CRYAB Missense Mutation Reveals Shared Pathogenesis of Familial Cardiomyopathy and Arrhythmia

TL;DR

A new CRYAB gene mutation is linked to both heart muscle disease and arrhythmia, showing shared causes in some families.

Contribution

Identifies a novel CRYAB missense mutation causing combined DCM and LQTS, expanding its known phenotypic spectrum.

Findings

A CRYAB c.368G>A (p.Arg123Gln) variant was found in affected family members with DCM and LQTS.

The mutation occurs in a conserved region and is predicted to be harmful by multiple tools.

Carriers showed overlapping clinical features of both DCM and prolonged QT interval.

Abstract

Background: Dilated cardiomyopathy (DCM) and long QT syndrome (LQTS) are genetically heterogeneous cardiac disorders that contribute significantly to morbidity and sudden cardiac death. Although they are typically considered distinct entities, co-occurrence within families has been increasingly recognized, complicating diagnosis and genetic counseling. Identifying shared genetic determinants may provide insights into overlapping disease mechanisms. Methods: We investigated a multi-generational family in which several members presented with features of both DCM and LQTS. Exome sequencing was performed to identify potential disease-causing variants, and candidate findings were validated by Sanger sequencing. In silico prediction tools and evolutionary conservation analysis were used to assess the pathogenic potential of the identified variant. Results: We identified a novel heterozygous missense variant in the CRYAB gene, c.368G>A (p.Arg123Gln). This variant is located in a highly conserved region critical for protein function and was consistently predicted to be deleterious across multiple computational algorithms. Segregation analysis demonstrated co-occurrence of the variant with disease phenotypes in affected family members. Clinically, several carriers exhibited overlapping features of both DCM and prolonged QT interval, suggesting a dual cardiac phenotype associated with this mutation. Conclusions: Our findings expand the phenotypic spectrum associated with CRYAB mutations, linking them to a combined presentation of dilated cardiomyopathy and long QT syndrome. This underscores the importance of including CRYAB in comprehensive gene panels for inherited cardiac disorders and highlights the need for integrated clinical and genetic evaluation in families presenting with complex cardiac phenotypes.

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