Autosomal recessive hypertrophic cardiomyopathy associated with variants in TRIM63

Int J Cardiol. 2026 Feb 1:444:134010. doi: 10.1016/j.ijcard.2025.134010. Epub 2025 Nov 5.

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is typically linked to dominant variants in sarcomeric genes, but rare minor genes, including TRIM63 coding for an E3 ubiquitin-protein ligase, have recently emerged as potential causes of recessive HCM.

Methods and results: Among 517 adult patients with clinical HCM who underwent next-generation sequencing, we found six index cases carrying biallelic TRIM63 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.

Conclusions: TRIM63-related HCM is rare but clinically distinct. Early identification of TRIM63 homozygous and two compound heterozygous variants in HCM is crucial and warrants proactive clinical surveillance.

Keywords: Autosomal recessive; Genetic testing; Hypertrophic cardiomyopathy; Minor genes; TRIM63 gene.

MeSH terms

  • Adult
  • Cardiomyopathy, Hypertrophic* / diagnosis
  • Cardiomyopathy, Hypertrophic* / diagnostic imaging
  • Cardiomyopathy, Hypertrophic* / genetics
  • Female
  • Genes, Recessive / genetics
  • Genetic Variation* / genetics
  • Humans
  • Male
  • Middle Aged
  • Muscle Proteins
  • Mutation* / genetics
  • Pedigree
  • Tripartite Motif Proteins* / genetics
  • Ubiquitin-Protein Ligases* / genetics
  • Young Adult

Substances

  • Ubiquitin-Protein Ligases
  • Tripartite Motif Proteins
  • TRIM63 protein, human
  • Muscle Proteins