Retrospective Analysis of Clinical Genetic Testing in Pediatric Primary Dilated Cardiomyopathy: Testing Outcomes and the Effects of Variant Reclassification


Quiat D, Witkowski L, Zouk H, Daly KP, Roberts AE.J Am Heart Assoc. 2020 Jun 2;9(11):e016195. doi: 10.1161/JAHA.120.016195. Epub 2020 May 27.PMID: 32458740


Take Home Points:


  • Clinical genetic testing identifies about ⅓ of patients with a primary dilated cardiomyopathy (DCM) with many variants of unknown significance (VUS).
  • Reevaluation/reclassification of prior genetic testing decreased the number of VUS but a large number still remained.
  • Familial genetic testing may help with interpretation of the results.


Commentary from Dr. Jared Hershenson (Greater Washington DC), section editor of Pediatric Cardiology Journal Watch:  Only ~ 30-50% of DCM cases have an identifiable etiology, with neuromuscular and myocarditis being the most common. With the improvement in genetic testing, many of the “idiopathic” cases have shown pathogenic variants. However, the amount of VUS has been quite high, and in some regards, this could be considered almost as a “worst case scenario” since it remains unclear if this is the pathogenic etiology or a benign variant. This can markedly affect future family planning or determine prognosis in genotypic carriers. In 2015, the American College of Medical Genetics and Genomics established a 5-tier classification system for VUS (pathogenic, likely pathogenic, uncertain significance, likely benign, benign). This, along with an increase in testing panel content and availability of allele databases, people with a VUS on testing in the past may be able to be reclassified, allowing for improved diagnosis, prognosis, and family counseling.


In this paper, a cohort of 63 patients over a 10 year period (2008-2018) with DCM was evaluated. 18% had a family history of cardiomyopathy or sudden death. 30% had a disease causing variant identified with nearly half occurring de novo. 116 variants were found on initial gene testing, 8 classified as pathogenic, 11 likely pathogenic, 90 VUS, 3 likely benign, and 2 benign (and an additional 2 as unclassified). Reclassification was performed which resulted in the downgrading of 29% (26/90) of VUS to either likely benign or benign and an absolute decrease in the number of BUS from 60% to 52% and an increase in likely benign/benign from 14% to 24%. See table 2. In those with a positive family history (9), 3 variants were inherited and 6 were de novo mutations. In 6 patients with potentially disease causing VUS, familial testing showed 3 occurring de novo and 3 inherited. Interestingly though, they did not find a difference in rates of positive cardiomyopathy genetic testing in patients with (27%) or without (33%) a family history cardiomyopathy or sudden death. With regards to testing, larger gene panels (> 50) found 27% with pathogenic variants vs. 20% in smaller panels (< 50). Of their cohort, 29/63 (46%) underwent heart transplantation or died during the follow up period.


This study shows that periodic reclassification and familial cascade genetic testing can reduce the number of VUS to allow for better diagnosis and future screening for DCM. Unfortunately, the percentage of VUS remains high, so hopefully with further reevaluation as larger panels and other advances are made (or use of whole genome testing is done), this can be improved. Since there are no clear guidelines for how to undergo this process, the authors recommend a review of genetic testing any time there is a VUS, more than a year has passed, and the parents are planning to have more children.