Purpose: Disorders of sex development (DSD) have been linked to gene defects that lead to gonadal dysgenesis. Herein, we aimed to identify the genetic cause of gonadal dysgenesis in a patient with primary amenorrhoea tracing it to a phenotypic female carrying a 46,XY karyotype of a consanguineous family.
Methods and results: Whole exome sequencing (WES) was performed and revealed in homozygosity the rare and only once reported p.Arg164Pro missense mutation in exon 2 of the desert hedgehog (DHH) gene. Sanger sequencing was used to validate this candidate variant both in the patient, the parents, and two siblings. Both brother and sister of the index patient were found negative for the p.Arg164Pro mutation, while the consanguineous parents were found to carry the mutation in the heterozygous state. Neither the parents nor the unaffected siblings showed any reproductive malformations.
Conclusions: Defects in the DHH gene have been reported as a very rare cause of DSD, and this report increases the number of 46,XY gonadal dysgenesis cases. Additionally, the present study highlights the importance of genetic validation of patients with DSD, since this is likely to alleviate the considerable psychological distress experienced by both the patient and the parents.
Keywords: 46XY; DHH gene; Desert hedgehog; Gonadal dysgenesis; Primary amenorrhea.