Rare LAMA4 Variants Identified in Egyptian Familial Psoriasis Vulgaris
Background Familial clustering of psoriasis vulgaris (PsV) provides a valuable opportunity to identify rare, high-impact genetic variants that may not be captured by population-based association studies. In this study, we investigated two unrelated Egyptian families with multiple affected members to identify novel genetic determinants underlying PsV.  Methods Whole exome sequencing was performed in affected and unaffected members of two PsV families, followed by Sanger sequencing and segregation analysis. Targeted resequencing and TaqMan? genotyping were conducted in independent sporadic PsV cohorts and matched controls. To assess functional relevance, a global Lama4 knockout (Lama4-/-) Mice were evaluated in two established murine models of psoriasiform dermatitis: IL-23-induced psoriasiform dermatitis (IL23PD) and Aldara?-induced psoriasiform dermatitis (AIPD). Disease severity and inflammatory gene expression were assessed.  Results Two rare heterozygous missense variants in LAMA4, c.3161C>T (p.G1054D) and c.3791C>A (p.R1257L), were identified and segregated with disease in the two families. Genotyping of sporadic cohorts identified additional PsV cases carrying the c.3791C>A variant. Notably, LAMA4 has previously been implicated as a risk gene for dilated cardiomyopathy, suggesting a potential genetic link between PsV and cardiovascular comorbidities. In murine studies, Lama4 deficiency significantly attenuated IL23PD and modestly reduced disease severity in AIPD. Protection was associated with decreased expression of Il23r and lower expression of psoriasis- associated inflammatory markers. Conclusions Our findings identify LAMA4 as a novel candidate gene in familial PsV and provide functional evidence for its role in psoriasiform inflammation. Together with prior associations with LAMA4 and cardiomyopathy, these results suggest that LAMA4 may represent a shared genetic factor linking psoriasis with cardiovascular disease and a potential target for therapeutic intervention.