Phenotypic spectrum and genomics of undiagnosed arthrogryposis multiplex congenita.
genomics
human genetics
nervous system malformations
neuromuscular diseases
Journal
Journal of medical genetics
ISSN: 1468-6244
Titre abrégé: J Med Genet
Pays: England
ID NLM: 2985087R
Informations de publication
Date de publication:
06 2022
06 2022
Historique:
received:
16
11
2020
revised:
23
02
2021
accepted:
14
03
2021
pubmed:
7
4
2021
medline:
25
5
2022
entrez:
6
4
2021
Statut:
ppublish
Résumé
Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families. Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants. We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes ( New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
Sections du résumé
BACKGROUND
Arthrogryposis multiplex congenita (AMC) is characterised by congenital joint contractures in two or more body areas. AMC exhibits wide phenotypic and genetic heterogeneity. Our goals were to improve the genetic diagnosis rates of AMC, to evaluate the added value of whole exome sequencing (WES) compared with targeted exome sequencing (TES) and to identify new genes in 315 unrelated undiagnosed AMC families.
METHODS
Several genomic approaches were used including genetic mapping of disease loci in multiplex or consanguineous families, TES then WES. Sanger sequencing was performed to identify or validate variants.
RESULTS
We achieved disease gene identification in 52.7% of AMC index patients including nine recently identified genes (
CONCLUSION
New genes recently identified in AMC represent 21% of causing genes in our cohort. A high proportion of de novo variants were observed indicating that this mechanism plays a prominent part in this developmental disease. Our data showed the added value of WES when compared with TES due to the larger clinical spectrum of some disease genes than initially described and the identification of novel genes.
Identifiants
pubmed: 33820833
pii: jmedgenet-2020-107595
doi: 10.1136/jmedgenet-2020-107595
pmc: PMC9132874
doi:
Substances chimiques
ASXL3 protein, human
0
MAGEL2 protein, human
0
Proteins
0
Transcription Factors
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
559-567Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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