Whole Exome Sequencing (WES) revealed underlying complexity in genetic studies of Familial IgA Nephropathy (flgAN)

Abstract

BACKGROUND: Diagnosis of familial glomerular diseases may be confounded by nonspecific clinical (i.e. hematuria and proteinuria) and/or pathological findings. Indeed, a recent study of familial focal segmental glomerulosclerosis (FSGS) has identified COL4A3 and COL4A4 mutations in ~10% of study families [Kidney Int 86:1253-59, 2014]. In the course of studying a cohort of fIgAN, we unexpectedly identified pathogenic mutations in 13 families with non-IgAN glomerular diseases. METHODS: We performed whole exome sequencing (WES) in 109 patients from 54 families all with at least 2 biopsy-proven cases. RESULTS: Our WES study identified heterozygous/hemizygous pathogenic COL4A3 (c.1504+1G>A; p.G291R; p.G695R; p.G1054E; p.G1286R), COL4A4 (p.Q970X; p.G1508A), and COL4A5 (p.G48R; p.G325R) mutations in 9 families with fIgAN. These mutations occurred at the canonical splice junction or conserved glycine residues and segregated in all affected subjects within family. In two multiplex families, co-existence of thin basement membrane disease (TBMD) with IgAN was also observed in the biopsied subjects in retrospect. Additionally, putative heterozygous pathogenic variants were found in 3 families in the known genes for FSGS (ACTN4, c.398-2A>G), CFHR5 nephropathy (CFHR5, p.C449fs), and membranous nephropathy (PLA2R1, p.C192G) and homozygous mutation in one family in another known gene for FSGS (ADCK4, p.S246N). CONCLUSIONS: The presence of other glomerular diseases may confound the diagnosis of fIgAN in some putatively affected subjects ascertained based on urinary findings or even kidney biopsy. Due to its high prevalence in the general population, TBMD may be an important cause of phenocopy that can confound genetic linkage studies in fIgAN.