Abstract
Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Although over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis. Recently, biallelic protein-truncating variants (PTVs) in the nebulin-related anchoring protein gene (NRAP) were identified in a few patients with sporadic DCM. We determined the frequency of rare NRAP variants in a cohort of DCM patients and control patients to further evaluate role of this gene in cardiomyopathies. A retrospective analysis of our internal variant database consisting of 31,639 individuals who underwent genetic testing (either panel or direct exome sequencing) was performed. The DCM group included 577 patients with either a confirmed or suspected DCM diagnosis. A control cohort of 31,062 individuals, including 25,912 individuals with non-cardiac (control group) and 5,150 with non-DCM cardiac indications (Non-DCM cardiac group). Biallelic (n = 6) or two (n = 5) NRAP variants (two PTVs or PTV+missense) were identified in 11 unrelated probands with DCM (1.9%) but none of the controls. None of the 11 probands had an alternative molecular diagnosis. Family member testing supports co-segregation. Biallelic or potentially biallelic NRAP variants were enriched in DCM vs. controls (OR 1052, p<0.0001). Based on the frequency of NRAP PTVs in the gnomAD reference population, and predicting full penetrance, biallelic NRAP variants could explain 0.25%-2.46% of all DCM cases. Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.
Highlights
Dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction in the absence of other etiological causes [1]
Patients who consented for Blueprint Genetics to contact them in relation to future research findings after initial testing, were contacted through their referring healthcare professional when possibly diagnostic biallelic variants in nebulin-related anchoring protein gene (NRAP) gene were found in sequence data
All variant calls from the NRAP gene were queried from the internal variant database in 31,639 individuals who underwent genetic testing using NGS-panels or direct whole exome sequencing platform (WES) approach
Summary
Dilated cardiomyopathy (DCM) is characterized by left ventricular enlargement and systolic dysfunction in the absence of other etiological causes [1]. It is typically an adult-onset disease but disease onset may take place as early as in infancy. Familial DCM is typically considered to be a monogenic disorder following most commonly an autosomal dominant pattern of inheritance [1,2,5]. Familial dilated cardiomyopathy (DCM) is typically a monogenic disorder with dominant inheritance. Over 40 genes have been linked to DCM, more than half of the patients undergoing comprehensive genetic testing are left without molecular diagnosis.
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