OBSCN – Hypertrophic Cardiomyopathy

The association between OBSCN and Hypertrophic Cardiomyopathy has been supported by multiple independent genetic studies. OBSCN variants have been reported in over 30 unrelated HCM probands across discovery and replication cohorts, with significant enrichment of truncating alleles in patients versus controls ([PMID:34601892]). Early reports and case series identified missense and frameshift mutations in cohorts of failing hearts and HCM patients, reinforcing gene‐disease validity ([PMID:28510120]).

Genetic evidence indicates an autosomal dominant mode of inheritance for OBSCN‐related HCM. Whole‐exome and targeted sequencing in large cohorts revealed 28 truncating variants in 26 patients (2.6% of cases) versus 6 in 761 controls ([PMID:34601892]), and six unique OBSCN missense variants in 74 HCM cases ([PMID:28510120]). The variant spectrum includes truncating, missense, and splice‐site changes. Recurrent or founder alleles are not yet established for OBSCN.

Segregation of OBSCN variants within families remains limited, with no additional affected relatives systematically reported. The lack of multi‐generational segregation studies underscores the need for pedigree analyses to confirm co‐segregation.

Functional studies provide concordant evidence for a pathogenic mechanism. A knock‐in mouse model carrying the R4344Q mutation exhibits age‐dependent arrhythmias and dilated cardiomyopathy under stress, with altered Ca2+ handling and phospholamban binding ([PMID:28630914]). In vitro binding assays demonstrate electrostatic perturbations in R4344Q and R4444W variants, affecting obscurin interactions, though allele frequency data raise questions about pathogenicity for common variants ([PMID:33438037]).

Conflicting evidence arises from population data indicating a 15% allele frequency of R4344Q in African Americans and in vitro studies failing to confirm pathogenic interactions in mammalian cells. These findings caution against classifying common OBSCN variants as definitively disease‐causing without further clinical correlation ([PMID:33438037]).

In summary, OBSCN meets criteria for a Strong gene‐disease association in HCM based on variant enrichment across large cohorts and supportive functional data. Additional family segregation and mechanistic studies are warranted. Key take-home: OBSCN sequencing can enhance diagnostic yield and inform prognostic stratification in HCM.

References

• Circulation. Genomic and precision medicine • 2021 • Truncating Variants in OBSCN Gene Associated With Disease-Onset and Outcomes of Hypertrophic Cardiomyopathy. PMID:34601892
• Biophysical Reviews • 2017 • Obscurin variants and inherited cardiomyopathies. PMID:28510120
• Science Advances • 2017 • Deregulated Ca2+ cycling underlies the development of arrhythmia and heart disease due to mutant obscurin. PMID:28630914
• Human Molecular Genetics • 2021 • When is an obscurin variant pathogenic? The impact of Arg4344Gln and Arg4444Trp variants on protein-protein interactions and protein stability. PMID:33438037

Evidence Based Scoring (AI generated)