Your weekly snapshot of clinically actionable genes from the ACMG Secondary Findings List.

Clinical Phenotype Summary: 
The DSC2 gene (NM_024422.3), which contains 16 coding exons and is located on chromosome 18q12.1, encodes the desmocollin-2 protein. Pathogenic variants in this gene have been associated with DSC2-related arrhythmogenic right ventricular cardiomyopathy (ARVC), which can be inherited in an autosomal dominant or autosomal recessive fashion.

ARVC is defined by fibrofatty replacement of cardiomyocytes impacting one or both ventricles and leading to:

• ventricular arrhythmia
• progressive ventricular dysfunction
• risk of sudden cardiac death

Diagnostic criteria includes a combination of major and minor findings from these categories of features. ARVC shows reduced penetrance and variable expressivity, particularly in heterozygotes. Loss of function has been reported as the mechanism of disease for DSC2-related ARVC.

Clinical Resources:

• Understanding your Secondary Findings Result

Citations:

• Gerull B et al. Circ Cardiovasc Genet, 2013 Aug;6:327-36. PMID: 23863954
• Corrado D et al. Int J Cardiol, 2020 11;319:106-114. PMID: 32561223
• James CA et al. Circ Genom Precis Med, 2021 06;14:e003273. PMID: 33831308

Ambry Genetics Gene-Disease Validity Scheme

Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early.

To learn more about the ACMG Secondary Findings list, click here.

To read all previous Gene Scene emails, click here.