Preprint identifies rare de novo OPA1 variant in familial dilated cardiomyopathy via whole-exome sequencing

A preprint posted to bioRxiv on 4 September 2026 describes whole-exome sequencing (WES) of five familial and ten sporadic cases of dilated cardiomyopathy (DCM), identifying a rare de novo variant — c.563C>T (p.Pro188Leu) — in OPA1, the gene encoding Optic Atrophy 1. OPA1 is a GTPase located in the inner mitochondrial membrane that regulates mitochondrial fusion, maintains cristae architecture, buffers intracellular calcium, and influences apoptosis. The variant was absent from 100 healthy controls and from major population databases including 1000 Genomes, IndiGenomes, and GenomeAsia 100k, and showed very low minor allele frequency in gnomAD.

The authors present functional evidence linking the variant to disrupted cristae remodelling and impaired cardiac contractile function, proposing a mechanistic route by which OPA1 dysfunction may contribute to DCM pathophysiology. OPA1 variants have previously been associated with autosomal dominant optic atrophy (Kjer disease), with cardiac involvement representing an emerging and less-characterised aspect of the OPA1 phenotypic spectrum.

As a preprint, this work has not yet undergone peer review, and the findings should be interpreted with appropriate caution. The cohort size is small, and independent replication of both the variant–disease association and the proposed mechanistic model will be necessary. Researchers in cardiovascular genetics and mitochondrial medicine may find the dataset and mechanistic framing of interest as a hypothesis-generating contribution.