TRIM63 – Hypertrophic Cardiomyopathy

Multiple independent studies have examined the role of TRIM63 in hypertrophic cardiomyopathy, and the aggregated evidence now supports a strong gene–disease association. TRIM63 mutations are implicated in disease only in the autosomal recessive setting, with affected individuals generally carrying homozygous or compound heterozygous loss‑of‑function variants (PMID:22821932).

Case reports and multi‑patient cohort studies have recurrently identified variants such as c.739C>T (p.Gln247Ter) in several probands. In one study, over 20 probands were reported with such variants, and familial segregation data demonstrated that only individuals with biallelic mutations exhibited disease features (PMID:32451364; PMID:35273634).

Functional studies provide further support for the pathogenic role of TRIM63. In vitro assays and animal models have shown that loss of TRIM63 function disrupts ubiquitin‑mediated degradation of key sarcomere proteins, leading to abnormal cardiac muscle remodeling—a mechanism consistent with the hypertrophic phenotype observed in patients (PMID:19850579).

It is important to note that early reports, such as one evaluating the p.Q247X variant in a symptomless sports player, had raised questions regarding penetrance (PMID:24436435). However, subsequent studies with larger cohorts and robust segregation analyses have clarified that when TRIM63 variants are present in a recessive state they exhibit clear pathogenicity.

Integrating the genetic and functional data, the evidence indicates a strong association between TRIM63 and hypertrophic cardiomyopathy. The autosomal recessive inheritance pattern, recurrence of the c.739C>T (p.Gln247Ter) variant, and supportive mechanistic studies collectively reinforce the clinical utility of including TRIM63 in diagnostic testing panels for cardiomyopathy.

Key Take‑home: Recessive loss‑of‑function variants in TRIM63, particularly the recurrent c.739C>T (p.Gln247Ter), represent a significant molecular etiology for hypertrophic cardiomyopathy, underscoring their importance in clinical evaluation and personalized risk assessment.

References

• Circulation research • 2012 • Human molecular genetic and functional studies identify TRIM63, encoding Muscle RING Finger Protein 1, as a novel gene for human hypertrophic cardiomyopathy PMID:22821932
• Frontiers in genetics • 2022 • Case Report: Two New Cases of Autosomal-Recessive Hypertrophic Cardiomyopathy Associated With TRIM63-Compound Heterozygous Variant PMID:35273634
• Heart • 2020 • Mutations in TRIM63 cause an autosomal-recessive form of hypertrophic cardiomyopathy PMID:32451364
• Circulation research • 2014 • Does p.Q247X in TRIM63 cause human hypertrophic cardiomyopathy? PMID:24436435

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