Biallelic loss-of-function in NRAP is a cause of recessive dilated cardiomyopathy

Abstract

Background: 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.

Methods and results: 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.

Conclusion: Loss-of-function in NRAP is a cause for autosomal recessive dilated cardiomyopathy, supporting its inclusion in comprehensive genetic testing.

Fig 1

Pedigree of the family-2 where the index patient and her affected brother were compound heterozygous for c.4371del, p.(Thr1458Glnfs*36) and c.72G>C, p.(Gln24His) in NRAP similarly as her 21-year brother who were on medication initiated before the results of genetic testing were available due to borderline imaging findings suggesting cardiomyopathy. He did not fulfill diagnostic criteria of DCM at the time of the study. DNA was not available from one affected individual who died for DCM at age of 34. All family members who were heterozygous only for the other variant or were homozygous for the wild type allele were unaffected.

Fig 2. Pedigree of the family-6 where the index patient and her affected brother were compound heterozygous for c.4504C>T, p.(Arg1502*) and c.72G>C, p.(Gln24His) in NRAP.

All family members who were heterozygous only for the other variant were unaffected.

Fig 3. Pedigree of the family-11 where the index patient was homozygous for c.1344T>A, p.(Tyr448*) in NRAP whereas all other family members who were heterozygous for the variant or had homozygous wild type allele were unaffected.