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.

Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy

“…The patient with homozygous NRAP LoF variants in our discovery cohort did show a RCM physiology in the context of DCM, while patients with FHOD3 variants primarily displayed either HCM or DCM consistent with published reports 19 – 22 . Together with previously published studies 16 – 23 , these findings provide strong support for a role for LoF variants in NRAP and FHOD3 in causing CMP. Overall, we identified pathogenic or high-risk coding SNVs, indels, and CNVs in known and candidate CMP genes in 44% of cases in our discovery cohort.…”

“…Our study also provided evidence for the contribution of variants in emerging candidate genes that are not yet routinely captured on gene panels 10 , 16 – 23 . NRAP , FHOD3 , and PDE4DIP are important in the maintenance of the cardiac sarcomere and actin cytoskeleton, and have been associated with CMP in mouse studies and small case series 10 , 16 – 23 .…”

“…Our study also provided evidence for the contribution of variants in emerging candidate genes that are not yet routinely captured on gene panels 10 , 16 – 23 . NRAP , FHOD3 , and PDE4DIP are important in the maintenance of the cardiac sarcomere and actin cytoskeleton, and have been associated with CMP in mouse studies and small case series 10 , 16 – 23 . LoF variants in these genes were found in DCM and HCM patients in the discovery and replication cohorts, including a patient with a rare homozygous frameshift variant in NRAP born of consanguineous parents, consistent with the association of bi-allelic LoF NRAP variants in DCM 16 .…”

“…2g . Homozygous or bi-allelic variants in NRAP have been reported as disease-causing in patients with DCM in several studies 16 , 17 . The patient in our study cohort was diagnosed with severe DCM that progressed to LV RCM physiology requiring cardiac transplantation by 7.7 years of age.…”

“…NRAP , FHOD3 , and PDE4DIP are important in the maintenance of the cardiac sarcomere and actin cytoskeleton, and have been associated with CMP in mouse studies and small case series 10 , 16 – 23 . LoF variants in these genes were found in DCM and HCM patients in the discovery and replication cohorts, including a patient with a rare homozygous frameshift variant in NRAP born of consanguineous parents, consistent with the association of bi-allelic LoF NRAP variants in DCM 16 . While most pathogenic FHOD3 variants reported thus far have been missense variants, we identified several LoF variants that were clustered within the same exon as other previously reported pathogenic variants, including a frameshift variant in our discovery cohort that was also seen in an independent replication cohort.…”