Comprehensive molecular analysis identifies eight novel variants in XY females with disorders of sex development

Abstract

Disorders of sex development (DSD) are a group of clinical conditions with variable presentation and genetic background. Females with or without development of secondary sexual characters and presenting with primary amenorrhea (PA) and a 46, XY karyotype are one of the classified groups in DSD. In this study, we aimed to determine the genetic mutations in 25 females with PA and a 46, XY karyotype to show correlations with their phenotypes. Routine Sanger sequencing with candidate genes like SRY, AR, SRD5A2 and SF1 which are mainly responsible for 46, XY DSD in adolescent females was performed. In a cohort of 25 patients of PA with 46, XY DSD where routine Sanger sequencing failed to detect the mutations, next generation sequencing (NGS) of a targeted gene panel with 81 genes was used for the molecular diagnosis. The targeted sequencing identified total 21 mutations including eight novel variants in 20 out of 25 patients with DSD. The most frequently identified mutations in our series were in AR (36%), followed by SRD5A2 (20%), SF1 (12%), DHX37 (4%), HSD17B3(4%) and DMRT2 (4%). We could not find any mutation in the DSD related genes in five (20%) patients due to complex molecular mechanisms in 46, XY DSD, highlighting the possibility of new DSD genes which are yet to be discovered in these disorders. In conclusion, genetic testing including cytogenetics and molecular genetics is important for the diagnosis and management of 46, XY DSD cases.

Virilization at puberty in adolescent girls may reveal a 46,XY disorder of sexual development

“…In the literature, there are only nine reports on pubertal virilization revealing 46,XY DSD in patients who were identified as females at birth ( 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ). We and others previously reported that pubertal virilization ( 19 ) and also isolated primary amenorrhea ( 31 , 32 ) should orient towards a diagnosis of 46,XY sex reversal related to NR5A1 alterations (MIM #612965).…”

“… 0.00035 Pathogenic Heterozygous (inherited from the father) PVS1 PM2 PM3 → Pathogenic Skipping of exon 3, frameshift with premature stop codon in exon 4 ( 23 ) 4 HSD17B3 NM_000197.2 c.278-1G>C p.(?) 0.00003 Pathogenic Heterozygous (inherited from the mother) PVS1 PM2 PM3 → Pathogenic Acceptor native site loss, predicted use of cryptic acceptor site in exon 3, frameshift with premature stop codon in exon 3 4 AR NM_000044.6 c.2395C>G p.(Gln799Glu) 0.0013 Conflicting interpretation of pathogenicity Hemizygous PM1 PP3 PP5 BS1 BP5 → Probably benign Missense, effect on the transactivation capacity of androgen receptor ( 32 ) …”

Identification and functional analysis of a rare variant of gene DHX37 in a patient with 46,XY disorders of sex development

“…Variations of DHX37 are reported to lead to neurodevelopmental disorders and 46,XY DSD (Buonocore et al., 2019 ; Karaca et al., 2015 ; McElreavey et al., 2019 ; Paine et al., 2019 ; Zidoune et al., 2021 ). To date, 21 heterozygous variants of DHX37 have been identified in 58 patients with 46,XY DSD (Buonocore et al., 2019 ; da Silva et al., 2019 ; de Oliveira et al., 2023 ; Globa et al., 2022 ; Gomes et al., 2022 ; Kulkarni et al., 2023 ; McElreavey et al., 2019 ; Shaomei et al., 2022 ; Wan et al., 2023 ; Yang et al., 2023 ; Zhang et al., 2023 ; Zidoune et al., 2021 ). All affected individuals have manifestations of gonadal dysgenesis, varying from micropenis and bilateral rudimentary gonadal tissue to absent, ambiguous, or atypical genitalia.…”

Phenotype‐Genotype Discordance and a Case of a Disorder of Sexual Differentiation

“…All of the patients in the study had testes, and none had a uterus or ovaries; thirteen patients had inguinal testes. Domenice et al found the most common clinical presentation to be “atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Müllerian derivatives [ 13 ].” Currently, there are over 200 known pathogenic variants in the NR5A1 gene reported in association with individuals with DSD [ 13 , 30 – 36 ].…”