Disease gene discovery for Familial IgA Nephropathy (FIgAN) by Whole Exome Sequencing (WES)

Abstract

BACKGROUND: IgAN is the most common primary glomerular disease worldwide. Genome-wide linkage scans have identified multiple susceptibility loci for fIgAN but no disease gene has yet been identified. METHODS: To identify susceptibility genes for fIgAN, we performed WES in 109 patients from 54 families all with >2 biopsy-proven cases and putatively affected members ascertained with persistent hematuria/proteinuria. In 3 multiplex families each with >5 affected cases, we also performed genome-wide linkage scans under a dominant model and focused WES on regions with suggestive linkage. Standard algorithms for sequence alignment, base calling, and QC filtering were applied to identify rare (MAF<1%) deleterious variants of high (i.e. protein-truncating) and moderate (i.e. inframe indels and deleterious non-synonymous missense variants predicted by PolyPhen-2, Sift, Mutation Assessor, CADD_phred, PhylopPMam_avg, and PhylopVert100_avg) impact. RESULTS: Overall, 99.8% of the targeted exome were covered with a mean depth of 100x. We examined 19 regions with LOD >1 in 3 multiplex families and ~3,000 immunologic candidate genes. We identified 26 candidate genes (i.e. IFIH1, CD33, MSH6, ERAP2, FUT2, MMRN1, MINA, OAS1, TLR1, RNASEL, MARCO, THADA, BTN1A1, PTPRK, RELT, ERCC1, ASB4, LCP1, HK3, ASH1L, LTB, FES, MPO, GP1BA, BACH2, and EMP3), each with rare deleterious variants affecting 2 or 3 unrelated families. CONCLUSIONS: Our results suggest extensive genetic heterogeneity in fIgAN with many disease genes each contributing to a small proportion of cases. Future studies with expanded sample size will aid selection of the most promising candidate genes for functional studies. Identification of disease genes for fIgAN has the potential to improve diagnosis and treatment. Funding: Government Support - Non-U.S.