Background: Disorders of sex development (DSD) are classified as a congenital discrepancy between external genitalia, and gonadal and chromosomal sex. Despite extensive laboratory and imaging investigations, the etiology of DSD is unknown in more than 50% of patients. We aimed to evaluate the etiology of DSD using whole exome sequencing (WES) technique.
Methods: Eleven patients with DSD (ten with 46,XY and one with 46,XX genotype) who underwent comprehensive laboratory investigations, including candidate gene approach sequencing, were enrolled. WES was performed for the probands and their parents.
Results: In 5 of the 11 patients, a pathogenic mutation was identified that explained the phenotype. In an 11-y-old 46,XX-DSD girl, a missense mutation in cytochrome P450 oxidoreductase (POR) was identified. In the other four 46,XY patients: a 2-y-old infant with severely delayed psychomotor development had a previously reported de-novo heterozygous missense mutation in chromodomain-helicase-DNA-binding protein 7 (CHD7); an 8-y-old boy, previously reared as a girl, had a novel homozygous missense mutation in HSD17B3; a 13-y-old boy had a novel de-novo splice mutation in WT1, and an 11-y-old boy had a novel de-novo mutation in bone morphogenetic protein 4 (BMP4). Identification of the etiologies of DSD in these patients enabled us to provide accurate genetic consultations for the families and appropriate therapy for the patients. In 4 patients, no potentially pathogenic variants were found in genes known to cause DSD and in 2 patients, variants of unknown significance were identified.
Conclusions: WES played a crucial role in the diagnosis of DSD; still, in 50% of the cases, no obvious etiology was found. Using WES is cost-effective, make extensive endocrine testing unnecessary and assist parents and physicians in making early and appropriate decisions regarding gender assignment.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology