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 1month 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