AUTHOR=Globa Evgenia , Zelinska Natalia , Shcherbak Yulia , Bignon-Topalovic Joelle , Bashamboo Anu , MсElreavey Ken 

TITLE=Disorders of Sex Development in a Large Ukrainian Cohort: Clinical Diversity and Genetic Findings

JOURNAL=Frontiers in Endocrinology

VOLUME=13

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.810782

DOI=10.3389/fendo.2022.810782

ISSN=1664-2392

ABSTRACT=<sec><title>Background</title><p>The clinical profile and genetics of individuals with Disorders/Differences of Sex Development (DSD) has not been reported in Ukraine.</p></sec><sec><title>Materials and Methods</title><p>We established the Ukrainian DSD Register and identified 682 DSD patients. This cohort includes, 357 patients (52.3% [303 patients with Turner syndrome)] with sex chromosome DSD, 119 (17.5%) with 46,XY DSD and 206 (30.2%) with 46,XX DSD. Patients with sex chromosome DSD and congenital adrenal hyperplasia (CAH, n=185) were excluded from further studies. Fluorescence <italic>in situ</italic> hybridization (FISH) was performed for eight 46,XX boys. 79 patients underwent Whole Exome Sequencing (WES).</p></sec><sec><title>Results</title><p>The majority of patients with 46,XY and 46,XX DSD (n=140), were raised as female (56.3% and 61.9% respectively). WES (n=79) identified pathogenic (P) or likely pathogenic (LP) variants in 43% of the cohort. P/LP variants were identified in the androgen receptor (<italic>AR</italic>) and <italic>NR5A1</italic> genes (20.2%). Variants in other DSD genes including <italic>AMHR2, HSD17B3, MYRF, ANOS1, FGFR11, WT1, DHX37, SRD5A1, GATA4, TBCE, CACNA1A</italic> and <italic>GLI2</italic> were identified in 22.8% of cases. 83.3% of all P/LP variants are novel. 35.3% of patients with a genetic diagnosis had an atypical clinical presentation. A known pathogenic variant in <italic>WDR11</italic>, which was reported to cause congenital hypogonadotropic hypogonadism (CHH), was identified in individuals with primary hypogonadism.</p></sec><sec><title>Conclusions</title><p>WES is a powerful tool to identify novel causal variants in patients with DSD, including a significant minority that have an atypical clinical presentation. Our data suggest that heterozygous variants in the <italic>WDR11</italic> gene are unlikely to cause of CHH.</p></sec>