The clinical diversity and molecular etiology in 46, XY disorders of sex development patients without uterus

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BACKGROUND: Disorders of sexual development (DSDs) are a group of rare conditions with a discordance of chromosomal, gonadal, or phenotypic features of the internal and/or external genitalia, which accounts for 0.5% of the population. The precise diagnosis of 46, XY DSDs without uterus is often obscure because of the similar clinical manifestations. Reverse phenotyping based on specific genetic variants helps to identify the cause of these diseases and reduces misdiagnosis caused by limitations in serum tests and imaging. METHODS: Patients with 46, XY DSDs without uterus were enrolled from the Department of Obstetrics and Gynecology, Reproductive Endocrinology and Infertility Center of the Peking Union Medical College Hospital between 2022 and 2023. Comprehensive clinical data, including the social gender, chief complaint, physical examination results and laboratory tests related to sexual development, and surgical information were collected from medical records. Whole exome sequencing (WES) was performed on all patients and the etiological diagnoses were made based on the results. Targeted Sanger sequencing for the candidate gene was performed in the parents. RESULTS: A total of twenty-one patients with 46, XY DSDs without uterus were included. Twenty-two variants from six genes associated with sex development were identified, including 14 recurrent variants and 8 novel variants. Based on the ACMG guidelines, 17 variants were classified as pathogenic (P) or likely pathogenic (LP), and 5 were defined as variants of uncertain significance (VUS). The genes LH/HCG receptor (LHCGR) (2/22), CYP17A1 (4/22), SRD5A2 (3/22), and AR (10/22) were involved in steroid hormone synthesis and androgen receptor action, while NR5A1(2/22) was associated with gonadal development. Furthermore, a DHX37 variant instead of an AR variant was identified in a patient clinically diagnosed with complete androgen insensitivity syndrome. Trio-WES revealed three de novo variants. CONCLUSION: This study identified several novel variants broadening the mutation spectrum of 46, XY DSD without uterus. The etiology of 46, XY DSDs is complex. Reverse phenotyping helps differentiate the abnormalities and explore the molecular etiology more accurately.

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