Genetic Causes of Disorders of Sex Development in Thai Children

A genetic diagnosis is essential for patients with disorders of sex development (DSD) in order to provide appropriate counseling and sex assignment. Therefore, a molecular diagnosis was made for DSD patients who were seen at our institute during 2002-2020.

Molecular diagnosis was performed using: polymerase chain reaction (PCR) for the SRY gene in 46,XX DSD patients; Sanger sequencing of the SRD5A2 and AR genes in 46,XY DSD patients; and next generation sequencing (NGS) of a 46-gene panel in patients without definite diagnoses. Patients with hypogonadotropic hypogonadism and 21-hydroxylase-deficient congenital adrenal hyperplasia were excluded.

A total of 150 patients with 46,XY DSD underwent genetic testing for the SRD5A2 gene (n=142) or the AR gene (n=121) or both (n=114). Eighteen patients had homozygous or compound heterozygous mutation in the SRD5A2 gene and 13 patients had hemizygous mutation in the AR gene. One hundred and two patients (46,XY DSD, n=92; 46,XX DSD, n=10) had DNA testing for NGS. Seven patients with 46,XY DSD were found to carry pathogenic or likely pathogenic variants in DSD-related genes: heterozygous variants in the WT1 gene (n=3); heterozygous variants in the SRD5A2 gene (n=2); and hemizygous variant in the MAMLD1 gene (n=2). Thirty-three patients were found to carry only variants of unknown significance (VUS) in DSD-related genes. Two out of six patients with 46,XX ovotesticular DSD were found to carry an SRY gene (one detected by SRY PCR and one by NGS).

In our cohort, 5α-reductase type 2 deficiency and androgen insensitivity syndrome were common causes of 46,XY DSD, followed by monoallelic mutations in the WT1, SRD5A2 and MAMLD1 genes.