A Novel LAMA5 Variant in Adult-Onset Focal Segmental Glomerulosclerosis: A Case Report

Focal segmental glomerulosclerosis (FSGS) is a common histopathological diagnosis among adult patients presenting with nephrotic syndrome. This pattern is associated with diverse underlying pathophysiological mechanisms, which may influence disease management, therapeutic response, and prognosis. Genetic forms of FSGS are caused by variants in genes encoding proteins expressed in podocytes or the glomerular basement membrane. Multiple genes have been implicated in the pathogenesis of genetic FSGS, and clinical presentation can vary depending on the specific gene involved. We report the case of a young man with nephrotic syndrome and a histopathological diagnosis of FSGS, in whom genetic testing identified a novel LAMA5 c.6940C > T p.(Arg2314Trp) variant in a consanguineous Saudi family, consistent with autosomal recessive inheritance. Family genetic analysis revealed that the proband's mother and two siblings are homozygous for the identified variant, whereas his father and the remaining two siblings are heterozygous. The variant is currently classified as a variant of uncertain significance (VUS). This report characterizes the associated clinical phenotype and discusses the findings of family segregation analysis in the context of variable expressivity and incomplete penetrance.