PKP2 – Left Ventricular Non-compaction Cardiomyopathy

PKP2, encoding the desmosomal protein plakophilin-2, has been implicated in autosomal recessive left ventricular non-compaction cardiomyopathy (Left Ventricular Non-compaction). A neonatal patient presented with severe LVNC and was homozygous for the splice site variant c.1511-1G>C, which induces exon 7 skipping and a frameshift truncation ([PMID:35059364]). Heterozygous parents were unaffected and no additional affected relatives were identified, supporting a recessive mode of inheritance.

A literature survey of eight families with biallelic PKP2 variants—three of which harbored null alleles—reveals a consistent association between PKP2 loss-of-function and lethal neonatal LVNC ([PMID:35059364]). Functional mRNA analysis confirmed aberrant splicing leading to premature termination, indicating haploinsufficiency as the pathogenic mechanism. Although evidence remains limited to early-onset, severe cases, PKP2 should be considered in diagnostic panels for recessive LVNC.

Key Take-home: Biallelic PKP2 loss-of-function variants cause severe neonatal LVNC, informing genetic testing and family counseling.

References

• Frontiers in Pediatrics • 2021 • A Novel Homozygous PKP2 Variant in Severe Neonatal Non-compaction and Concomitant Ventricular Septal Defect: A Case Report PMID:35059364

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