severe developmental and epileptic encephalopathy (DEE5) and a wide spectrum of neurodevelopmental disorders, as epilepsy with or without intellectual disability (ID) or ID with cerebellar syndrome. A certain genotype-phenotype correlation has been proposed according to the type and location of the mutation. Herein, we report three novel cases with de novo SPTAN1 mutations, one of them associated to a mild phenotype not previously described. They range from (1) severe developmental encephalopathy with ataxia and a mild cerebellar atrophy, without epilepsy; (2) moderate intellectual disability, severe language delay, ataxia and tremor; (3) normal intelligence, chronic migraine, and generalized tonic-clonic seizures. Remarkably, all these patients showed brain MRI abnormalities, being of special interest the subependymal heterotopias detected in the latter patient. Thus we extend the SPTAN1-related phenotypic spectrum, both in its radiological and clinical involvement. Furthermore, after systematic analysis of all the patients so far reported, we noted an excess of male versus female patients (20:9, p = 0.04), more pronounced among the milder phenotypes. Consequently, some protection factor might be suspected among female carriers, which if confirmed should be considered when establishing the pathogenicity of milder genetic variants in this gene.
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Affiliation(s)
- Ana Victoria Marco Hernández
- Genetics Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain.,Neuropediatrics Section, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Alfonso Caro
- Genetics Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | | | - Miguel Tomás Vila
- Neuropediatrics Section, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Sandra Monfort
- Genetics Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - Beatriz Beseler Soto
- Neuropediatrics Section, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | | | - Francisco Martínez
- Genetics Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
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42
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Abstract
Almost 25 years have passed since a mutation of a formin gene, DIAPH1, was identified as being responsible for a human inherited disorder: a form of sensorineural hearing loss. Since then, our knowledge of the links between formins and disease has deepened considerably. Mutations of DIAPH1 and six other formin genes (DAAM2, DIAPH2, DIAPH3, FMN2, INF2 and FHOD3) have been identified as the genetic cause of a variety of inherited human disorders, including intellectual disability, renal disease, peripheral neuropathy, thrombocytopenia, primary ovarian insufficiency, hearing loss and cardiomyopathy. In addition, alterations in formin genes have been associated with a variety of pathological conditions, including developmental defects affecting the heart, nervous system and kidney, aging-related diseases, and cancer. This review summarizes the most recent discoveries about the involvement of formin alterations in monogenic disorders and other human pathological conditions, especially cancer, with which they have been associated. In vitro results and experiments in modified animal models are discussed. Finally, we outline the directions for future research in this field.
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Affiliation(s)
| | - Miguel A. Alonso
- Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Madrid, Spain;
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43
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SPTAN1 variants likely cause autosomal recessive complicated hereditary spastic paraplegia. J Hum Genet 2021; 67:165-168. [PMID: 34526651 DOI: 10.1038/s10038-021-00975-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/24/2021] [Accepted: 08/24/2021] [Indexed: 11/09/2022]
Abstract
Heterozygous mutations in SPTAN1 are associated with a broad phenotypical spectrum ranging from axonal neuropathy phenotypes to neurodevelopmental phenotypes with or without epilepsy. Recently, biallelic mutations in SPTAN1 were reported as a potential cause of autosomal recessive pure hereditary spastic paraplegia (HSP). However, no further HSP cases with biallelic SPTAN1 mutations have been reported. Herein, we report the clinical and genetic findings of a patient with complicated HSP likely caused by a novel homozygous SPTAN1 mutation. A patient with complicated HSP from a consanguineous family was recruited. The proband underwent detailed neurological examinations. Homozygosity mapping was performed in the proband and her healthy sister. Whole exome sequencing was performed in the proband. Our patient had early onset motor symptoms with upper motor neuron paralysis and intellectual disability, which is compatible with complicated HSP. Genetic analysis identified a rare homozygous missense mutation in SPTAN1 (c.4162A>G, p.I1388V), which was predicted to be deleterious by in silico tools. Her healthy parents and sister all carried the heterozygous mutation. Our results provided further support for the association of biallelic SPTAN1 variants with HSP and suggested that screening for the SPTAN1 gene should be considered not only in patients with pure HSP but also in patients with complicated HSP.
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44
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Lenglez S, Sablon A, Fénelon G, Boland A, Deleuze JF, Boutoleau-Bretonnière C, Nicolas G, Demoulin JB. Distinct functional classes of PDGFRB pathogenic variants in primary familial brain calcification. Hum Mol Genet 2021; 31:399-409. [PMID: 34494111 DOI: 10.1093/hmg/ddab258] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/30/2021] [Accepted: 08/31/2021] [Indexed: 01/30/2023] Open
Abstract
Platelet-derived growth factor receptor beta (PDGFRB) is one of the genes associated with primary familial brain calcification (PFBC), an inherited neurological disease (OMIM:173410). Genetic analysis of patients and families revealed at least 13 PDGFRB heterozygous missense variants, including two novel ones described in the present report. Limited experimental data published on five of these variants had suggested that they decrease the receptor activity. No functional information was available on the impact of variants located within the receptor extracellular domains. Here, we performed a comprehensive molecular analysis of PDGFRB variants linked to PFBC. Mutated receptors were transfected in various cell lines to monitor receptor expression, signaling, mitogenic activity, and ligand binding. Four mutants caused a complete loss of tyrosine kinase activity in multiple assays. One of the novel variants, p.Pro154Ser, decreased the receptor expression and abolished binding of platelet-derived growth factor (PDGF-BB). Others showed a partial loss of function related to reduced expression or signaling. Combining clinical, genetic and molecular data, we consider nine variants as pathogenic or likely pathogenic, three as benign or likely benign and one as a variant of unknown significance. We discuss the possible relationship between the variant residual activity, incomplete penetrance, brain calcification and neurological symptoms. In conclusion, we identified distinct molecular mechanisms whereby PDGFRB variants may result in a receptor loss of function. This work will facilitate genetic counselling in PFBC.
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Affiliation(s)
- Sandrine Lenglez
- De Duve Institute, Université catholique de Louvain, BE-1200, Brussels, Belgium
| | - Ariane Sablon
- De Duve Institute, Université catholique de Louvain, BE-1200, Brussels, Belgium
| | - Gilles Fénelon
- Department of Neurology, APHP, CHU Henri Mondor, Créteil, France
| | - Anne Boland
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, F-91057, Evry, France
| | - Jean-François Deleuze
- Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine, F-91057, Evry, France
| | - Claire Boutoleau-Bretonnière
- CHU Nantes, Centre Mémoire Ressource et Recherche (CMRR), Department of Neurology, F-44093, Nantes, France.,Inserm CIC 04, F-4409, Nantes, France
| | - Gaël Nicolas
- Normandie Univ, UNIROUEN, Inserm U1245, CHU Rouen, Department of Genetics and CNR-MAJ, FHU G4 Génomique, F-76000, Rouen, France
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45
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Konovalova J, Gerasymchuk D, Arroyo SN, Kluske S, Mastroianni F, Pereyra AV, Domanskyi A. Human-Specific Regulation of Neurotrophic Factors MANF and CDNF by microRNAs. Int J Mol Sci 2021; 22:9691. [PMID: 34575854 PMCID: PMC8466963 DOI: 10.3390/ijms22189691] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/16/2022] Open
Abstract
Mesencephalic astrocyte derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are novel evolutionary conserved trophic factors, which exhibit cytoprotective activity via negative regulation of unfolded protein response (UPR) and inflammation. Despite multiple reports demonstrating detrimental effect of MANF/CDNF downregulation, little is known about the control of their expression. miRNAs-small non-coding RNAs-are important regulators of gene expression. Their dysregulation was demonstrated in multiple pathological processes and their ability to modulate levels of other neurotrophic factors, glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF), was previously reported. Here, for the first time we demonstrated direct regulation of MANF and CDNF by miRNAs. Using bioinformatic tools, reporter assay and analysis of endogenous MANF and CDNF, we identified that miR-144 controls MANF expression, and miR-134 and miR-141 downregulate CDNF levels. We also demonstrated that this effect is human-specific and is executed via predicted binding sites of corresponding miRNAs. Finally, we found that miR-382 suppressed hCDNF expression indirectly. In conclusion, we demonstrate for the first time direct regulation of MANF and CDNF expression by specific miRNAs, despite the fact their binding sites are not strongly evolutionary conserved. Furthermore, we demonstrate a functional effect of miR-144 mediated regulation of MANF on ER stress response markers. These findings emphasize that (1) prediction of miRNA targets based on evolutionary conservation may miss biologically meaningful regulatory pairs; and (2) interpretation of miRNA regulatory effects in animal models should be cautiously validated.
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Affiliation(s)
- Julia Konovalova
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland; (J.K.); (D.G.); (S.N.A.); (S.K.); (F.M.); (A.V.P.)
| | - Dmytro Gerasymchuk
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland; (J.K.); (D.G.); (S.N.A.); (S.K.); (F.M.); (A.V.P.)
- Institute of Molecular Biology and Genetics, NASU, 03143 Kyiv, Ukraine
| | - Sergio Navarette Arroyo
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland; (J.K.); (D.G.); (S.N.A.); (S.K.); (F.M.); (A.V.P.)
| | - Sven Kluske
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland; (J.K.); (D.G.); (S.N.A.); (S.K.); (F.M.); (A.V.P.)
| | - Francesca Mastroianni
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland; (J.K.); (D.G.); (S.N.A.); (S.K.); (F.M.); (A.V.P.)
| | - Alba Vargas Pereyra
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland; (J.K.); (D.G.); (S.N.A.); (S.K.); (F.M.); (A.V.P.)
| | - Andrii Domanskyi
- Institute of Biotechnology, HiLIFE, University of Helsinki, Viikinkaari 5D, 00790 Helsinki, Finland; (J.K.); (D.G.); (S.N.A.); (S.K.); (F.M.); (A.V.P.)
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46
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Ali Alghamdi M, Alrasheedi A, Alghamdi E, Adly N, AlAali WY, Alhashem A, Alshahrani A, Shamseldin H, Alkuraya FS, Alfadhel M. Molecular autopsy by proxy in preconception counseling. Clin Genet 2021; 100:678-691. [PMID: 34406647 PMCID: PMC9290025 DOI: 10.1111/cge.14049] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 08/15/2021] [Accepted: 08/17/2021] [Indexed: 01/06/2023]
Abstract
Monogenic diseases that result in early pregnancy loss or neonatal death are genetically and phenotypically highly variable. This often poses significant challenges in arriving at a molecular diagnosis for reproductive planning. Molecular autopsy by proxy (MABP) refers to the genetic testing of relatives of deceased individuals to deduce the cause of death. Here, we specifically tested couples who lost one or more children/pregnancies with no available DNA. We developed our testing strategy using whole exome sequencing data from 83 consanguineous Saudi couples. We detected the shared carrier state of 50 pathogenic variants/likely pathogenic variants in 43 families and of 28 variants of uncertain significance in 24 families. Negative results were seen in 16 couples after variant reclassification. In 10 families, the risk of more than one genetic disease was documented. Secondary findings were seen in 10 families: either genetic variants with potential clinical consequences for the tested individual or a female carrier for X‐linked conditions. This couple‐based approach has enabled molecularly informed genetic counseling for 52% (43/83 families). Given the predominance of autosomal recessive causes of pregnancy and child death in consanguineous populations, MABP can be a helpful approach to consanguineous couples who seek counseling but lack molecular data on their deceased offspring.
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Affiliation(s)
- Malak Ali Alghamdi
- Medical Genetic Division, Pediatric Department, College of Medicine, King Saud University, Riyadh, Saudi Arabia.,Medical Genetics Division, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Ameinah Alrasheedi
- Department of Pediatrics, College of Medicine and Medical Sciences, Qassim University, Al Qassim, Saudi Arabia
| | - Esra Alghamdi
- College of Medicine, Imam Mohammed Ibn Saud Islamic University, Riyadh, Saudi Arabia
| | - Nouran Adly
- College of Medicine Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Wajeih Y AlAali
- Dr. Sulaiman Al Habib Medical Group, Riyadh, Saudi Arabia.,Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | - Amal Alhashem
- Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.,College of Medicine, Alfaisal University, Riyadh, Saudi Arabia
| | | | - Hanan Shamseldin
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Fowzan S Alkuraya
- Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Majid Alfadhel
- King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia.,Genetics and Precision Medicine department, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
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47
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Vincent KM, Eaton A, Yassaee VR, Miryounesi M, Hashemi-Gorji F, Rudichuk L, Goez H, Leonard N, Lazier J. Delineating the expanding phenotype of HERC2-related disorders: The impact of biallelic loss of function versus missense variation. Clin Genet 2021; 100:637-640. [PMID: 34370298 DOI: 10.1111/cge.14039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 07/06/2021] [Accepted: 07/24/2021] [Indexed: 11/28/2022]
Abstract
HECT And RLD Domain-Containing E3 Ubiquitin Protein Ligase 2, or HERC2, codes an ubiquitin ligase that has an important role in key cellular processes including cell cycle regulation, DNA repair, mitochondrial functions, and spindle formation during mitosis. While HERC2 Neurodevelopmental Disorder in Old Order Amish is a well characterized human disorder involving HERC2, bi-allelic HERC2 loss of function has only been described in three families and results in a more severe neurodevelopmental disorder. Herein, we delineate the HERC2 loss of function phenotype by describing three previously unreported patients, and by summarizing the molecular and phenotypic information of all known HERC2 missense variants and biallelic loss of function patients. Collectively, these twelve individuals present with recurring features that define a syndrome with varying combinations of severe neurodevelopmental delay, structural brain anomalies, seizures, hypotonia, feeding difficulties, hearing and vision issues, and renal anomalies. This study describes a distinct neurodevelopmental disorder, emphasizing the importance of further characterization of HERC2-related disorders, as well as highlighting the importance of ongoing work into understanding these critical neurodevelopmental pathways.
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Affiliation(s)
- Krista M Vincent
- Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada
| | - Alison Eaton
- Department of Medical Genetics, University of Alberta, Edmonton, Canada
| | - Vahid Reza Yassaee
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Miryounesi
- Genomic Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Lauren Rudichuk
- Department of Medical Genetics, University of Alberta, Edmonton, Canada
| | - Helly Goez
- Department of Pediatrics, University of Alberta, Edmonton, Canada
| | - Norma Leonard
- Department of Medical Genetics, University of Alberta, Edmonton, Canada.,Women's and Children's Research Institute, Edmonton, Canada
| | - Joanna Lazier
- Department of Medical Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada.,Department of Medical Genetics, University of Alberta, Edmonton, Canada.,Women's and Children's Research Institute, Edmonton, Canada
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48
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Liu S, Yan Z, Huang Y, Zheng W, Deng Y, Zou Y, Xie H. A case of White-Sutton syndrome arising from a maternally-inherited mutation in POGZ. Psychiatr Genet 2021; 31:135-139. [PMID: 34133408 PMCID: PMC8265545 DOI: 10.1097/ypg.0000000000000288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 05/17/2021] [Indexed: 11/27/2022]
Abstract
POGZ is located on chromosome 1q21.3, encoding a pogo transposable element-derived protein with a zinc finger cluster. White-Sutton syndrome (WHSUS, OMIM:616364) is a genetic disorder resulting from de novo heterozygous pathogenic variants in POGZ, which manifests as intellectual disability, autism spectrum disorder, specific facial features and other phenotypic spectra. To date, a total of twenty-one de novo POGZ mutations in WHSUS have been reported. Here we report the identification of a novel missense variant in the coding region of the POGZ gene (c.4042G>C), which occurred in a 15-year-old male and his mother with WHSUS. We describe their clinical features and compare them with clinical data of patients with WHSUS from the literature. Our finding broadens the spectrum of POGZ mutations and provides a good example of precision medicine through the combination of exome sequencing and clinical testing.
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Affiliation(s)
- Siqin Liu
- Department of Neurology, Zhujiang Hospital
| | | | | | - Wenxia Zheng
- Department of Neurology, Shunde Hospital, Southern Medical University, Guangzhou City, China
| | | | - Yang Zou
- Department of Neurology, Zhujiang Hospital
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49
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Narayanan DL, Udyawar D, Kaur P, Sharma S, Suresh N, Nampoothiri S, do Rosario MC, Somashekar PH, Rao LP, Kausthubham N, Majethia P, Pande S, Ramesh Bhat Y, Shrikiran A, Bielas S, Girisha KM, Shukla A. Multilocus disease-causing genomic variations for Mendelian disorders: role of systematic phenotyping and implications on genetic counselling. Eur J Hum Genet 2021; 29:1774-1780. [PMID: 34276053 PMCID: PMC8633282 DOI: 10.1038/s41431-021-00933-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 04/24/2021] [Accepted: 06/22/2021] [Indexed: 11/09/2022] Open
Abstract
Multilocus disease-causing genomic variations (MGVs) and multiple genetic diagnoses (MGDs) are increasingly being recognised in individuals and families with Mendelian disorders. This can be mainly attributed to the widespread use of genomic tests for the evaluation of these disorders. We conducted a retrospective study of families evaluated over the last 6 years at our centre to identify families with MGVs and MGDs. MGVs were observed in fourteen families. We observed five different consequences: (i) individuals with MGVs presenting as blended phenotypes (ii) individuals with MGVs presenting with distinct phenotypes (iii) individuals with MGVs with age-dependent penetrance (iv) individuals with MGVs with one phenotype obscured by another more predominant phenotype (v) two distinct phenotypes in different individuals in families with MGVs. Consanguinity was present in eight (8/14, 57.1%) of them. Thirteen families had two Mendelian disorders and one had three Mendelian disorders. The risk of recurrence of one or more conditions in these families ranged from 25% to 75%. Our findings underline the importance of the role of a clinical geneticist in systematic phenotyping, challenges in genetic counselling and risk estimation in families with MGVs and MGDs, especially in highly inbred populations.
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Affiliation(s)
- Dhanya Lakshmi Narayanan
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Divya Udyawar
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Parneet Kaur
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Suvasini Sharma
- Department of Pediatrics (Neurology division), Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India
| | - Narayanaswamy Suresh
- Department of Pediatrics (Neurology division), Lady Hardinge Medical College and Kalawati Saran Children's Hospital, New Delhi, India
| | - Sheela Nampoothiri
- Department of Pediatric Genetics, Amrita Institute of Medical Sciences and Research Centre, Cochin, India
| | - Michelle C do Rosario
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Puneeth H Somashekar
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Lakshmi Priya Rao
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Neethukrishna Kausthubham
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Purvi Majethia
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Shruti Pande
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Y Ramesh Bhat
- Department of Pediatrics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Aroor Shrikiran
- Department of Pediatrics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Stephanie Bielas
- Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI, USA
| | - Katta Mohan Girisha
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India
| | - Anju Shukla
- Department of Medical Genetics, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India.
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50
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Molina-Ramírez LP, Kyle C, Ellingford JM, Wright R, Taylor A, Bhaskar SS, Campbell C, Jackson H, Fairclough A, Rousseau A, Burghel GJ, Dutton L, Banka S, Briggs TA, Clayton-Smith J, Douzgou S, Jones EA, Kingston HM, Kerr B, Ealing J, Somarathi S, Chandler KE, Stuart HM, Burkitt-Wright EM, Newman WG, Bruce IA, Black GC, Gokhale D. Personalised virtual gene panels reduce interpretation workload and maintain diagnostic rates of proband-only clinical exome sequencing for rare disorders. J Med Genet 2021; 59:393-398. [PMID: 33879512 PMCID: PMC8961756 DOI: 10.1136/jmedgenet-2020-107303] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 01/17/2021] [Accepted: 02/14/2021] [Indexed: 01/20/2023]
Abstract
Purpose The increased adoption of genomic strategies in the clinic makes it imperative for diagnostic laboratories to improve the efficiency of variant interpretation. Clinical exome sequencing (CES) is becoming a valuable diagnostic tool, capable of meeting the diagnostic demand imposed by the vast array of different rare monogenic disorders. We have assessed a clinician-led and phenotype-based approach for virtual gene panel generation for analysis of targeted CES in patients with rare disease in a single institution. Methods Retrospective survey of 400 consecutive cases presumed by clinicians to have rare monogenic disorders, referred on singleton basis for targeted CES. We evaluated diagnostic yield and variant workload to characterise the usefulness of a clinician-led approach for generation of virtual gene panels that can incorporate up to three different phenotype-driven gene selection methods. Results Abnormalities of the nervous system (54.5%), including intellectual disability, head and neck (19%), skeletal system (16%), ear (15%) and eye (15%) were the most common clinical features reported in referrals. Combined phenotype-driven strategies for virtual gene panel generation were used in 57% of cases. On average, 7.3 variants (median=5) per case were retained for clinical interpretation. The overall diagnostic rate of proband-only CES using personalised phenotype-driven virtual gene panels was 24%. Conclusions Our results show that personalised virtual gene panels are a cost-effective approach for variant analysis of CES, maintaining diagnostic yield and optimising the use of resources for clinical genomic sequencing in the clinic.
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Affiliation(s)
- Leslie Patricia Molina-Ramírez
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Claire Kyle
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Jamie M Ellingford
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Ronnie Wright
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Algy Taylor
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Sanjeev S Bhaskar
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Christopher Campbell
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Harriet Jackson
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Adele Fairclough
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Abigail Rousseau
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - George J Burghel
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Laura Dutton
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Siddharth Banka
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Tracy A Briggs
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Jill Clayton-Smith
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Sofia Douzgou
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Elizabeth A Jones
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK
| | - Helen M Kingston
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Bronwyn Kerr
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - John Ealing
- Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK.,Department of Neurology, Salford Royal NHS Foundation Trust, Salford, Salford, UK
| | - Suresh Somarathi
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Kate E Chandler
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Helen M Stuart
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Emma Mm Burkitt-Wright
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - William G Newman
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Iain A Bruce
- Division of Infection, Immunity and Respiratory Medicine, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.,Paediatric ENT Department, Royal Manchester Children's Hospital, Manchester University NHS Foundation Trust, Manchester, UK
| | - Graeme C Black
- Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK .,North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - David Gokhale
- North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
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