Whole-exome Sequencing Study of Hypospadias

Abstract

ABSTRACTWhile hypospadias is one of the most common male congenital disorders, the missing heritability contributed by rare variants with larger effects is poorly understood. To systematically explore the variant patterns in the developing of hypospadias, we performed whole exome sequencing (WES) in 191 severe hypospadias cohort and three trios. Subsequent RNA sequencing of 12 severe hypospadiac foreskins and 6 non-hypospadiac foreskins were conducted. Among previous reported hypospadias risk associated genes, we found thatNR5A1, SRD5A2andARgenes are mutational hotspots in the etiology of severe hypospadias. Additionally, rare damaging variants in novel identified outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, andDNAH17) (p= 4.8×10−17) were significantly enriched in 191 sporadic severe hypospadias compared with 208 controls. The following transcriptomic analysis further demonstrated that the mutations in theDNAH8andDNAH17genes might affect the network regulation of testosterone (T)-dihydrotestosterone-androgen receptor (T-DHT-AR) signaling. We also identified a novel rare damaging variant ofDNAH8in a severe hypospadias case which was transmitted from the mother. Overall, a panel ofODNAHgenes with rare damaging variants were identified in 22.5% of severe hypospadias patients. This study provides unequivocal evidence for association ofODNAHgenes and hypospadias. This knowledge may guide the genetic counseling for hypospadias.One Sentence SummaryRare damaging variants in outer DNAH genes were identified in 22.5% of severe hypospadias patients, which may guide the genetic counseling of families facing familial hypospadias.