SMYD1 – Hypertrophic Cardiomyopathy

SMYD1 encodes a striated muscle-specific histone methyltransferase critical for sarcomere assembly and cardiac development. Hypertrophic cardiomyopathy (HCM) is defined by unexplained left ventricular hypertrophy with risk of heart failure and sudden death. Although over 50 genes are implicated in HCM, many cases remain genetically unresolved. Recent case reports implicate SMYD1 variants in HCM, suggesting a novel gene-disease relationship.

Genetic evidence comprises one proband with a de novo heterozygous missense variant c.814T>C (p.Phe272Leu) presenting with syncope and left ventricular hypertrophy (PMID:30205637) and two unrelated siblings homozygous for c.302A>G (p.Asn101Ser) with infantile HCM and biventricular failure (PMID:36980931). Altogether, three unrelated probands harbor SMYD1 missense variants in both autosomal dominant and autosomal recessive contexts without reported segregation in additional relatives.

Inheritance is observed in an autosomal dominant de novo setting and autosomal recessive homozygous setting. No additional affected relatives with segregating variants have been documented. The variant spectrum in HCM includes two distinct missense changes affecting conserved domains of SMYD1.

Functional studies of p.Phe272Leu in AC16 cardiomyocytes demonstrated impaired nuclear localization by immunofluorescence, and dysregulated expression of β-myosin heavy chains, the SMYD1 chaperone HSP90, and downstream TGF-β signaling by Western blot and RT-PCR (PMID:30205637). These findings align with SMYD1’s established role in sarcomere organization and heart development.

No conflicting evidence has been reported. Although the number of cases is limited, combined genetic and functional data support a moderate level of clinical validity under ClinGen criteria. Further studies, including broader cohort screening and animal models, would strengthen this association.

Key Take-home: SMYD1 missense variants contribute to HCM through disrupted nuclear localization and sarcomere gene regulation, supporting inclusion of SMYD1 in genetic testing panels for unexplained HCM.

References

• Clinical chemistry and laboratory medicine • 2019 • A de novo mutation of SMYD1 (p.F272L) is responsible for hypertrophic cardiomyopathy in a Chinese patient. PMID:30205637
• Genes • 2023 • Identification of Two Homozygous Variants in MYBPC3 and SMYD1 Genes Associated with Severe Infantile Cardiomyopathy. PMID:36980931

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