Mutation analysis of the SRD5A2, AR and SF-1 genes in 52 Chinese boys with hypospadias

Shi

et al. 2019

Molec Gen & Gen Med

Self Cite

Background Hypospadias is a common congenital malformation of male external genitalia, which mainly manifests as an abnormal urethral opening on the ventral side of the penis. The etiology and clinical phenotype of hypospadias is highly heterogeneous, and its clinical diagnosis is challenging. Currently, over 70% of patients have an unknown etiology. Here, we performed a targeted analysis of gene mutations in 130 patients with hypospadias of unknown etiology to find the precise genetic cause. Methods We developed a targeted next‐generation sequencing (NGS) panel, encompassing the exon coding regions of 105 genes involved in external genitalia and urogenital tract development and performed sequencing analysis on 130 children with hypospadias of unknown etiology. Results In total, 25 patients with hypospadias (19.2%) were found to have 20 mutations among the nine genes involved in external genitalia and urogenital tract development, including 16 reported and four novel mutation sites. Twenty‐two patients (16.9%) had diagnostic variants. Multiple genetic mutations were identified in three of the 25 patients. Hypospadias combined with micropenis was the most common phenotype (68%) in 25 patients. Conclusions Higher frequency mutations were identified in SRD5A2 (52%) and AR (24%) in our patient cohort. Middle or posterior hypospadias with micropenis may be significant indicators of genetic variations. Polygenic inheritance may be a rare genetic cause of hypospadias.

Section: Discussionsupporting

confidence: 93%

Identification of gene variants in 130 Han Chinese patients with hypospadias by targeted next‐generation sequencing

Shi

et al. 2019

Molec Gen & Gen Med

Self Cite

“…Like HSD17B3, mutations in SRD5A2 can lead to a variety of phenotypes [Akcay et al, 2014], and the role of SRD5A2 in 46,XY DSD has been studied for almost 40 years. Indeed, various mutations in this gene have been linked with an increased risk of hypospadias [Silver and Russell, 1999; Wang et al, 2004; Samtani et al, 2011; Wang R et al, 2013; Carmichael et al, 2014] and one hypospadias-associated variant, the SRD5A2 V89L polymorphism, is less active in vitro [Thai et al, 2005]. Differences in the activity of SRD5A2 variants may explain why some are associated with hypospadias [Silver and Russell, 1999], while others are reported to reduce the risk of both mild and severe hypospadias [Thai et al, 2005] (tables 1, 2).…”

Section: Androgens and Hypospadiasmentioning

confidence: 99%

The Genetic and Environmental Factors Underlying Hypospadias

Bouty

Ayers

Pask

et al. 2015

Sex Dev

170

137

Hypospadias results from a failure of urethral closure in the male phallus and affects 1 in 200-300 boys. It is thought to be due to a combination of genetic and environmental factors. The development of the penis progresses in 2 stages: an initial hormone-independent phase and a secondary hormone-dependent phase. Here, we review the molecular pathways that contribute to each of these stages, drawing on studies from both human and mouse models. Hypospadias can occur when normal development of the phallus is disrupted, and we provide evidence that mutations in genes underlying this developmental process are causative. Finally, we discuss the environmental factors that may contribute to hypospadias and their potential immediate and transgenerational epigenetic impacts.

Arab Journal of Urology

“…Significant increase of CAG repeats [18,29] and no significant differences [20,21]. Mutations associated [17,32] and no mutations identified [21,33,34].…”

Section: New Promising Molecular Approachesmentioning

confidence: 91%

“…Mutations associated with the condition were identified [41,48]. Pathogenic mutations found [34,35].…”

Section: New Promising Molecular Approachesmentioning

confidence: 99%

New frontiers on the molecular underpinnings of hypospadias according to severity

Piñeyro-Ruiz

Serrano

Perez-Brayfield

et al. 2020

Hypospadias, which is characterised by the displacement of the urethral meatus from its typical anatomical location in males, shows various degrees of severity. In this systematic review, we surveyed our current understanding of the genetics of isolated hypospadias in humans according to the severity of the condition. We found that sequencing and genotyping approaches were the preferred methods of study and that single nucleotide polymorphisms were the most common finding associated with hypospadias. Most genes fell into four genepathway categories related to androgens, oestrogens, growth factors, or transcription factors. Few hypospadias studies classify their findings by severity. Taken together, we argue that it is advantageous to take into consideration the severity of the condition in search of novel candidates in the aetiology of hypospadias.