LAMA4 – Dilated Cardiomyopathy

Heterozygous missense variants in LAMA4 have been reported in autosomal dominant dilated cardiomyopathy (DCM). A Chinese family with DCM and conduction system disease harbored c.652G>A (p.Gly218Arg) segregating in the proband and two affected brothers (PMID:39686469). In an independent infantile DCM cohort, digenic inheritance of LAMA4 c.3925G>A (p.Asp1309Asn) with a MYH7 mutation was observed in a 7-month-old patient, supporting a contributory role for LAMA4 in early-onset disease (PMID:30650640).

Functional assessment in zebrafish identified epistasis between lama4 and ilk in myocardial and endothelial development. Human LAMA4 Pro950Leu and Arg1080Ter mutants exhibit >10-fold reduced integrin-binding affinity in Biacore assays compared with wild-type and recapitulate endothelial loss consistent with DCM pathogenesis (PMID:17646580). These data support a haploinsufficiency or dominant-negative mechanism disrupting extracellular matrix–cell interactions in cardiomyopathy.

Key take-home: LAMA4 heterozygous variants cause autosomal dominant DCM with supportive segregation and functional evidence, informing genetic diagnosis and family counselling.

References

• Medicine • 2024 • A potential pathogenic mutation of LAMA4 in a Chinese family with dilated cardiomyopathy and conduction system disease PMID:39686469
• Medicina (Kaunas, Lithuania) • 2019 • Digenic Inheritance of LAMA4 and MYH7 Mutations in Patient with Infantile Dilated Cardiomyopathy PMID:30650640
• Circulation • 2007 • Laminin-alpha4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and endothelial cells PMID:17646580

Evidence Based Scoring (AI generated)