Exome sequencing identified compound heterozygous mutations in theSRD5A2gene in a case of 46,XY ambiguous genitalia

Abstract

Differentiation of the bi-potential gonad into testes or ovaries is driven by the chromosome complement of the foetus. It is believed that the differentiation into ovaries is a default setting, which in the presence of SRY gets diverted to testicular development. Chromosomal anomalies at this stage or mutations in the SRY gene or its translocation to the X-chromosome gives rise to an array of ambiguous gonad phenotypes, resulting in partial to complete discordance between the chromosome complement and the gonadal sex (Mendonca et al., 2009). Once the gonads are differentiated, the production of testosterone by the testis drives the differentiation of the external genitals into male, the absence of which would result in their development into female external genitals (Arnold, 2017). However, errors in testosterone production or the failure of its action due to mutations in the androgen receptor (AR) may result in the development of the external genitals in contrast to the chromosomal complement. In genetic males, testosterone is converted into dihydrotestosterone (DHT) by SRD5A2 protein, encoded by the SRD5A2 gene. DHT production is essential as its drives the differentiation of the external male genitals. The lack of testosterone production, failure of its conversion into DHT or failure of their action due to AR mutations results in an array of ambiguous genitalia phenotypes, named as the disorders of sexual development (DSD) (Rajender et al., 2007). Ambiguous external genitalia are a rare phenotype where genitals cannot be distinguished as a male or a female. This uncertainty about