Whole-exome Sequencing Study of Hypospadias

Abstract

While 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 that NR5A1, SRD5A2 and AR genes 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, and DNAH17) (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 the DNAH8 and DNAH17 genes might affect the network regulation of testosterone (T)-dihydrotestosterone-androgen receptor (T-DHT-AR) signaling. We also identified a novel rare damaging variant of DNAH8 in a severe hypospadias case which was transmitted from the mother. Overall, a panel of ODNAH genes with rare damaging variants were identified in 22.5% of severe hypospadias patients. This study provides unequivocal evidence for association of ODNAH genes and hypospadias. This knowledge may guide the genetic counseling for hypospadias.

An expanded view of infertility: The challenge of the changing profiling of major birth defects in China

“…Moreover, damaging variants of ciliary genes were found to be enriched in patients with transposition of the great arteries (TGA) (13), a complex congenital heart defect. Chen et al reported that knockout of the Dnah8 gene causing hypospadias resulted in decreased testosterone levels in male mice and failure to produce offspring (14). These results further substantiate the established link between ciliary function and CHD, hypospadias, and infertility.…”

Molecular genetics and general management of androgen insensitivity syndrome

“…We proposed that genetic contribution to PAIS is heavily concentrated in genes related to androgen-AR signaling or AR-centered network that are transcribed or expressed in relevant tissues. Rare damaging variants are likely to be causative than other classes of variants and hence explain some of the unknown genetic causes of birth defects, such as hypospadias (48,49). Furthermore, new genomic approaches for identifying non-coding, mosaic, structural or epigenetic variants will improve the understanding of the molecular causes (50).…”

Urogenital sinus malformation: From development to management

“…Disruptions in the process of tubulization are associated with disturbances in the androgen signaling pathway. Genetic variations in the androgen signaling pathway can affect the development of the urethra, such as the formation of hypospadias (21). Unlike males, in female fetuses, the urethral sulcus remains open to form the vestibule due to the low levels of testosterone.…”