Correspondence to

2 Background- Dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder, typically exhibiting autosomal dominant inheritance. Genomic strategies enable discovery of novel, unsuspected molecular underpinnings of familial DCM. We performed genome-wide mapping and exome sequencing in a unique family wherein DCM segregated as an autosomal recessive (AR) trait. Methods and Results- Echocardiography in 17 adult descendants of first cousins revealed DCM in two female siblings and idiopathic left ventricular enlargement in their brother. Genotyping and linkage analysis mapped an AR DCM locus to chromosome 7q21, which was validated and refined by high-density homozygosity mapping. Exome sequencing of the affected sisters was then employed as a complementary strategy for mutation discovery. An iterative bioinformatics process was used to filter>40,000 genetic variants, revealing a single shared homozygous missense mutation localized to the 7q21 critical region. The mutation, absent in HapMap, 1000Genomes and 474 ethnically matched controls, altered a conserved residue of GATAD1