PRDM16 – Left Ventricular Noncompaction Cardiomyopathy

PRDM16 encodes a zinc-finger transcription factor critical for cardiomyocyte fate and development. Heterozygous loss-of-function variants in PRDM16 have been implicated in left ventricular noncompaction (LVNC), characterized by excessive trabeculation and impaired myocardial compaction. The evidence linking PRDM16 to LVNC includes multiple unrelated human probands with truncating mutations and concordant functional models demonstrating haploinsufficiency effects on myocardial development.

Genetic Evidence: Six unrelated probands with LVNC harbor PRDM16 loss-of-function variants, including three nonsyndromic truncating mutations identified in a cohort of 75 LVNC cases ([PMID:23768516]), a single case report of a teenager with LVNC and Wolff-Parkinson-White syndrome ([PMID:39895316]), and two pediatric probands carrying a PRDM16-Q187X nonsense allele ([PMID:38113297]). All variants occurred de novo or in isolated families, consistent with an autosomal dominant inheritance pattern. No detailed segregation beyond proband status has been described.

Variant Spectrum: Reported mutations in LVNC include truncating and frameshift alleles. A representative variant is c.3271C>T (p.Arg1091Ter) identified in LVNC cases ([PMID:23768516]). All pathogenic variants are predicted to abolish PRDM16 methyltransferase activity through premature termination.

Functional Evidence: Cardiac-specific Prdm16 knockout mice exhibit prolonged QRS and QTc intervals, myocardial fibrosis, and cellular hypertrophy, mirroring human conduction abnormalities and noncompaction phenotypes ([PMID:32083975]). A CRISPR knock-in Prdm16Q187X mouse model recapitulates compact myocardium underdevelopment and increased apoptosis; homozygotes are embryonic lethal while heterozygotes display LVNC and altered TGF-β signaling ([PMID:38113297]). Zebrafish and murine haploinsufficiency models further validate that reduced Prdm16 dosage impairs cardiomyocyte proliferation and compaction ([PMID:23768516]).

Mechanism of Pathogenicity: PRDM16 haploinsufficiency disrupts TGF-β pathway regulation, leading to defective myocardial compaction. Single-cell RNA+ATAC studies show loss of PRDM16 skews cardiomyocyte fate toward conduction-system hyperplasia at the expense of working myocardium ([PMID:39304345]). These data support haploinsufficiency as the underlying mechanism.

Conflicting Evidence: No reported studies dispute the association of PRDM16 loss-of-function with LVNC.

Key Take-home: Heterozygous truncating variants in PRDM16 cause autosomal dominant LVNC through haploinsufficiency, with robust support from human genetics and animal models, justifying inclusion of PRDM16 in clinical LVNC gene panels.

References

• Cardiology in the young • 2025 • A rare genetic variant in PRDM16 is associated with Wolff-Parkinson-White syndrome with complex accessory pathway characteristics and left ventricular non-compaction cardiomyopathy. PMID:39895316
• American journal of human genetics • 2013 • Fine mapping of the 1p36 deletion syndrome identifies mutation of PRDM16 as a cause of cardiomyopathy. PMID:23768516
• Circulation. Heart failure • 2023 • Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice. PMID:38113297
• American journal of physiology. Heart and circulatory physiology • 2020 • Cardiac-specific inactivation of Prdm16 effects cardiac conduction abnormalities and cardiomyopathy-associated phenotypes. PMID:32083975
• Life science alliance • 2024 • PRDM16 determines specification of ventricular cardiomyocytes by suppressing alternative cell fates. PMID:39304345

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