Whole MYBPC3 NGS sequencing as a molecular strategy to improve the efficiency of molecular diagnosis of patients with hypertrophic cardiomyopathy.
Aged
Alleles
Alternative Splicing
Cardiomyopathy, Hypertrophic
/ diagnosis
Carrier Proteins
/ genetics
Exons
Female
Gene Expression
Genes, Reporter
Genetic Association Studies
Genetic Predisposition to Disease
High-Throughput Nucleotide Sequencing
/ methods
Humans
Introns
Male
Middle Aged
Molecular Diagnostic Techniques
Mutation
Pedigree
RNA Splice Sites
Next-generation sequencing
hypertrophic cardiomyopathy
intronic variation
minigene reporter assay
splicing
Journal
Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
26
08
2019
revised:
23
10
2019
accepted:
31
10
2019
pubmed:
16
11
2019
medline:
23
7
2021
entrez:
16
11
2019
Statut:
ppublish
Résumé
Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy, historically believed to affect 1 of 500 people. MYBPC3 pathogenic variations are the most frequent cause of familial HCM and more than 90% of them introduce a premature termination codon. The current study aims to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations. To improve molecular diagnosis, a next-generation sequencing (NGS) workflow based on whole MYBPC3 sequencing of a cohort of 93 HCM patients, for whom no putatively causative point mutations were identified after NGS sequencing of a panel of 48 cardiomyopathy-causing genes, was performed. Our approach led us to reconsider the molecular diagnosis of six patients of the cohort (6.5%). These HCM probands were carriers of either a new large MYBPC3 rearrangement or splice intronic variations (five cases). Four pathogenic intronic variations, including three novel ones, were detected. Among them, the prevalence of one of them (NM_000256.3:c.1927+ 600 C>T) was estimated at about 0.35% by the screening of 1,040 unrelated HCM individuals. This study suggests that deep MYBPC3 splice mutations account for a significant proportion of HCM cases (6.5% of this cohort). Consequently, NGS sequencing of MYBPC3 intronic sequences have to be performed systematically.
Substances chimiques
Carrier Proteins
0
RNA Splice Sites
0
myosin-binding protein C
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
465-475Informations de copyright
© 2019 Wiley Periodicals, Inc.
Références
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