We aimed to survey the monogenic causes of disorders of sex development (DSD) and thereby its prevalence in India. This study revealed mutations resulting in androgen insensitivity syndrome, 5α-reductase type 2 deficiency, and gonadal dysgenesis were commonly reported. Intriguingly, AR deficits were the most prevalent (32 mutations) and of 11/26 missense mutations were in exons 4–8 (encoding ligand binding domain). The unique features of SRD5A2 defects were p.R246Q (most prevalent) and p.G196S could be mutational hotspots, dual gene defects (p.A596T in AR and p.G196S in SRD5A2) in a patient with hypospadias and novel 8 nucleotide deletion (exon 1) found in a patient with perineal hypospadias. Deficits in SRY, WT1, DHH, NR5A1, and DMRT1 caused 46,XY gonadal dysgenesis. Notably, mutations in AR, SRD5A2, MAMLD1, WT1, and MAP3K1 have led to hypospadias and only one CYP19A1 mutation caused aromatase deficiency was reported to date. Data mining from various databases has not only reinforced the role of well-established genes (e.g., SRY, WT1, DHH, NR5A1, DMRT1, AR, SRD5A2, MAMLD1) involved in DSD but also provided us 12 more potential candidate genes (ACVR1, AMHR2, CTNNB1, CYP11A1, CYP19A1, FGFR2, FGF9, PRKACA, PRKACG, SMAD9, TERT, ZFPM2), which benefit from a close association with the well-established genes involved in DSD and might be useful to screen owing to their direct gene–phenotype relationship or through direct functional interaction. As more genes have been revealed in relation to DSD, we believe ultimately it holds a better scenario for therapeutic regimen. Despite the advances in translational medicine, hospitals are yet to adopt genetic testing and counseling facilities in India that shall have potential impact on clinical diagnosis.

Abbreviations: 5α-RD2: 5α-Reductase type 2; AIS: androgen insensitivity syndrome; AMH: antimullerian hormone; AMHR: antimullerian hormone receptor; AR: androgen receptor gene; CAH: congenital adrenal hyperplasia; CAIS: complete AIS; CAH: congenital adrenal hyperplasia; CHH: congenital hypogonadotropic hypogonadism; CXORF6: chromosome X open reading frame 6 gene; CYP19A1: cytochrome P450 family 19 subfamily A member 1 gene; DHT: dihydrotestosterone; DMRT1: double sex and mab-3 related transcription factor 1 gene; DSD: disorders of sexual development; GD: gonadal dysgenesis; HGMD: human gene mutation database; IH: isolated hypospadias; MAMLD1: mastermind like domain containing 1 gene; MIS: mullerian inhibiting substance; NTD: N-terminal domain; OT DSD: ovotesticular DSD; PAIS: partial AIS; SOX9: SRY-related HMG-box 9 gene; SRY: sex-determining region Y gene; STAR: steroidogenic acute regulatory protein gene; SRD5A2: steroid 5 alpha-reductase 2 gene; T DSD: testicular DSD; T: testosterone; WNT4: Wnt family member 4 gene; WT1: Wilms tumor 1 gene; Δ₄: androstenedione

我们旨在调查性发育障碍（DSD）的单基因原因，从而探讨其在印度的流行情况。这项研究揭示了导致雄激素不敏感综合症，5α-还原酶2型缺乏和性腺发育不全的突变的报道。有趣的是，AR缺陷是最普遍的（32个突变），而11/26个错义突变的第4-8外显子（编码配体结合域）。SRD5A2缺陷的独特特征是p.R246Q（最普遍），而p.G196S可能是突变热点，双基因缺陷（AR中的p.A596T和SRD5A2中的p.G196S ）是尿道下裂和新的8个核苷酸缺失（外显子1）发现于会阴性尿道下裂的患者中。赤字SRY，WT1，DHH，NR5A1和DMRT1导致46，XY性腺发育不良。值得注意的是，AR，SRD5A2，MAMLD1，WT1和MAP3K1中的突变已导致尿道下裂，迄今为止，据报道仅一种CYP19A1突变引起芳香酶缺乏症。来自各种数据库的数据挖掘不仅增强了DSD中涉及的成熟基因（例如SRY，WT1，DHH，NR5A1，DMRT1，AR，SRD5A2，MAMLD1）的作用，还为我们提供了12个潜在的候选基因（ACVR1， AMHR2，CTNNB1，CYP11A1，CYP19A1，FGFR2，FGF9，PRKACA，PRKACG，SMAD9，TERT，ZFPM2），其受益于与DSD中涉及的成熟基因的紧密联系，并且由于其直接的基因表型关系或通过直接的功能相互作用而可能对筛选有用。随着与DSD相关的更多基因的发现，我们相信最终它将为治疗方案提供更好的方案。尽管转化医学取得了进步，但医院仍未在印度采用基因检测和咨询设施，这将对临床诊断产生潜在影响。

缩写： 5α-RD2：5α-还原酶类型2；AIS：雄激素不敏感综合征；AMH：抗苗勒激素；AMHR：抗苗勒激素受体；AR：雄激素受体基因；CAH：先天性肾上腺增生；CAIS：完整的AIS；CAH：先天性肾上腺增生；CHH：先天性性腺功能减退性腺功能减退；CXORF6：染色体X开放阅读框6基因；CYP19A1：细胞色素P450家族19亚家族A成员1基因；DHT：二氢睾丸激素；DMRT1：双重性和与mab-3相关的转录因子1基因；DSD：性发育障碍；GD：性腺发育不全；HGMD：人类基因突变数据库；IH：孤立性尿道下裂；MAMLD1：包含1个基因的类策划领域；MIS：米勒抑制物质；NTD：N端结构域；OT DSD：卵睾DSD；PAIS：部分AIS；SOX9：与SRY相关的HMG-box 9基因；SRY：决定性别的区域Y基因；STAR：类固醇生成的急性调节蛋白基因；SRD5A2：类固醇5α还原酶2基因；T DSD：睾丸DSD；T：睾丸激素；WNT4：Wnt家族成员4基因；WT1：威尔姆斯肿瘤1基因；Δ ₄：雄烯二酮