Autosomal recessive hypertrophic cardiomyopathy associated with variants in TRIM63

<h2>Abstract</h2><h3>Background</h3> Hypertrophic cardiomyopathy (HCM) is typically linked to dominant variants in sarcomeric genes, but rare minor genes, including <i>TRIM63</i> coding for an E3 ubiquitin-protein ligase, have recently emerged as potential causes of recessive HCM. <h3>Methods and results</h3> Among 517 adult patients with clinical HCM who underwent next-generation sequencing, we found six index cases carrying biallelic <i>TRIM63</i> variants—four homozygous and two compound heterozygous. They presented with early-onset disease, marked concentric hypertrophy, diffuse myocardial fibrosis, and progressive left ventricular dysfunction. One patient underwent heart transplantation. No cardiac disease was found in heterozygous relatives. <h3>Conclusions</h3> <i>TRIM63</i>-related HCM is rare but clinically distinct. Early identification of <i>TRIM63</i> homozygous and two compound heterozygous variants in HCM is crucial and warrants proactive clinical surveillance. <b>Take home messages:</b><ul><li>•TRIM63-related HCM is a rare autosomal-recessive subtype with early onset and severe phenotypes.</li><li>•Rapid disease progression is common, with extensive fibrosis and frequent transition to hypokinetic-dilated end-stage cardiomyopathy.</li><li>•Early genetic diagnosis supports proactive management, including timely ICD implantation for arrhythmia risk and reproductive counselling for families due to the recessive inheritance.</li></ul>