title: Novel Heterozygous Genetic Variants in Patients with 46,XY Gonadal Dysgenesis.
abstract: 46,XY gonadal dysgenesis (GD) constitutes a rare group of disorders characterized by the presence of dysfunctional testes in genotypic males. The molecular etiology is not known in about 2 thirds of instances. The aim of this study was to identify the genetic cause in patients with 46,XY gonadal dysgenesis. Based on clinical, cytogenetic, and biochemical screening, 10 patients with 46,XY GD were recruited. Direct sequencing ofSRY,NR5A1,SOX9,DAX1,DHH,DMRT1genes was carried out for molecular analysis. Among 10 patients, 5 were diagnosed with complete gonadal dysgenesis (CGD), 3 with partial gonadal dysgenesis (PGD), and 3 with testicular agenesis. Molecular analysis revealed 12 heterozygous genetic changes, 4 of which were novel. One (c.416T>A) was observed in evolutionary conserved region ofDMRT1gene in a patient with CGD and was found to be probably damaging on in silico analysis. Other 3 were identified inNR5A1gene (c.990+22 C>A, c.1387+1403T>A and p.131P), but their association with gonadal dysgenesis is not evident from our study. These genetic changes were absent in parents and 50 healthy control samples, which were also studied. With targeted sequencing approach, a molecular diagnosis was made in only one patient with 46,XY GD. The application of new genomic technologies is required for the precise evaluation of these rare genetic defects.
authors.affiliation: Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Vasundhera
authors.initials: V
authors.lastname: Chauhan
authors.affiliation: Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Viveka P
authors.initials: VP
authors.lastname: Jyotsna
authors.affiliation: Division of Paediatric Endocrinology, Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Vandana
authors.initials: V
authors.lastname: Jain
authors.affiliation: Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Khadgawat
authors.affiliation: Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Rima
authors.initials: R
authors.lastname: Dada
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D057137:DAX-1 Orphan Nuclear Receptor / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D024282:Genes, sry; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics*; D053823:Hedgehog Proteins / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D055758:SOX9 Transcription Factor / Q000235:genetics; D054339:Steroidogenic Factor 1 / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D055815:Young Adult
chemical_list: D057137:DAX-1 Orphan Nuclear Receptor; C509245:DHH protein, human; C110547:DMRT1 protein; D053823:Hedgehog Proteins; C539965:NR0B1 protein, human; C515057:NR5A1 protein, human; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D054339:Steroidogenic Factor 1; D014157:Transcription Factors