Genotype-phenotype correlations in recessive titinopathies.
arthrogryposis
cardiomyopathy
congenital myopathy
skeletal muscle disorders
titin
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
12 2020
12 2020
Historique:
received:
30
04
2020
accepted:
16
07
2020
revised:
15
07
2020
pubmed:
12
8
2020
medline:
28
4
2021
entrez:
12
8
2020
Statut:
ppublish
Résumé
High throughput sequencing analysis has facilitated the rapid analysis of the entire titin (TTN) coding sequence. This has resulted in the identification of a growing number of recessive titinopathy patients. The aim of this study was to (1) characterize the causative genetic variants and clinical features of the largest cohort of recessive titinopathy patients reported to date and (2) to evaluate genotype-phenotype correlations in this cohort. We analyzed clinical and genetic data in a cohort of patients with biallelic pathogenic or likely pathogenic TTN variants. The cohort included both previously reported cases (100 patients from 81 unrelated families) and unreported cases (23 patients from 20 unrelated families). Overall, 132 causative variants were identified in cohort members. More than half of the cases had hypotonia at birth or muscle weakness and a delayed motor development within the first 12 months of life (congenital myopathy) with causative variants located along the entire gene. The remaining patients had a distal or proximal phenotype and a childhood or later (noncongenital) onset. All noncongenital cases had at least one pathogenic variant in one of the final three TTN exons (362-364). Our findings suggest a novel association between the location of nonsense variants and the clinical severity of the disease.
Identifiants
pubmed: 32778822
doi: 10.1038/s41436-020-0914-2
pii: S1098-3600(21)00807-8
doi:
Substances chimiques
Connectin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2029-2040Subventions
Organisme : Telethon
ID : 22431
Pays : Italy
Organisme : Wellcome Trust
ID : 203141/Z/16/Z
Pays : United Kingdom
Organisme : Medical Research Council
Pays : United Kingdom
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