OBSCN – Dilated Cardiomyopathy

Whole exome sequencing of 30 end-stage failing hearts identified 5 unique OBSCN variants in patients with dilated cardiomyopathy, including missense, frameshift, and splice-site changes (PMID:28510120). Although these findings suggest an autosomal dominant inheritance, no multigenerational segregation has been documented, and the overall number of affected probands remains small. The variant spectrum spans multiple immunoglobulin domains of obscurin, but familial co‐segregation data are lacking.

Functional studies of one OBSCN variant, c.15902G>A (p.Arg5301Gln), in a knock-in mouse model demonstrated Ca2+ handling abnormalities, spontaneous arrhythmias, and under pressure overload developed a DCM-like phenotype (PMID:28630914). In contrast, the related p.Arg4344Gln allele shows high population frequency in African‐Americans without clear disease correlation, arguing against its standalone pathogenicity (PMID:33438037).

Overall, the clinical validity of OBSCN in dilated cardiomyopathy is Limited due to few probands and absent segregation, despite Moderate functional support. Key take-home: OBSCN variants should be interpreted with caution in DCM genetic testing; additional large‐scale and segregation studies are required to confirm pathogenic roles.

References

• 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

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