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Article: Neurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics

TitleNeurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics
Authors
Issue Date2021
PublisherBMJ Group. The Journal's web site is located at http://jmg.bmj.com/
Citation
Journal of Medical Genetics, 2021, v. 58 n. 9, p. 609-618 How to Cite?
AbstractBackground Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions. Methods We performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required. Results Of the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with CACNA1S, CHRNB1, GMPPB and STAC3. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations—SMPD4. Conclusions Comprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.
Persistent Identifierhttp://hdl.handle.net/10722/305420
ISSN
2023 Impact Factor: 3.5
2023 SCImago Journal Rankings: 1.690
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorRavenscroft, G-
dc.contributor.authorClayton, JS-
dc.contributor.authorFaiz, F-
dc.contributor.authorSivadorai, P-
dc.contributor.authorMilnes, D-
dc.contributor.authorCincotta, R-
dc.contributor.authorMoon, P-
dc.contributor.authorKamien, B-
dc.contributor.authorEdwards, M-
dc.contributor.authorDelatycki, M-
dc.contributor.authorLamont, PJ-
dc.contributor.authorChan, SHS-
dc.contributor.authorColley, A-
dc.contributor.authorMa, A-
dc.contributor.authorCollins, F-
dc.contributor.authorHennington, L-
dc.contributor.authorZhao, T-
dc.contributor.authorMcGillivray, G-
dc.contributor.authorGhedia, S-
dc.contributor.authorChao, K-
dc.contributor.authorO'Donnell-Luria, A-
dc.contributor.authorLaing, NG-
dc.contributor.authorDavis, MR-
dc.date.accessioned2021-10-20T10:09:09Z-
dc.date.available2021-10-20T10:09:09Z-
dc.date.issued2021-
dc.identifier.citationJournal of Medical Genetics, 2021, v. 58 n. 9, p. 609-618-
dc.identifier.issn0022-2593-
dc.identifier.urihttp://hdl.handle.net/10722/305420-
dc.description.abstractBackground Fetal akinesia and arthrogryposis are clinically and genetically heterogeneous and have traditionally been refractive to genetic diagnosis. The widespread availability of affordable genome-wide sequencing has facilitated accurate genetic diagnosis and gene discovery in these conditions. Methods We performed next generation sequencing (NGS) in 190 probands with a diagnosis of arthrogryposis multiplex congenita, distal arthrogryposis, fetal akinesia deformation sequence or multiple pterygium syndrome. This sequencing was a combination of bespoke neurogenetic disease gene panels and whole exome sequencing. Only class 4 and 5 variants were reported, except for two cases where the identified variants of unknown significance (VUS) are most likely to be causative for the observed phenotype. Co-segregation studies and confirmation of variants identified by NGS were performed where possible. Functional genomics was performed as required. Results Of the 190 probands, 81 received an accurate genetic diagnosis. All except two of these cases harboured class 4 and/or 5 variants based on the American College of Medical Genetics and Genomics guidelines. We identified phenotypic expansions associated with CACNA1S, CHRNB1, GMPPB and STAC3. We describe a total of 50 novel variants, including a novel missense variant in the recently identified gene for arthrogryposis with brain malformations—SMPD4. Conclusions Comprehensive gene panels give a diagnosis for a substantial proportion (42%) of fetal akinesia and arthrogryposis cases, even in an unselected cohort. Recently identified genes account for a relatively large proportion, 32%, of the diagnoses. Diagnostic-research collaboration was critical to the diagnosis and variant interpretation in many cases, facilitated genotype-phenotype expansions and reclassified VUS through functional genomics.-
dc.languageeng-
dc.publisherBMJ Group. The Journal's web site is located at http://jmg.bmj.com/-
dc.relation.ispartofJournal of Medical Genetics-
dc.rightsJournal of Medical Genetics. Copyright © BMJ Group.-
dc.rightsThis article has been accepted for publication in Journal of Medical Genetics, 2021 following peer review, and the Version of Record can be accessed online at http://dx.doi.org/10.1136/jmedgenet-2020-106901 © Authors 2021-
dc.titleNeurogenetic fetal akinesia and arthrogryposis: genetics, expanding genotype-phenotypes and functional genomics-
dc.typeArticle-
dc.identifier.emailChan, SHS: sophehs@hku.hk-
dc.identifier.authorityChan, SHS=rp02210-
dc.description.naturepostprint-
dc.identifier.doi10.1136/jmedgenet-2020-106901-
dc.identifier.pmid33060286-
dc.identifier.pmcidPMC8328565-
dc.identifier.scopuseid_2-s2.0-85094211903-
dc.identifier.hkuros328068-
dc.identifier.volume58-
dc.identifier.issue9-
dc.identifier.spage609-
dc.identifier.epage618-
dc.identifier.isiWOS:000691008100005-
dc.publisher.placeUnited Kingdom-

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