Abstract Body (Do not enter title and authors here): Dilated cardiomyopathy (DCM) is a clinical condition with tremendous diversity of etiology. In familial forms of DCM, there has been a compelling evidence of immense genetic heterogeneity that implicate various mechanisms. Recently, biallelic loss-of-function (LOF) variants in the nebulin-related-anchoring protein (NRAP) gene have been reported in an ultra-rare form of DCM inherited recessively.
In this study, we sought to describe the clinical and genetic spectrum associated with NRAP variants in our highly consanguineous population. Genetic analysis with whole exome sequencing, conducted on consecutively recruited cases of DCM, identified 13 consanguineous families with 6 different LOF variants in NRAP. Segregation analysis detected 25 homozygous and 25 heterozygous individuals. Interestingly, only 18 of the 25 homozygous cases were symptomatic with a remarkable variability of age of onset (9 months to 47 years, median 5 years), of whom 9 cases died with a median age of death of 3 years (range: 9 months to 13 years). None of the heterozygous individuals was clinically symptomatic. Of note, 3 homozygous cases underwent heart transplantation at the ages of 8, 11, and 14 years who are alive with a follow up of 6 years, 3 years, and 3 months respectively.
Our work illustrates a notable clinical variability of DCM associated with NRAP LOF variants. This observation suggests an underling complex mechanism of NRAP-related DCM that deviates from simple mendelian inheritance and plausibly implicates modifiers. The reduced penetrance and variable expression underscore the need of exercising precaution when counseling individuals and families found to have NRAP variants.