Analysis of clinical phenotype and genotype of Chinese children with disorders of sex development / 中华儿科杂志

Objective: To explore the heterogeneity and correlation of clinical phenotypes and genotypes in children with disorders of sex development (DSD). Methods: A retrospective study of 1 235 patients with clinically proposed DSD in 36 pediatric medical institutions across the country from January 2017 to May 2021. After capturing 277 DSD-related candidate genes, second-generation sequencing was performed to analyzed the heterogeneity and correlation combined with clinical phenotypes. Results: Among 1 235 children with clinically proposed DSD, 980 were males and 255 were females of social gender at the time of initial diagnosis with the age ranged from 1 day of age to 17.92 years. A total of 443 children with pathogenic variants were detected through molecular genetic studies, with a positive detection rate of 35.9%. The most common clinical phenotypes were micropenis (455 cases), hypospadias (321 cases), and cryptorchidism (172 cases) and common mutations detected were in SRD5A2 gene (80 cases), AR gene (53 cases) and CYP21A2 gene (44 cases). Among them, the SRD5A2 mutation is the most common in children with simple micropenis and simple hypospadias, while the AMH mutation is the most common in children with simple cryptorchidism. Conclusions: The SRD5A2 mutation is the most common genetic variant in Chinese children with DSD, and micropenis, cryptorchidism, and hypospadias are the most common clinical phenotypes. Molecular diagnosis can provide clues about the biological basis of DSD, and can also guide clinicians to perform specific clinical examinations. Target sequence capture probes and next-generation sequencing technology can provide effective and economical genetic diagnosis for children with DSD.

Identification of three novel SRD5A2 mutations in Chinese patients with 5α-reductase 2 deficiency / 亚洲男科学杂志(英文版)

In this study, we investigated the genetics, clinical features, and therapeutic approach of 14 patients with 5α-reductase deficiency in China. Genotyping analysis was performed by direct sequencing of PCR products of the steroid 5α-reductase type 2 gene (SRD5A2). The 5α-reductase activities of three novel mutations were investigated by mutagenesis and an in vitro transfection assay. Most patients presented with a microphallus, variable degrees of hypospadias, and cryptorchidism. Eight of 14 patients (57.1%) were initially reared as females and changed their social gender from female to male after puberty. Nine mutations were identified in the 14 patients. p.G203S, p.Q6X, and p.R227Q were the most prevalent mutations. Three mutations (p.K35N, p.H162P, and p.Y136X) have not been reported previously. The nonsense mutation p.Y136X abolished enzymatic activity, whereas p.K35N and p.H162P retained partial enzymatic activity. Topical administration of dihydrotestosterone during infancy or early childhood combined with hypospadia repair surgery had good therapeutic results. In conclusion, we expand the mutation profile of SRD5A2 in the Chinese population. A rational clinical approach to this disorder requires early and accurate diagnosis, especially genetic diagnosis.

Association between diacylglycerol kinase kappa variants and hypospadias susceptibility in a Han Chinese population / 亚洲男科学杂志(英文版)

Previous genome-wide association studies have identified variants in the diacylglycerol kinase kappa (DGKK) gene associated with hypospadias in populations of European descent. However, no variants of DGKK were confirmed to be associated with hypospadias in a recent Han Chinese study population, likely due to the limited number of single-nucleotide polymorphisms (SNPs) included in the analysis. In this study, we aimed to address the inconsistent results and evaluate the association between DGKK and hypospadias in the Han Chinese population through a more comprehensive analysis of DGKK variants. We conducted association analyses for 17 SNPs in or downstream of DGKK with hypospadias among 322 cases (58 mild, 113 moderate, 128 severe, and 23 unknown) and 1008 controls. Five SNPs (rs2211122, rs4554617, rs7058226, rs7063116, and rs5915254) in DGKK were significantly associated with hypospadias (P < 0.05), with odds ratios (ORs) of 1.64-1.76. When only mild and moderate cases were compared to controls, 10 SNPs in DGKK were significant (P < 0.05), with ORs of 1.56-2.13. No significant SNP was observed when only severe cases were compared to controls. This study successfully implicated DGKK variants in hypospadias risk among a Han Chinese population, especially for mild/moderate cases. Severe forms of hypospadias are likely due to other genetic factors.

New single nucleotide variation in the promotor region of androgen receptor [AR] gene in hypospadic patients

Hypospadias is one of the most common congenital abnormalities in the male which is characterized by altered development of urethra, foreskin and ventral surface of the penis. Androgen receptor gene plays a critical role in the development of the male genital system by mediating the androgens effects. In present study, we looked for new variations in androgen receptor promotor and screened its exon 1 for five single nucleotide polymorphisms [SNP] in healthy and hypospadias Iranian men. In our study, at first DNA was extracted from patients [n=100] and controls [n=100] blood samples. Desired fragments of promoter and exon 1 were amplified using polymerase chain reaction. The promoter region was sequenced for the new variation and exone 1 screened for five SNPs [rs139767835, rs78686797, rs62636528, rs62636529, rs145326748] using restriction fragment length polymorphism technique. The results showed a new single nucleotide variation [CT] at -480 of two patients' promoter region [2%]. None of the mentioned SNPs were detected in patients and controls groups [0%].This finding indicates that new single nucleotide polymorphism in androgen receptor promoter may have role in etiology of hypospadias and development of this anomaly