Autosomal recessive hypertrophic cardiomyopathy associated with TRIM63 gene defects: family screening unravels the null clinical effect of heterozygous variants

Background There are increasing reports of autosomal recessive (AR) hypertrophic cardiomyopathy (HCM) caused by defects in the Tripartite Motif-Containing Protein 63 (TRIM63) gene although autosomal dominant (AD) transmission has occasionally been reported. TRIM63 is currently classified as a HCM curated gene with moderate evidence for AR inheritance pattern (GCEP on June 6, 2024). The gene encodes the muscle-specific RING-finger protein 1 involved in diverse biological processes, including signal transduction, peroxisome biogenesis, development, transcription, and ubiquitination. In cardiomyocytes, TRIM63 regulates sarcomeric protein ubiquitination and autophagy and links myofibrils to intermediate filaments and microtubules. Purpose To establish the pattern of inheritance and to characterize the phenotypes associated with biallelic pathogenic/likely pathogenic (P/LP) TRIM63 variants compared with monoallelic heterozygous variants in patients with familial cardiomyopathies undergoing comprehensive clinical and genetic evaluation according to the 2023 ESC guidelines. Methods The series consists of 57 members of 11 families. The 11 probands underwent deep phenotyping, biomarker assessment, cardiac magnetic resonance, genetic counseling, and testing using next-generation sequencing of multigene panels (MGP). Relatives underwent cascade clinical and genetic screening. Written informed consent was obtained from all participants. Right heart catheterization and endomyocardial biopsy (EMB) were performed when clinically indicated, including evaluation for heart transplantation. Results Patients were grouped according to biallelic or monoallelic TRIM63 P/LP variants. The TRIM63 biallelic group included four probands (Figure 1), all with non-obstructive HCM, variable age at diagnosis and different LV thickness progression. Among 19 screened relatives, 16 carried at least one TRIM63 P/LP variant: none showed HCM or other cardiac phenotypes (Figure 1). The TRIM63 monoallelic group comprised seven probands with phenotypes driven by non-TRIM63 genes and each carrying a P/LP variant in the disease gene: HCM: TPM1 de novo (n=1) and MYBPC3 inherited (n=2) and de novo (n=1); ARVC: PKP2 (n=1) and DSP (n=1); DCM: BAG3 (n=1). Among 26 screened relatives, none of the 7 carriers of the single heterozygous TRIM63 variant showed HCM or other cardiac traits. In contrast, carriers of pathogenic variants in MYBPC3, PKP2, DSP, or BAG3 showed the corresponding phenotypes (HCM, ARVC, DCM) (Figure 2). EMBs (in 2 carriers of biallelic TRIM63 variants and in two carriers of TRIM63 + second gene) showed autophagic bodies on ultrastructural analysis; the findings were deemed to be non-disease-specific. Conclusions Recent literature and our data support TRIM63 as a rare but clinically relevant gene for AR HCM. The increased evidence of AR inheritance justifies upgrading its level of evidence from moderate to definitive.