LRRC10 – Dilated Cardiomyopathy

This summary provides an integrated evaluation of the association between LRRC10 and dilated cardiomyopathy. The evidence derives from multiple independent studies, including a pediatric case report and a multi‐patient genetic study, which collectively support a strong gene‑disease association (PMID:29431102, PMID:26017719).

In a pediatric case, a homozygous recessive variant, c.584T>C (p.Ile195Thr), was identified in a patient with early‐onset dilated cardiomyopathy. Functional assays in cellular models demonstrated that coexpression of I195T LRRC10 with cardiac L‑type Ca2+ channels led to a significant decrease in current amplitude, providing experimental support for a disease‐causing mechanism (PMID:29431102).

A subsequent multi‐patient study screening 220 unrelated individuals with idiopathic dilated cardiomyopathy identified two novel heterozygous missense variants (c.487C>A [p.Leu163Ile] and c.121T>G [p.Leu41Val]), which co‑segregated with the disease in two families with complete penetrance. This observation strongly reinforces the genetic evidence in support of an autosomal dominant mode of inheritance (PMID:26017719).

The combined genetic evidence indicates varying mutation types, including a recessive variant in a severe pediatric case and heterozygous variants in familial cases. Although the pediatric report suggested a recessive presentation, the dominant segregation observed in multi‐patient studies is currently more robust. Overall, the pattern of inheritance is best classified as autosomal dominant based on the weight of the pedigree data.

Functional assessments have revealed that LRRC10 acts as a cardiac‐specific auxiliary subunit modulating the L‑type Ca2+ channel. The altered channel gating and decreased calcium current observed for the I195T variant provide a plausible mechanistic link to dilated cardiomyopathy. These experimental findings, together with the variant co‑segregation data, cement the role of LRRC10 in the pathogenesis of dilated cardiomyopathy.

In conclusion, the multilayered evidence from genetic and functional studies supports a strong association between LRRC10 variants and dilated cardiomyopathy. This comprehensive evaluation is expected to aid diagnostic decision‑making and spur future research developments, making the LRRC10–dilated cardiomyopathy association a valuable target for commercial and clinical applications.

References

• Journal of the American Heart Association • 2018 • Pediatric Dilated Cardiomyopathy-Associated LRRC10 Variant Reveals LRRC10 as an Auxiliary Subunit of Cardiac L-Type Ca2+ Channels PMID:29431102
• Molecular Medicine Reports • 2015 • Prevalence and Spectrum of LRRC10 Mutations Associated with Idiopathic Dilated Cardiomyopathy PMID:26017719

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