Identification by whole exome sequencing of a novel candidate HSD3B2 gene variant for familial hypospadias

Introduction: Hypospadias is one of the most frequent congenital malformations ofmale external genitalia. The spectrum of genetic variants causing hypospadias is varied, with studiescommonly implicating genes critical in fetal steroidogeneic pathway. This is the first study to reportHSD3B2 mutations in more than one affected individual from the same family. Moreover, it is also thefirst genetic study on hypospadias from the Yemen ethnicity.Material and Methods: Surgical hypospadias repair was performed on two hypospadias affectedsiblings from a consanguineous family. Whole Exome Sequencing (WES) was done to identify thepotential pathogenic variant for hypospadias, which was later confirmed by Sanger Sequencing. Theidentified variant was further analyzed for its pathogenicity by using in silico tools as SIFT,PolyPhen2, Mutation assessor, Mutation Taster, FATHMM and ConSurf.Results: We identified a novel missense mutation (Chr1:119964631T>A,c.507T>A, p.N169K) in HSD3B2 gene by WES. Sanger sequencing confirmed that thevariant segregated the disease in the family between the affected and non-affected individuals. Boththe patients are homozygous, while parents and two unaffected siblings are heterozygous carriers,indicating autosomal recessive pattern of inheritance. The in silico analysis by all the six in silico tools(SIFT, PolyPhen2, Mutation assessor, Mutation Taster, FATHMM and ConSurf) predicted the variantto be pathogenic/deleterious.Discussion: Abnormal fetal steroidogeneic pathway, due to genetic influences may affect thedevelopment of male genital tract including the urethral tract closure and morphogenesis of malegenitalia. Further, the pathogenicity confirmation of observed variant in this study, by multiple in silicotools characterizes the influence HSD3B2 gene variants may have in the etiology of hypospadias.Conclusion: Understanding of pathogenic manifestation and inheritance of confounding geneticvariants in hypospadias is a matter of great concern in particular in familial cases.