Identification of a locus on the X-chromosome linked to familial membranous nephropathy

ABSTRACT Introduction Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases, yet currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the aetiology of MN. Methods We identified three families with a total of 8 members affected by primary MN. Genotyping was performed utilizing single nucleotide polymorphism (SNP) microarrays, and serum was sent for anti-PLA2R antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted and genetic risk scores (GRS) based on known MN-associated variants were determined. Results Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant LOD score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the three families. GRS in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls. Conclusions Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate aetiologic entity.