Department of Molecular Genetics, Function and Therapy, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.
Cyprus School of Molecular Medicine, Nicosia, Cyprus.
Hormones (Athens). 2019 Sep;18(3):315-320. doi: 10.1007/s42000-019-00116-6. Epub 2019 Jun 25.
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.
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.
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.
性发育障碍（DSD）与导致性腺发育不良的基因缺陷有关。在此，我们旨在通过对一名原发性闭经的患者进行全外显子组测序（WES），以确定性腺发育不良的遗传原因，该患者为表型女性，携带同一家系的 46,XY 核型。
进行全外显子组测序（WES），并在纯合状态下发现了 DHH 基因外显子 2 中罕见且仅报道过一次的 p.Arg164Pro 错义突变。使用 Sanger 测序在患者、父母和两个兄弟姐妹中验证了该候选变体。指数患者的哥哥和姐姐均未发现 p.Arg164Pro 突变，而近亲父母则发现处于杂合状态。父母和未受影响的兄弟姐妹均未表现出任何生殖畸形。
DHH 基因突变已被报道为 DSD 的非常罕见原因，本报告增加了 46,XY 性腺发育不良的病例数量。此外，本研究强调了对 DSD 患者进行遗传验证的重要性，因为这可能减轻患者和父母所经历的相当大的心理困扰。
