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

Abstract

BackgroundThe clinical profile and genetics of individuals with Disorders/Differences of Sex Development (DSD) has not been reported in Ukraine.Materials and MethodsWe 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 in situ hybridization (FISH) was performed for eight 46,XX boys. 79 patients underwent Whole Exome Sequencing (WES).ResultsThe 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 (AR) and NR5A1 genes (20.2%). Variants in other DSD genes including AMHR2, HSD17B3, MYRF, ANOS1, FGFR11, WT1, DHX37, SRD5A1, GATA4, TBCE, CACNA1A and GLI2 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 WDR11, which was reported to cause congenital hypogonadotropic hypogonadism (CHH), was identified in individuals with primary hypogonadism.ConclusionsWES 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 WDR11 gene are unlikely to cause of CHH.

MYRF: A New Regulator of Cardiac and Early Gonadal Development—Insights from Single Cell RNA Sequencing Analysis

“…Subsequently, studies characterized the function of MYRF as a membrane-associated transcription factor for oligodendrocyte differentiation, stimulating myelin gene expression in the CNS [ 2 , 3 ]. Currently, it is known that MYRF is also expressed in other tissues in addition to the CNS, especially during the early development of the diaphragm, heart, eyes, lungs and genitourinary tract, which is consistent with the fact that variants in this gene have been associated with congenital diaphragmatic hernia [ 4 ], congenital heart diseases [ 5 ], nanophthalmos and other ocular defects [ 6 ], and more recently, with a new cardiac and urogenital syndrome (CUGS), as well as with disorders/differences of sex development (DSD) [ 7 , 8 ], a group of conditions in which development of chromosomal, gonadal or anatomic sex is atypical [ 9 ]. Sex determination in mammals is controlled by the interaction between many genes that drive a bistable embryonic gonadal development program.…”

“…All of them presented different phenotypes of DSD; however, only one had a diaphragmatic hernia, and neither heart defects nor nanophthalmos were associated in those patients. More recently, Globa et al [ 8 ] reported two other cases of MYRF heterozygous variants as a cause of DSD. Both individuals were 46,XY; the first one registered as a female with ambiguous genitalia, later raised as a boy, and the second one was a girl with primary amenorrhea, a lack of secondary sexual characteristics and high-grade hypermetropia.…”

Disorder of Sex Development Due to 17-Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency: A Case Report and Review of 70 Different HSD17B3 Mutations Reported in 239 Patients

“…Sixty-eight articles reported one or more patients with HSD17B3 mutations ( Supplemental Table S1 ) [ 1 , 3 , 4 , 5 , 9 , 10 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 ...…”

Genetics of Differences of Sex Development

“…In addition, a genetic diagnosis enables recurrence risk counselling and reproductive decision-making for parents. Despite these benefits, until recently, only a minority of DSD patients received a clinical genetic diagnosis [Eggers et al, 2016;Abualsaud et al, 2021;Globa et al, 2022].…”

“…Importantly, this has coincided with the ease and reduced costs of sequencing the entire genome. Genomic sequencing as a diagnostic test has now largely been translated into the clinic and is having a major impact on DSD diagnostic rates which are hovering around 40-50% [Eggers et al, 2016;Globa et al, 2022].…”