Common Ancestry from Southern Italy: Two Families with Dilated Cardiomyopathy Share the Same Homozygous Loss-of-Function Variant in NRAP

<b>Background:</b> Cardiomyopathies are a heterogeneous group of heart muscle disorders with diverse genetic origins. Biallelic loss-of-function (LoF) variants in the nebulin-related anchoring protein (<i>NRAP</i>) gene have been linked to dilated cardiomyopathy (DCM) and left ventricular noncompaction cardiomyopathy, though only a few families have been described. NRAP, a member of the Nebulin family, plays a key role in cardiomyocyte development, structural integrity, and muscle function. <b>Methods:</b> We investigated two Italian siblings with DCM born to consanguineous parents from a small village in Campania. Exome sequencing, homozygosity mapping, and comparative analyses with other reported cases were performed. Genealogical research was conducted using civil registry data to reconstruct extended family pedigrees. <b>Results:</b> Both siblings were homozygous for a LoF variant in <i>NRAP</i> (NM_198060.4:c.619del; p.Val207TrpfsTer20). A third brother with tachycardia-induced cardiomyopathy, as well as their living mother, who did not have cardiac abnormalities, were found to be heterozygous. The same homozygous variant was recently identified in another Italian family with DCM coming from North-eastern Italy, whose proband also originated from a nearby village in Campania. These two families exhibited heterogeneity in clinical presentation. Homozygosity analysis revealed a >25 Mb shared region on chromosome 10 encompassing <i>NRAP</i>, supporting a common ancestral origin. While genealogical reconstruction did not allow identification of a shared ancestor, it confirmed consanguinity and enabled the recognition of potential carriers across both families. <b>Conclusions:</b> Our findings strengthen the evidence for <i>NRAP</i> as a disease-causing gene in cardiomyopathies and highlight a likely founder effect in Campania. Incorporating <i>NRAP</i> into genetic testing panels is warranted, especially in populations with high rates of consanguinity or suspected founder variants.