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

Clinical Phenotype Summary:

The DES gene (NM_001927.3), which contains 9 coding exons and is located on chromosome 2q35, encodes the desmin protein. Pathogenic variants in this gene have been associated with a spectrum of DES­-related myopathies, including dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), which are inherited in an autosomal dominant fashion, and myofibrillar myopathy (MFM), which is inherited in autosomal dominant and autosomal recessive fashions.

DES-related DCM is defined by:

• ventricular dilation
• reduced systolic function
• impaired contractility
  generally presenting with:
• heart failure with symptoms of congestion
• arrhythmias and/or conduction system disease
• thromboembolic disease, including stroke.

DES-related ARVC is characterized by:

• fibrofatty replacement of cardiomyocytes, primarily in the right ventricle (RV), leading to ventricular arrhythmia, progressive ventricular dysfunction, and sudden cardiac death.

DES-related MFM is characterized by:

• progressive weakness of proximal and distal muscles with respiratory insufficiency
• cardiomyopathy
• cardiac conduction defects

However, there is significant clinical variability, even among carriers from the same family. 

Unique Considerations:

• Earlier ages of onset have been described in autosomal recessive cases, and de novo occurrences have been reported with autosomal dominant DES-related MFM.
• Dominant negative and biallelic loss of function have been reported as the mechanisms of disease for autosomal dominant and recessive DES-related myopathies, respectively.

Clinical Resources:

• Understanding your Secondary Findings Result

Citations:

• Li D et al. Circulation, 1999 Aug;100:461-4. PMID: 10430757
• Dalakas MC et al. N Engl J Med, 2000 Mar;342:770-80. PMID: 10717012
• Taylor MR et al. Circulation, 2007 Mar;115:1244-51. PMID: 17325244
• Bergman JE et al. Eur J Med Genet 2007 Jul;50:355-66. PMID: 17720647
• van Tintelen JP et al. Heart Rhythm, 2009 Nov;6:1574-83. PMID: 19879535

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.