Almaramhy Hamdi Hameed, Abdul Samad Firoz, Al-Harbi Ghadeer, Zaytuni Dimah, Imam Syed Nazar, Masoodi Tariq, Shamsi Monis Bilal
College of Medicine, Taibah University, Medina, Saudi Arabia.
College of Applied Medical Science, Taibah University, Medina, Saudi Arabia.
Front Genet. 2023 Jun 13;14:1106933. doi: 10.3389/fgene.2023.1106933. eCollection 2023.
Hypospadias [MIM: 300633] is one of the most frequent congenital malformations of male external genitalia. The spectrum of genetic variants causing hypospadias is varied, with studies commonly implicating genes critical in the fetal steroidogenic pathway. This is the first genetic study on hypospadias from the Yemen ethnicity and the second to report mutations in more than one affected individual from the same family. Surgical hypospadias repair was performed on two hypospadias-affected siblings from a consanguineous family. Whole-exome sequencing (WES) was performed to identify the potential pathogenic variant for hypospadias, which was later confirmed by Sanger sequencing. The identified variant was further analyzed for its pathogenicity by using tools such as SIFT, PolyPhen-2, MutationAssessor, MutationTaster, FATHMM, and ConSurf. We identified a novel missense mutation (Chr1:119964631T>A, c.507T>A, p. N169K) in 3β-hydroxysteroid 2-dehydrogenase () gene by WES. Sanger sequencing confirmed that the variant segregated the disease in the family between the affected and non-affected individuals. Both patients are homozygous, while parents and two unaffected siblings are heterozygous carriers, indicating an autosomal recessive pattern of inheritance. The analysis by all six tools (SIFT, PolyPhen-2, MutationAssessor, MutationTaster, FATHMM, and ConSurf) predicted the variant to be pathogenic/deleterious. An abnormal fetal steroidogenic pathway due to genetic influences may affect the development of the male genital tract, including the urethral tract closure and morphogenesis of male genitalia. Furthermore, the pathogenicity of the observed variant in this study, confirmed by multiple tools, characterizes the influence HSD3B2 gene variants may have in the etiology of hypospadias. Understanding of pathogenic manifestation and inheritance of confounding genetic variants in hypospadias is a matter of great concern, especially in familial cases.
尿道下裂[MIM: 300633]是男性外生殖器最常见的先天性畸形之一。导致尿道下裂的基因变异谱各不相同，研究通常认为胎儿类固醇生成途径中的关键基因与之相关。这是首次针对也门族裔尿道下裂的基因研究，也是第二次报告来自同一家族的不止一名患病个体的突变情况。对一个近亲家庭中两名患有尿道下裂的同胞进行了尿道下裂修复手术。进行了全外显子组测序（WES）以确定尿道下裂的潜在致病变异，随后通过桑格测序进行了确认。使用SIFT、PolyPhen-2、MutationAssessor、MutationTaster、FATHMM和ConSurf等工具对鉴定出的变异进行了致病性进一步分析。通过WES，我们在3β-羟基类固醇2-脱氢酶（）基因中鉴定出一个新的错义突变（Chr1:119964631T>A，c.507T>A，p.N169K）。桑格测序证实该变异在家族中患病个体和未患病个体之间呈疾病分离状态。两名患者均为纯合子，而父母和两名未患病的同胞为杂合子携带者，表明为常染色体隐性遗传模式。所有六种工具（SIFT、PolyPhen-2、MutationAssessor、MutationTaster、FATHMM和ConSurf）的分析均预测该变异具有致病性/有害性。由于基因影响导致的胎儿类固醇生成途径异常可能会影响男性生殖道的发育，包括尿道闭合和男性生殖器的形态发生。此外，本研究中观察到的变异的致病性经多种工具确认，表明HSD3B2基因变异可能在尿道下裂病因中发挥作用。了解尿道下裂中混杂基因变异的致病表现和遗传情况是一个备受关注的问题，尤其是在家族性病例中。
