Novel genes and variants associated with IgA nephropathy by co-segregating with the disease phenotypes in 10 IgAN families

Abstract

Background: Previously, a large proportion of the genetic components predisposing individuals to IgA nephropathy (IgAN) have been unidentified. Familial IgAN is enriched with genetic variations predisposing individuals to the disease. Whole exome sequencing is an effective way to explore disease-causing genes and gene variants.

Methods: We performed exome sequencing on the probands from each of ten IgAN families, and on one of the unaffected member from 7 of the families. Sanger sequencing, bioinformatics and co-segregation analysis were performed for all available family members to detect deleterious genetic variation. The relatedness of the families was tested by haplotype analyses.

Results: Six deleterious variants in 4 genes were observed to be associated with IgA nephropathy by co-segregating with the disease phenotypes in study families. MYCT1 p.Asp22Glufs*34 was associated with IgAN by co-segregating with its phenotypes in families 2, 7, and 9; DEFA4 p.Ala8Pro, p.Ala8Val, c.172+1G>T co-segregated in families 1, 2, and 3; ZNF543 p.Pro226Ala co-segregated in families 3, 5, and 6 and CARD8 p.Val98Lysfs*26 co-segregated in families 7 and 8. Among these genes, MYCT1, CARD8 and ZNF543 are novel. Our haplotype analyses showed that families in which the same variation(s) were co-segregating with IgAN were unrelated, except for DEFA4. Of the families carrying DEFA4, families 2 and 3 were possibly related, but not family 1, indicating that common genes/variations in these families were not due to the same founder. Interfamilial sharing of different co-segregating genes was also observed, demonstrating the polygenic nature of this disease.

Conclusions: We discovered 6 deleterious variants in 4 genes associated with familial IgAN. These genes are good candidate genes that appear to be causally related to IgAN and warrant further study.

Keywords: Caspase recruitment domain-containing protein 8 (CARD8); Defensin, Alpha 4 (DEFA4); Familial; IgA nephropathy (IgAN); Myc Target 1 (MYCT1); Zinc Finger Protein 543 (ZNF543).