The Genomics of Arthrogryposis, a Complex Trait: Candidate Genes and Further Evidence for Oligogenic Inheritance.
Adolescent
Adult
Arthrogryposis
/ genetics
Child
Child, Preschool
Cohort Studies
Connectin
/ genetics
DNA Copy Number Variations
Female
Genetic Markers
Genomics
/ methods
Gestational Age
Humans
Infant
Infant, Newborn
Male
Mosaicism
Multifactorial Inheritance
/ genetics
Mutation
Pedigree
Ryanodine Receptor Calcium Release Channel
/ genetics
Vesicular Transport Proteins
/ genetics
Exome Sequencing
Young Adult
ES reanalysis
absence of heterozygosity
arthrogryposis
identity-by-descent
joint contracture
multilocus pathogenic variation
neuromuscular disease
trio-exome
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
03 07 2019
03 07 2019
Historique:
received:
18
12
2018
accepted:
21
05
2019
pubmed:
25
6
2019
medline:
12
3
2020
entrez:
25
6
2019
Statut:
ppublish
Résumé
Arthrogryposis is a clinical finding that is present either as a feature of a neuromuscular condition or as part of a systemic disease in over 400 Mendelian conditions. The underlying molecular etiology remains largely unknown because of genetic and phenotypic heterogeneity. We applied exome sequencing (ES) in a cohort of 89 families with the clinical sign of arthrogryposis. Additional molecular techniques including array comparative genomic hybridization (aCGH) and Droplet Digital PCR (ddPCR) were performed on individuals who were found to have pathogenic copy number variants (CNVs) and mosaicism, respectively. A molecular diagnosis was established in 65.2% (58/89) of families. Eleven out of 58 families (19.0%) showed evidence for potential involvement of pathogenic variation at more than one locus, probably driven by absence of heterozygosity (AOH) burden due to identity-by-descent (IBD). RYR3, MYOM2, ERGIC1, SPTBN4, and ABCA7 represent genes, identified in two or more families, for which mutations are probably causative for arthrogryposis. We also provide evidence for the involvement of CNVs in the etiology of arthrogryposis and for the idea that both mono-allelic and bi-allelic variants in the same gene cause either similar or distinct syndromes. We were able to identify the molecular etiology in nine out of 20 families who underwent reanalysis. In summary, our data from family-based ES further delineate the molecular etiology of arthrogryposis, yielded several candidate disease-associated genes, and provide evidence for mutational burden in a biological pathway or network. Our study also highlights the importance of reanalysis of individuals with unsolved diagnoses in conjunction with sequencing extended family members.
Identifiants
pubmed: 31230720
pii: S0002-9297(19)30202-2
doi: 10.1016/j.ajhg.2019.05.015
pmc: PMC6612529
pii:
doi:
Substances chimiques
Connectin
0
ERGIC1 protein, human
0
Genetic Markers
0
MYOM2 protein, human
0
RYR3 protein, human
0
Ryanodine Receptor Calcium Release Channel
0
Vesicular Transport Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
132-150Subventions
Organisme : NHGRI NIH HHS
ID : K08 HG008986
Pays : United States
Organisme : NINDS NIH HHS
ID : R35 NS105078
Pays : United States
Organisme : NINDS NIH HHS
ID : T32 NS043124
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006542
Pays : United States
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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