Molecular diagnostics of disorders of sexual development: an Indian survey and systems biology perspective
Creators: name: MR Nagaraja
name: Gubbala, Satya Prakash
name: C. R. Wilma Delphine Silvia
name: Ramars Amanchy
Publisher: name: Taylor & Francis
Year: 2018
Subjects: subject: Medicine
subject: Cell Biology
subject: Genetics
subject: FOS: Biological sciences
subject: FOS: Biological sciences
subject: Molecular Biology
subject: 59999 Environmental Sciences not elsewhere classified
subject: FOS: Earth and related environmental sciences
subject: FOS: Earth and related environmental sciences
subject: 69999 Biological Sciences not elsewhere classified
subject: Developmental Biology
subject: Cancer
subject: Science Policy
subject: Computational Biology

description: 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, <i>AR</i> 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 <i>SRD5A2</i> defects were p.R246Q (most prevalent) and p.G196S could be mutational hotspots, dual gene defects (p.A596T in <i>AR</i> and p.G196S in <i>SRD5A2</i>) in a patient with hypospadias and novel 8 nucleotide deletion (exon 1) found in a patient with perineal hypospadias. Deficits in <i>SRY, WT1, DHH, NR5A1</i>, and <i>DMRT1</i> caused 46,XY gonadal dysgenesis. Notably, mutations in <i>AR, SRD5A2, MAMLD1, WT1</i>, and <i>MAP3K1</i> have led to hypospadias and only one <i>CYP19A1</i> 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., <i>SRY, WT1, DHH, NR5A1, DMRT1, AR, SRD5A2, MAMLD1</i>) involved in DSD but also provided us 12 more potential candidate genes (<i>ACVR1, AMHR2, CTNNB1, CYP11A1, CYP19A1, FGFR2, FGF9, PRKACA, PRKACG, SMAD9, TERT, ZFPM2</i>), 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. <b>Abbreviations:</b> 5α-RD2: 5α-Reductase type 2; AIS: androgen insensitivity syndrome; AMH: antimullerian hormone; AMHR: antimullerian hormone receptor; <i>AR</i>: androgen receptor gene; CAH: congenital adrenal hyperplasia; CAIS: complete AIS; CAH: congenital adrenal hyperplasia; CHH: congenital hypogonadotropic hypogonadism; <i>CXORF6</i>: chromosome X open reading frame 6 gene; <i>CYP19A1</i>: cytochrome P450 family 19 subfamily A member 1 gene; DHT: dihydrotestosterone; <i>DMRT1</i>: 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; <i>MAMLD1</i>: mastermind like domain containing 1 gene; MIS: mullerian inhibiting substance; NTD: N-terminal domain; OT DSD: ovotesticular DSD; PAIS: partial AIS; <i>SOX9</i>: SRY-related HMG-box 9 gene; <i>SRY</i>: sex-determining region Y gene; <i>STAR</i>: steroidogenic acute regulatory protein gene; <i>SRD5A2: s</i>teroid 5 alpha-reductase 2 gene; T DSD: testicular DSD; T: testosterone; <i>WNT4</i>: Wnt family member 4 gene; <i>WT1</i>: Wilms tumor 1 gene; Δ<sub>4</sub>: androstenedione