Dilated cardiomyopathy in patients with PRDM16 haploinsufficiency

PRDM16 has been identified as a potential causal gene for cardiomyopathies, supported by reports of several cases associated with loss-of-function (LoF) variants in PRDM16. In this multi-centric study, we present the largest cohort to date of dilated cardiomyopathy (DCM) patients harboring PRDM16 LoF variants, including eleven previously unreported cases. Genetic testing was conducted by three French molecular genetics laboratories (Hôpital Européen Georges Pompidou, Lyon and Nantes) on 4900 index cases with DCM and/or hypertrabeculation using targeted next-generation sequencing. The gene panel included all coding and flanking intronic regions of 59 genes, including PRDM16 (NM_022114.4). In nine families, heterozygous LoF variants were detected in 11 cardiomyopathy patients. These variants included 2 deletions encompassing the entire gene, 1 multi-exonic deletion, 3 frameshift variants, 2 nonsense, and 1 splice-site variant. At diagnosis, the median age was 18.5 years for females and 49 years for males. Ten patients presented with DCM and 6 with hypertrabeculation. Follow-up data were available for five patients, with an average duration of 11 years. Four patients showed an improvement in their ejection fraction. Notably, females, mainly pediatric cases, appeared to have a poorer prognosis. This study supports the hypothesis that haploinsufficiency of PRDM16 is involved in cardiomyopathy, with females exhibiting a more severe phenotype and earlier onset. Although PRDM16 is not currently included in the standard gene panel for cardiomyopathies, we propose that it be systematically screened in cases of DCM or symptomatic cardiac hypertrabeculation. KEY MESSAGES: PRDM16 haploinsufficiency leads to dilated cardiomyopathy and hypertrabeculation. More severe phenotypes and earlier disease onset are observed in females with PRDM16 haploinsufficiency. PRDM16 should be added to the gene panels used in genetic screening for cardiomyopathy.