In:
PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 2 ( 2021-2-3), p. e0245681-
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. 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.
Type of Medium:
Online Resource
ISSN:
1932-6203
DOI:
10.1371/journal.pone.0245681
DOI:
10.1371/journal.pone.0245681.g001
DOI:
10.1371/journal.pone.0245681.g002
DOI:
10.1371/journal.pone.0245681.g003
DOI:
10.1371/journal.pone.0245681.t001
DOI:
10.1371/journal.pone.0245681.t002
DOI:
10.1371/journal.pone.0245681.t003
DOI:
10.1371/journal.pone.0245681.t004
DOI:
10.1371/journal.pone.0245681.s001
DOI:
10.1371/journal.pone.0245681.s002
DOI:
10.1371/journal.pone.0245681.r001
DOI:
10.1371/journal.pone.0245681.r002
DOI:
10.1371/journal.pone.0245681.r003
DOI:
10.1371/journal.pone.0245681.r004
DOI:
10.1371/journal.pone.0245681.r005
DOI:
10.1371/journal.pone.0245681.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2021
detail.hit.zdb_id:
2267670-3
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