Key result
Whole MYBPC3 sequencing establishes a molecular diagnosis in 6.5% of panel-negative HCM patients.
Why the study?
The study aimed to determine the prevalence of deep intronic MYBPC3 pathogenic variations that could lead to splice mutations and improve molecular diagnosis in hypertrophic cardiomyopathy.
Does whole MYBPC3 NGS sequencing improve the molecular diagnosis in patients with hypertrophic cardiomyopathy who lack causative point mutations on standard panels?
Observational (n=93)
Does whole MYBPC3 NGS sequencing improve the molecular diagnosis in patients with hypertrophic cardiomyopathy who lack causative point mutations on standard panels?
Whole MYBPC3 sequencing, including deep intronic regions, improves the molecular diagnostic yield by approximately 6.5% in HCM patients without identified point mutations on standard panels.
Answers are grounded in this paper and cite their sources.
May enhance diagnostic yield in unresolved HCM; leaves open whether routine deep sequencing alters management or prognosis.
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.
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Janin et al. (2019) conducted an observational in Hypertrophic cardiomyopathy (n=93). Whole MYBPC3 next-generation sequencing was evaluated on Molecular diagnosis via detection of deep intronic MYBPC3 pathogenic variations. Whole MYBPC3 next-generation sequencing established a molecular diagnosis in 6.5% of hypertrophic cardiomyopathy patients who lacked causative mutations on a standard 48-gene panel.
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