Key result
Adding 11 RASopathy-associated genes to cardiomyopathy panels identified disease-causing variants in 0.6% of HCM cases and yielded ~3 variants of uncertain significance per 100 cases.
Why the study?
Does testing 11 RASopathy-associated genes by NGS improve diagnostic yield in individuals referred for genetic testing for hypertrophic or dilated cardiomyopathy?
Observational (n=1,111)
Does testing 11 RASopathy-associated genes by NGS improve diagnostic yield in individuals referred for genetic testing for hypertrophic or dilated cardiomyopathy?
Adding RASopathy-associated genes to cardiomyopathy panels increases clinical diagnoses without significantly increasing the number of variants of uncertain significance.
May modestly boost HCM diagnostic yield; leaves open net benefit and optimal panel design pending prospective validation.
RASopathies include a group of syndromes caused by pathogenic germline variants in RAS-MAPK pathway genes and typically present with facial dysmorphology, cardiovascular disease, and musculoskeletal anomalies. Recently, variants in RASopathy-associated genes have been reported in individuals with apparently nonsyndromic cardiomyopathy, suggesting that subtle features may be overlooked. To determine the utility and burden of adding RASopathy-associated genes to cardiomyopathy panels, we tested 11 RASopathy-associated genes by next-generation sequencing (NGS), including NGS-based copy number variant assessment, in 1,111 individuals referred for genetic testing for hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Disease-causing variants were identified in 0.6% (four of 692) of individuals with HCM, including three missense variants in the PTPN11, SOS1, and BRAF genes. Overall, 36 variants of uncertain significance (VUSs) were identified, averaging ∼3VUSs/100 cases. This study demonstrates that adding a subset of the RASopathy-associated genes to cardiomyopathy panels will increase clinical diagnoses without significantly increasing the number of VUSs/case.
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Ceyhan‐Birsoy et al. (2018) conducted an observational in Hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM) (n=1,111). Next-generation sequencing (NGS) of 11 RASopathy-associated genes was evaluated on Identification of disease-causing variants. Adding 11 RASopathy-associated genes to cardiomyopathy panels identified disease-causing variants in 0.6% of HCM cases and yielded ~3 variants of uncertain significance per 100 cases.
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