Identification of a novel homozygous NEXN gene mutation in recessively inherited dilated cardiomyopathy

Familial dilated cardiomyopathy (DCM) is genetically heterogeneous. Mutations in more than 30 genes have been identified in familial cases; mostly inherited as autosomal dominant. Defective genes in isolated recessive DCM are rarely observed. Recently, heterozygous mutations in NEXN gene, which encodes a cardiac Z-disc protein, have been identified in patients with dominantly inherited dilated and hypertrophic forms of cardiomyopathy. Through our Cardiovascular Genetics Program, we have conducted genome-wide analysis in 43 consanguineous Saudi families with recessive forms of cardiomyopathy. The analysis detected a region of homozygosity (ROH) on chromosome 1p31 in one family who has two affected infants with severe DCM. The index case presented at the age of 1 month with severely dilated left ventricle with ejection fraction of 21%. The identified ROH in this family was found to be shared by the 2 affected siblings and was not found in their parents and unaffected sibling. Direct sequencing of 6 candidate genes within the identified ROH revealed a novel homozygous deletion (c.1582-1584delGAA) in NEXN gene in both affected siblings. This mutation leads to a deletion of glutamate, at position 528, which is a highly conserved amino acid. To our knowledge, this is the first study identifying a homozygous mutation in NEXN gene in association with recessive cardiomyaopthy. This finding could be utilized to prevent the recurrence of DCM through preimplantation genetic diagnosis and carrier screening for at-risk family members. Our work also illustrates the importance of homozygosity analysis in identifying genetic causes of familial cardiovascular disorders in our highly consanguineous population.