Systematic Analysis of Cardiac Disease Genes Reveals Genetic Variants in PRDM16 as Important Cause of cardiomyopathies

Cardiomyopathy in pediatric patients is life-threatening and may result from genetic defects. While well established in adults, genetic mechanisms, early pathological events, and other disease promoting factors are poorly characterized in children. Recently, we identified pathogenic variants in the gene PR/SET domain 16 (PRDM16) underlying isolated cardiomyopathy in patients with nonsyndromic left ventricular noncompaction cardiomyopathy (LVNC).

To further analyze the genetic burden and frequency of genetic variants in PRDM16, we screened pediatric and adult primary cardiomyopathy cohorts of 222 patients with next-generation sequencing (Illumina TruSight Cardio Sequencing Panel). The cohort included patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, restricted cardiomyopathy, LVNC, and arrhythmogenic right ventricular cardiomyopathy. Evaluation of genetic variants in 89 cardiomyopathy-associated genes was performed after bioinformatic filtering with a minor allele frequency of 0.1%. Case-specific interpretation of the variants occurred in the familial and functional protein context according to the American College of Medical Genetics and Genomics guidelines.

In total, we identified 14 heterozygous PRDM16 variants in patients from different pediatric and adult cohorts. Three of these variants were classified as pathogenic, one was likely pathogenic and nine were VUS. More specifically, three truncating variants c.1573dup, c.1627C>T, and c.2104A>T were detected that may induce haploinsufficiency. One missense variant c.1110C>A localizes within the N-terminal zinc finger region, which may affect its structural property. Surprisingly, genetic variants in PRDM16 were frequent in our cohort as similar variant frequencies were observed for typical cardiomyopathy genes such as DSP and TNNT2.

The phenotypes of the patients with PRDM16 variants included all five cardiomyopathies mentioned earlier, and therefore, PRDM16 is an important general cardiomyopathy gene. Interpretation of PRDM16 variants in the specific-disease context is restrained due to limited information about the PRDM16 protein function. Thus, functional analysis of PRDM16 truncating and missense variants will provide further understanding into the underlying disease mechanism.