PRDM16 – Dilated Cardiomyopathy

PRDM16 is a transcriptional regulator whose haploinsufficiency has been implicated in autosomal dominant dilated cardiomyopathy (PRDM16; Dilated Cardiomyopathy).

Multiple unrelated pediatric cases have demonstrated de novo PRDM16 frameshift variants in dilated cardiomyopathy. In a cohort of pediatric heart failure, one child harbored a de novo c.1047dup (p.Ser350fs) variant in PRDM16 (PMID:29367541). In a separate series of 131 adult dilated cardiomyopathy biopsies, five individuals carried four rare nonsynonymous PRDM16 variants, including c.2104A>T (p.Lys702Ter) (PMID:23768516).

Inheritance is predominantly autosomal dominant with de novo occurrence; no multi-generation segregation has been reported. Across these six probands, variant classes include frameshift and nonsense, supporting loss-of-function as a key mechanism.

Experimental data substantiate PRDM16’s role in cardiac structure and function. Zebrafish modeling of PRDM16 haploinsufficiency recapitulates contractile dysfunction and impaired cardiomyocyte proliferation (PMID:23768516). Cardiac-specific Prdm16 knockout mice develop conduction abnormalities, fibrosis, and cardiomyocyte hypertrophy consistent with dilated cardiomyopathy (PMID:32083975).

No studies have reported conflicting phenotypes for PRDM16 in dilated cardiomyopathy. The genetic and functional concordance across species supports a pathogenic haploinsufficiency mechanism.

Key Take-home: PRDM16 loss-of-function variants cause autosomal dominant dilated cardiomyopathy, warranting inclusion of PRDM16 in clinical cardiomyopathy gene panels.

References

• Journal of cardiovascular development and disease • 2017 • Diagnostic Yield of Whole Exome Sequencing in Pediatric Dilated Cardiomyopathy PMID:29367541
• American journal of human genetics • 2013 • Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy PMID:23768516
• American journal of physiology. Heart and circulatory physiology • 2020 • Cardiac-specific inactivation of Prdm16 effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes PMID:32083975

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