Pediatric Cardiomyopathy Exome Sequencing Study Suggests More Disease Genes to be Found

NEW YORK — Many of the genes tied to cardiomyopathy risk in adults are also linked to the condition in children, but additional genes contributing to the disorder and its subtypes remain to be found, according to a new analysis.

Cardiomyopathy can affect both children and adults and leads to heart failure and death. But most of the genetic analyses of the condition have relied on adult populations, leaving pediatric cardiomyopathy understudied.

To change this, researchers from the Pediatric Cardiomyopathy Registry Study Group conducted exome sequencing on a cohort of 528 children with cardiomyopathy. As they reported this week in the American Journal of Human Genetics, they could uncover a genetic cause of disease in about a third of their cohort by following clinical interpretation guidelines and genes already linked to the condition. However, molecular diagnoses varied by age, ancestry, and cardiomyopathy subtypes, and the researchers further uncovered an excess of damaging variants in affected individuals, suggesting additional genes contributing to cardiomyopathy risk remain to be identified.

"Specifically, our results suggest that the expansion of more diverse study populations, including infants and individuals with non-European ancestry, will be essential to improve diagnostic genetic testing yields," Indiana University School of Medicine's Stephanie Ware and her colleagues wrote in their paper.

The researchers recruited pediatric cardiomyopathy patients from 14 sites in the US and Canada to their study. Most of the participants had dilated cardiomyopathy, though nearly a third had hypertrophic cardiomyopathy. There were also differences in ancestry by disease subtype, the scientists noted.

They sequenced the exomes of these patients, focusing their analysis on 37 genes curated from the literature and clinical genetic testing panels identified for possible return of results. These genes had largely been identified in adults with cardiomyopathy.

Overall, 32 percent of the pediatric cardiomyopathy cohort had a pathogenic or likely pathogenic variant in these genes, and 35 percent had a variant of uncertain significance.

Diagnostic yield, though, varied by disease subtype, which the researchers noted was in line with studies in adults. Dilated cardiomyopathy had a diagnostic yield of 19 percent, while hypertrophic cardiomyopathy had one of 51.3 percent and restrictive cardiomyopathy of 50 percent. Yield also varied by ancestry and age, with a higher diagnostic yield among patients with European ancestry as well as among older, non-infant patients — 40 percent for older children and 20 percent for infants.

In particular, the researchers identified pathogenic or likely pathogenic variants in 22 of the 37 genes. Variants in MYH7 and MYBPC3, both sarcomeric genes, were the most common, with a respective 56 and 36 variants. However, no MYBPC3 variants were uncovered in African-American children.

By subtype, MYH7 variants were found in 23 percent of hypertrophic cardiomyopathy, while TNNI3 and MYH7 variants were found among restrictive cardiomyopathy patients. Only about 3.2 percent of the children with dilated cardiomyopathy had a truncating variant in TTN, at the low end of previously reported rates, according to the researchers.

By further comparing their pediatric cardiomyopathy patient cohort to a cohort of unaffected individuals, the researchers uncovered a higher burden of likely damaging variants in the affected children.

These findings indicated there are still more disease-causing genes to be identified. "[T]he demonstration of increased rare damaging variant burden suggests the need to consider additional genes as well as multigenic inheritance models," they wrote.