Key result
Heterozygous VCL loss-of-function variants are linked to ~9-fold higher odds of dilated cardiomyopathy.
Why the study?
Assessing and expressing the pathogenicity of low-penetrance variants under the ACMG/AMP framework is challenging, and family studies clarifying the clinical significance of rare vinculin loss-of-function variants in cardiomyopathy are scarce.
Are VCL loss-of-function variants associated with an increased risk of inherited cardiomyopathy?
Cross-Sectional (n=18,135)
Yes
Are VCL loss-of-function variants associated with an increased risk of inherited cardiomyopathy?
VCL loss-of-function variants are rare genetic modifiers associated with an increased risk of dilated cardiomyopathy, particularly with early or pediatric onset, but display reduced penetrance.
VCL LoF variants may elevate pediatric DCM risk; leaves open their utility for genetic testing and counseling.
The ACMG/AMP variant classification framework was intended for highly penetrant Mendelian conditions. While it is appreciated that clinically relevant variants exhibit a wide spectrum of penetrance, accurately assessing and expressing the pathogenicity of variants with lower penetrance can be challenging. The vinculin (VCL) gene illustrates these challenges. Model organism data provide evidence that loss of function of VCL may play a role in cardiomyopathy and aggregate case-control studies suggest low penetrance. VCL loss of function variants, however, are rarely identified in affected probands and therefore there is a paucity of family studies clarifying the clinical significance of individual variants. This study, which aggregated data from >18,000 individuals who underwent gene panel or exome testing for inherited cardiomyopathies, identified 32 probands with VCL loss-of-function variants and confirmed enrichment in probands with dilated cardiomyopathy (odds ratio [OR] = 9.01; confidence interval [CI] = 4.93-16.45). Our data revealed that the majority of these individuals (89.5%) had pediatric onset of disease. Family studies demonstrated that heterozygous loss of function of VCL alone is insufficient to cause cardiomyopathy but that these variants do contribute to disease risk. In conclusion, VCL loss-of-function variants should be reported in a diagnostic setting but need to be clearly distinguished as having lower penetrance.
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Hawley et al. (2020) conducted a cross-sectional in Inherited cardiomyopathies (predominantly dilated cardiomyopathy) (n=18,135). VCL loss-of-function variants vs. gnomAD reference population was evaluated on Prevalence of VCL loss-of-function variants in dilated cardiomyopathy probands vs reference population (OR 9.01, 95% CI 4.93-16.45). Heterozygous VCL loss-of-function variants were significantly enriched in probands with dilated cardiomyopathy (OR 9.01) and predominantly presented with early/pediatric onset of disease.
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