PDLIM3 – Hypertrophic Cardiomyopathy

PDLIM3 has been implicated in hypertrophic cardiomyopathy (HCM) through copy-number variant (CNV) screening in a large cohort. In a study of 505 unrelated HCM patients, high-throughput targeted exome sequencing with ExomeDepth identified 12 candidate CNVs, of which a heterozygous deletion spanning PDLIM3 was validated in one patient (0.2%) (PMID:26455666). No additional family segregation or recurrence has been reported to date.

Proteomic analyses of human heart chambers revealed an atrium-enriched PDLIM3 isoform (PDLIM3-2), generated by alternative splicing of intrinsically disordered regions and predicted to mediate protein binding through its PDZ and LIM domains (PMID:38456420). This chamber-specific expression underscores the role of PDLIM3 in sarcomeric Z-disc architecture but stops short of demonstrating a direct pathogenic mechanism in HCM.

Current evidence for a PDLIM3–HCM association remains limited. Further reports of independent probands, segregation in multiplex families, and functional studies—such as in vitro cardiomyocyte modeling—are needed to establish causality. Key take-home: PDLIM3 CNVs may represent rare contributors to HCM, but additional genetic and mechanistic data are required to inform clinical interpretation.

References

• European journal of medical genetics • 2015 • Use of high-throughput targeted exome-sequencing to screen for copy number variation in hypertrophic cardiomyopathy. PMID:26455666
• Journal of proteome research • 2024 • Tissue Usage Preference and Intrinsically Disordered Region Remodeling of Alternative Splicing Derived Proteoforms in the Heart. PMID:38456420

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