Mutational Analysis of NR5A1,SRY, DAX1, SOX9, DHH Genes in Indian Patients with Gonadal Dysgenesis and 46, XY Karyotype

Presentation Number: OR21-3
Date of Presentation: March 6th, 2015

Vasundhera Chauhan*1, Madan L Khurana1, Vandana Jain2, Rajesh Khadgawat1 and Rima Dada2
1All India Institute of Medical Sciences, New Delhi, India, 2All India Institute of Medical Sciences, Delhi, India


Background: 46, XY Gonadal Dysgenesis (GD) is often due to the disruption in genetic network that regulates the development of gonads. Causative mutations have only been explained in less than 20% of all cases of 46, XY GD. NR5A1, SRY, DAX1, SOX9, DHH genes play a crucial role in the cascade of events during sexual development. Mutations in these genes may be the cause of abnormal phenotype in our patients.

Objective: Molecular analysis of NR5A1, SRY, DAX1, SOX9, DHH genes in Indian patients with 46, XY GD attending a tertiary care hospital.

Methodology: Clinical examination, psychological assessment, cytogenetic evaluation, hormonal profile (LH, FSH, Testosterone) and molecular analysis of NR5A1, SRY, DAX1, SOX9, DHH genes was done.

Results: Eight patients were recruited in a period of 6 months. Age at intial presentation ranged from 6 days to 19 years (7.7±8.2). One patient had ambiguous genitalia, 3 presented with primary amennorhoea, 2 with unilateral undescended testis and 2 with bilateral undescended testis. Three patients were diagnosed with complete gonadal dysgenesis and five with partial gonadal dygenesis. On psychological assessment, sex of rearing in these patients was found to be concordant with their assigned sex. Cytogenetic analysis showed 46, XY karyotype in all the patients. The hormonal profile in these patients ranged from 0.24mIU/ml to 37.72mIU/ml for LH, 2.76mIU/ml to 111mIU/ml for FSH, 0.02ng/ml to 0.3ng/ml for Testosterone. On molecular analysis, heterozygous mutations were noted in five out of 8 patients. We found 3 novel (one heterozygous missense mutation V69E in high mobility group box of SRY gene, one heterozygous intronic change g.8079G>A and one heterozygous transversion c.2790T>A in the untranslated region of NR5A1 gene) and 4 previously reported genetic changes (rs1110061, rs1889311, rs10120967, rs10283445 ) in our patients.

Conclusion: We describe for the first time a missense mutation p.69V>E in SRY gene in three patients (one patient with unilateral and two patients with bilateral dysgenetic gonads). Two novel heterozygous changes were also found in NR5A1 gene in patients with bilateral dysgenetic gonads. These results reiterate the importance of NR5A1 and SRY genes in evaluation of patients with 46, XY GD.



Nothing to Disclose: VC, MLK, VJ, RK, RD