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

• DOI: 10.1371/journal.pone.0245681
• Publication Date: 2021-02-03T18:47:58Z
• Authors: Juha W. Koskenvuo; Inka Saarinen; Saija Ahonen; Johanna Tommiska; Sini Weckström; Eija H. Seppälä; Sari Tuupanen; Tiia Kangas-Kontio; Jennifer Schleit; Krista Heliö; Julie Hathaway; Anders Gummesson; Pia Dahlberg; Tiina H. Ojala; Ville Vepsäläinen; Ville Kytölä; Mikko Muona; Johanna Sistonen; Pertteli Salmenperä; Massimiliano Gentile; Jussi Paananen; Samuel Myllykangas; Tero-Pekka Alastalo; Tiina Heliö
• Keywords: Dilated Cardiomyopathy; Penetrance; Proband

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 nebulin-related anchoring protein gene (NRAP) were identified few sporadic DCM.We determined frequency rare NRAP cohort DCM and control further evaluate role this cardiomyopathies. A retrospective analysis our internal variant database consisting 31,639 individuals who underwent (either panel or direct exome sequencing) was performed. The group included 577 either confirmed suspected 31,062 individuals, including 25,912 non-cardiac (control group) 5,150 non-DCM cardiac indications (Non-DCM group). Biallelic (n = 6) two 5) (two PTVs PTV+missense) 11 unrelated probands (1.9%) but none controls. None had an alternative Family member supports co-segregation. potentially enriched vs. controls (OR 1052, p<0.0001). Based on gnomAD reference population, predicting full penetrance, could explain 0.25%-2.46% all cases.Loss-of-function cause for autosomal recessive cardiomyopathy, supporting its inclusion testing.