Novel Heterozygous Genetic Variants in Patients with 46,XY Gonadal Dysgenesis

Vasundhera Chauhan; Viveka P. Jyotsna; Vandana Jain; Rajesh Khadgawat; Rima Dada

doi:10.1055/s-0042-114778

Hormone and Metabolic Research, Table of Contents

Horm Metab Res 2017; 49(01): 36-42
DOI: 10.1055/s-0042-114778

Endocrine Care

Novel Heterozygous Genetic Variants in Patients with 46,XY Gonadal Dysgenesis

Vasundhera Chauhan

¹Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

,

Viveka P. Jyotsna

¹Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

,

Vandana Jain

²Division of Paediatric Endocrinology, Department of Paediatrics, All India Institute of Medical Sciences, New Delhi, India

,

Rajesh Khadgawat

¹Department of Endocrinology and Metabolism, All India Institute of Medical Sciences, New Delhi, India

,

Rima Dada

³Department of Anatomy, All India Institute of Medical Sciences, New Delhi, India

› Author Affiliations

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 of SRY, NR5A1, SOX9, DAX1, DHH, DMRT1 genes 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 of DMRT1 gene in a patient with CGD and was found to be probably damaging on in silico analysis. Other 3 were identified in NR5A1 gene (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.

Key words

46,XY gonadal dysgenesis - genes - mutation - molecular diagnosis

Full Text

References

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