XY Disorders Of Sex Development Research Articles

Long-term outcome of gender assignment in individuals with 46, XY DSD assigned female sex in multicultural society

The decision regarding sex rearing in patients with Disorders of Sex Development (DSD) is heavily connected to the shared decision-making model within multidisciplinary team. Some of these patients might develop gender dysphoria, when they become adults. We have aimed to evaluate the long-term outcomes of patients with XY DSD who underwent female gender assignment at our center. We have conducted a retrospective study of all 46, XY DSD patients who underwent female assignment in our institution over the last 30 years. we have found 25 46, XY patients who were raised as a female after birth. After excluding the Androgen insensitivity syndrome (AIS) patients we have identified 15 patients who have matched study criteria. The decision on gender rearing was made by the parents in 11(74%) and by the surgical team 2(13%) during hernia repair/inguinal exploration. In 2(13%) cases, the patients opted to continue identifying as women after learning about the pathology during adolescence. Nine (60%) out of 15 patients (age17.9±4.7 years (mean±SD)) agreed to answer questionnaires regarding sexual function and satisfaction from gender assignment. Mean follow up was 11.1±8.2 years (mean±SD). only one participant consented to respond to a questionnaire regarding sexual intercourse (homosexual). The overall FSFI score was 24 which included the scores 4, 4, 3, 4, 3, 2 in the categories desire, arousal, lubrication, orgasm, satisfaction, and pain respectively. Two patients regretted the decision of female gender assignment. The first with 5α-reductase deficiency, he made the decision for assignment himself as an adult and the other (3β-hydroxysteroid dehydrogenase) who underwent gonadectomy during inguinal exploration as a child. The rest of the patients were satisfied with the choice of gender, 2 need psychological support on the daily basis. In the study group, relationship and cohabitation were significantly later in life compared to the general population. Despite the sensitivity of the subject and cultural differences, most patients (78%) were satisfied with the decision to undergo female gender assignment. Over the years, patients require meticulous follow-up in order to consider additional interventions, and mental support if it is necessary. The two cases of later regret highlight the importance of proper education of patients, their families and medical providers upon decision on gender assignment.

2. Surgical Treatment of a Rare Case of 46,XY Disorder of Sexual Development

2. Surgical Treatment of a Rare Case of 46,XY Disorder of Sexual Development

[Value of the human chorionic gonadotropin stimulation test in the diagnosis of disorder of sexual development in children].

To investigate the value of the human chorionic gonadotropin (hCG) stimulation test in the diagnosis of disorder of sexual development (DSD) in children. A retrospective analysis was conducted on 132 children with DSD. According to the karyotype, they were divided into three groups: 46,XX group (n=10), 46,XY group (n=87), and sex chromosome abnormality group (n=35). The above groups were compared in terms of sex hormone levels before and after hCG stimulation test, and the morphological manifestation of the impact of testicular tissue on the results of the hCG stimulation test was analyzed. There was no significant difference in the multiple increase of testosterone after stimulation among the three groups (P>0.05). In the 46,XY group, the children with 5α-reductase type 2 deficiency had a testosterone-to-dihydrotestosterone ratio higher than that of the 46,XY DSD children with other causes. Morphological analysis showed that DSD children with testicular tissue demonstrated a significantly higher multiple increase in testosterone after stimulation compared to children without testicular tissue (P<0.05). The hCG stimulation test has an important value in assessing the presence and function of testicular interstitial cells in children with different types of DSD, and it is recommended to perform the hCG stimulation test for DSD children with unclear gonadal type.

Clinical Presentation and Etiologic Diagnosis of Disorders of Sex Development in Children in Senegal

Introduction: Disorders of Sex Development (DSD) refer to situations where chromosomal, gonadal or anatomical sex is atypical. We aimed to describe the baseline characteristics on clinical and etiological diagnosis of DSD in Senegalese children. Methods: This retrospective cohort study over a period of 8 years (2015-2022) included all children aged 0 to 18 years followed for DSD at the pediatric endocrinology department of NCHAR in Dakar. Sociodemographic clinical, paraclinical (genetics, imaging, hormonal) parameters were collected and analyzed with Epi Info 7.2. The description was made using position and dispersion parameters and illustrations in the form of appropriate tables and graphs. Bivariate analysis was used for associations between variables, with an alpha error risk of 5% and a CI of 95%. All ethical rules have been respected. Results: We included 102 DSD cases. Only 61 patients (59.80%) had a genetic diagnosis. Mean age at diagnosis was 31.2 ± 46.6 months. Rearing sex of child was male in 35 cases (57.38%) and female in 22 cases (36.06%) and undetermined in 4 cases (6.56%). Based on karyotype analysis, 31(50.82%) of children had 46,XY DSD, 27 (44.26%) had 46,XX DSD and three (4.92%) children with sex chromosome DSD. Etiologies were dominated by congenital adrenal hyperplasia (81.48%) and androgen insensitivity (38.71%) in 46,XX  and 46,XY DSD respectively. External masculinization score &gt; 4, palpation of a gonad, a phallus length &gt; 2.5, a single urogenital orifice as well as ultrasound sex were associated with the XY karyotype. Conclusion: Health care professional and medical students should be trained for early diagnosis. A national guideline should be developed for diagnosis and management of DSD during and beyond the pediatric age group, and adapted to evidence and available resources. This can only be achieved if the management of DSD is supported by universal health insurance.

[Clinical, genetic, and pathological analysis in 165 children with disorders of sex development].

To investigate the clinical phenotypes, genetic characteristics, and pathological features of children with disorders of sex development (DSD). A retrospective analysis was conducted on epidemiological, clinical phenotype, chromosomal karyotype, gonadal pathology, and genotype data of 165 hospitalized children with DSD at Children's Hospital of Hebei Province and Tangshan Maternal and Child Health Hospital from August 2008 to December 2022. Among the 165 children with DSD, common presenting symptoms were short stature (62/165, 37.6%), clitoromegaly (33/165, 20.0%), cryptorchidism (28/165, 17.0%), hypospadias (24/165, 14.5%), and skin pigmentation abnormalities/exteriorized pigmented labia majora (19/165, 11.5%). Chromosomal karyotype analysis was performed on 127 cases, revealing 36 cases (28.3%) of 46,XX DSD, 34 cases (26.8%) of 46,XY DSD, and 57 cases (44.9%) of sex chromosome abnormalities. Among the sex chromosome abnormal karyotypes, the 45,X karyotype (11/57, 19%) and 45,X/other karyotype mosaicism (36/57, 63%) were more common. Sixteen children underwent histopathological biopsy of gonadal tissues, resulting in retrieval of 25 gonadal tissues. The gonadal tissue biopsies revealed 3 cases of testes, 3 cases of dysplastic testes, 6 cases of ovaries, 11 cases of ovotestes, and 1 case each of streak gonad and agenesis of gonads. Genetic testing identified pathogenic/likely pathogenic variants in 23 cases (23/36, 64%), including 12 cases of 21-hydroxylase deficiency congenital adrenal hyperplasia caused by CYP21A2 pathogenic variants. Short stature, clitoromegaly, cryptorchidism, hypospadias, and skin pigmentation abnormalities are common phenotypes in children with DSD. 45,X/other karyotype mosaicism and CYP21A2 compound heterozygous variants are major etiological factors in children with DSD. The most commonly observed gonadal histopathology in children with DSD includes ovotestes, ovaries, and testes/dysgenetic testes.

Is earlier better in feminizing or masculinizing surgical assignment in patients with 46,XY disorder of sex development (DSD) with 17ß-hydroxysteroid dehydrogenase type 3 deficiency?

Is earlier better in feminizing or masculinizing surgical assignment in patients with 46,XY disorder of sex development (DSD) with 17ß-hydroxysteroid dehydrogenase type 3 deficiency?

In vitro functional study of fifteen SRD5A2 variants found in Chinese patients and the relation between the SRD5A2 genotypes and phenotypes

The 5α-reductase type 2 (5α-RD2) deficiency is one of the most common etiology of 46, XY disorders of sex development and is caused by pathogenic variants in SRD5A2. Massively parallel sequencing contributes to identification of numerous novel SRD5A2 variants, in vitro functional study could help to determine their pathogenicity. In this study, we aim to present the functional study of fifteen SRD5A2 variants found in Chinese patients and explore the genotype–phenotype association. We collected the clinical manifestation and genotype of 38 patients with 5α-RD2 deficiency who visited our center between 2009 and 2021. The pathogenicity of seven missense SRD5A2 variants, were predicted by in-silico tools. Furthermore, fifteen SRD5A2 variants without reported functional assay were studied in vitro to analyze the role of these variants in enzymatic activity. Twenty-four SRD5A2 rare variants were identified in 38 patients with 5α-RD2 deficiency. Fifteen variants without reported functional assay decreased the conversation of testosterone (T) to dihydrotestosterone(DHT) and caused the almost complete loss of enzyme activity (<8 %) in our in-vitro functional study. Thirty-eight patients with three different external genital phenotypes (complete female, clitoromegaly and hypospadias) were found to have same variants. Patients with different testicular position (scrotum/clitoris and cryptorchidism) were found to have same variants. Our study showed 15 SRD5A2 variants caused complete loss of 5α-RD2 enzyme activity by functional study. Patients with different clinical phenotypes can have the same genotypes and no obvious genotype–phenotype association exist in our series patients.

Swyer Syndrome: An in-Depth Exploration of Phenotypic and Genotypic Features in 46, XY Disorders of Sex Development

Swyer Syndrome, also known as 46, XY Complete Gonadal Dysgenesis, is a rare and intriguing disorder of sexual development characterized by a phenotypic female appearance in individuals possessing a 46,XY karyotype. This enigmatic condition results from a cascade of genetic and hormonal events, which ultimately lead to the absence of functional gonads, presenting a challenging diagnostic and therapeutic conundrum. In this comprehensive review, we delve into the intricate landscape of Swyer syndrome, elucidating its genetic underpinnings, clinical manifestations, diagnostic approaches, and contemporary management strategies. By consolidating current knowledge, this article aims to provide a valuable resource for healthcare professionals, geneticists, and researchers interested in unraveling the complexities of disorders of sex development and the genetic determinants of sexual differentiation.

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

Although hyperandrogenism is a frequent cause of consultation in adolescent girls, more severe forms with virilization must lead to suspicion of an adrenal or ovarian tumor. However, they may also reveal a 46,XY disorder of sexual development (DSD). Here, we describe four adolescent girls referred for pubertal virilization and in whom we diagnosed a 46,XY DSD. We performed gene mutation screening by Sanger sequencing (all patients) and by next-generation sequencing (NGS) in patient #4. We identified new heterozygous NR5A1 gene variants in patients #1 and #2 and a homozygous SRD5A2 gene deletion in patient #3. Patient #4 received a diagnosis of complete androgen insensitivity in childhood; however, due the unusual pubertal virilization, we completed the gene analysis by NGS that revealed two heterozygous HSD17B3 variants. This work underlines the importance of considering the hypothesis of 46,XY DSD in adolescent girls with unexplained virilization at puberty.

THU185 Molecular Etiologic Spectrum Of Patients With 46,XY And 46,XX Disorders Of Sex Development

Abstract Disclosure: J. Kim: None. S. Park: None. S. Hwang: None. J. Yoon: None. G. Kim: None. H. Yoo: None. J. Choi: None. Background: Disorders of sexual development (DSDs) is a group of congenital conditions associated with discordant development of chromosomal, gonadal, and anatomical sex. Sex development is a complex process with a precise synergistic temporal-spatial transcriptional regulation of multiple genes. Advances in next-generation sequencing (NGS) techniques have achieved genetic diagnosis for up to 40 % of 46,XY DSDs. This study investigated the etiological distribution of DSDs identified by NGS. Methods: This study included 70 patients with DSDs (56 patients with 46,XY DSD and 14 patients with 46,XX DSD). Molecular genetic analysis was performed using targeted gene panel sequencing (n = 43) and whole-exome sequencing (WES, n = 26), including 25 patients for the first-line test and one without sequence variants by targeted gene panel sequencing. Whole-genome sequencing (WGS) was performed on 7 patients, including two patients for the first-line test and five patients without sequence variants by targeted gene panel sequencing or WES. Results: Patients with DSDs presented in infancy with ambiguous genitalia and at older children with aberrant pubertal development or discordance between karyotype and external genitalia. Twenty-four of 56 patients (42.9%) with 46,XY DSD were reared female, and 5 of 14 patients (35.7%) with 46,XX DSD were raised as a male. Pathogenic or likely pathogenic variants were identified in 21 of 56 patients with 46,XY DSD (37.5%); however, no rare sequence variants were found in patients with 46,XX DSD. The AR variants were the most common (8/70, 11.4%), followed by CYP17A1 (4/70, 5.7%), SRD5A2 (4/70, 5.7%), NR5A1 (2/70, 2.8%), GATA4 (1/70, 1.4%), MYRF (1/70, 1.4%), and deletion of DMRT1/2 (1/70, 1.4%). Mutation-positive patients with 46, XY DSD were assigned as female more frequently than mutation-negative patients (19/21 vs. 6/35, P-value &amp;lt;0.001). The lower diagnostic yield was observed in patients with a less severe phenotype, such as hypospadias or micropenis. Conclusions: This study demonstrated that genetic etiologies could be identified in 37.5% of patients with 46,XY DSD, whereas there were no genetic variants in patients with 46,XX DSD. Patients with a more severe phenotype were more likely to have a conclusive genetic diagnosis. NGS is a helpful technique to improve diagnostic efficiency in patients with DSD because of phenotypic and genetic heterogeneity. Presentation: Thursday, June 15, 2023

Predictors of surgical complications in boys with hypospadias: data from an international registry

BackgroundComplications are frequently reported after hypospadias repair and there is a need to understand the factors that influence their occurrence.MethodsData from boys with hypospadias born between 2000 and 2020 were...

Study of 5 Alpha Reductase Enzyme Gene Mutations in a Group of Patients with 46XY Disorders of Sex Development

Background Disorders of sex development (DSD) are a wide range of conditions with diverse features and pathophysiology that most often present in the newborn or the adolescent periods. Affected patients usually present with atypical genitalia like hypospadias, isolated micropenis and undescended testis. These clinical situations can often be difficult to manage, particularly in those cases where the sex rearing is uncertain. Aim of the Work Studying 5alpha reductase enzyme gene mutations (SRD5A2) in patients with 46XY DSD to detect its molecular characteristics. Patients and Methods This cross-sectional study was performed on 25 male patients with clinical, laboratory and genetic molecular analysis of SRD5A2 gene mutation fitting the diagnosis of 46XY DSD. To assess the degree of virilization external masculinization score (EMS) was used where EMS less than 7 is considered ambiguous. All parameters were evaluated at the pediatrics endocrinology clinic and genetics department, Ain Shams University from December 2019 to December 2020. Results Only 12 patients showed laboratory and molecular results compatible with the diagnosis of SRD5A2 gene mutation, The mean age of the patients was 3.64 ± 4.75 years. Results showed EMS of 4.3 denoting the high degree of genital ambiguity in our cases. Scrotum was bifid in 5 patients (41.6%), underdeveloped in 5 patients (41.6%) and fused in 2 patients (16.8%). Cryptorchidism was found in 4 patients only (33.3%). Four patients (33.3%) had normal urethral opening while hypospadias was present in 8 patients being perineal in 1 patient (8.3%), perineoscrotal in 5 patients (41.6%) and scrotal in 2 patients (16.6%). Micropenis was present in 7 patients (58.3%), four patients had 2 openings (33.3%) compared to a single opening in 8 patients (66.7%). Regarding type of SRD5A2 gene mutations 56.2% of mutations were Insertion deletion, 25% were Insertion, 12.5 % were Missense, 6.25% were Deletion. Conclusion This study demonstrated ten novel mutations of SRD5A2 gene were identified in association with 5alpha reductase enzyme deficiency. These mutations were reported among 12 patients with 46 XY DSD from total of 25 patients were fit for this study. No distinct relationships were observed between genotypic and phenotypic characteristics in the participants.

Clinical characteristics and genetic expansion of 46,XY disorders of sex development children in a Chinese prospective study.

Diagnosis and management strategy of disorders of sex development (DSD) are difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanisms have been identified and proposed as genetic causes of 46,XY DSD. In this study, 178 46,XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting, respectively, for 40.90 and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 35.96% (64/178) pathogenic/likely pathogenic variants and 13.48% (24/178) variants of uncertain significance. Of all, 19.42% (20/103) variants were first reported in 46,XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (steroid 5-alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in the Chinese population. Novel candidate genes related to DSD (GHR (growth hormone receptor) and PHIP (pleckstrin homology domain-interacting protein)) were identified. Overall, this was a large cohort of 46,XY DSD patients with a common clinical classification and phenotype spectrum of Chinese patients. Targeted gene panel sequencing covered most of the genes contributing to DSD, whereas whole-exome sequencing detected more candidate genes.

The alternate pathway of androgen metabolism and window of sensitivity.

Since the discovery in 1968 that dihydrotestosterone (DHT) is a major mediator of androgen action, a convincing body of evidence has accumulated to indicate that the major pathway of DHT formation is the 5α-reduction of circulating testosterone in androgen target tissues. However, we now know that DHT can also be formed in peripheral tissues by the oxidation of 5α-androstane-3α,17β-diol (adiol). This pathway is responsible for the formation of the male phenotype. We discuss the serendipitous discovery in the tammar wallaby of an alternate pathway by which adiol is formed in the testes, secreted into plasma and converted in peripheral tissues to DHT. This alternate pathway is responsible for virilisation of the urogenital system in this species and is present in the testes at the onset of male puberty of all mammals studied so far. This is the first clear-cut function for steroid 5α-reductase 1 in males. Unexpectedly, the discovery of this pathway in this Australian marsupial has had a major impact in understanding the pathophysiology of aberrant virilisation in female newborns. Overactivity of the alternate pathway appears to explain virilisation in congenital adrenal hyperplasia CAH, in X-linked 46,XY disorders of sex development. It also appears to be important in polycystic ovarian syndrome (PCOS) since PCOS ovaries have enhanced the expression of genes and proteins of the alternate pathway. It is now clear that normal male development in marsupials, rodents and humans requires the action of both the classic and the alternate (backdoor) pathways.

A case of 17-beta-hydroxysteroid dehydrogenase deficiency type 3 in adult endocrinologist practice

17β-Hydroxysteroid dehydrogenase 3 deficiency (17HSD3) is a rare autosomal recessive cause of 46, XY disorders of sex development resulting from HSD17B3 gene mutations, in which conversion of androstenedione to testosterone is impared. The clinical signs of 17HSD3 deficiency depend on the residual activity of the enzyme. The diagnosis of 17HSD3 deficiency is based on reduced testosterone/androstenedione ratio (T/AD &lt; 0.8). Patients are usually assigned at birth and raise as female. If the diagnosis is made before puberty, gonadectomy is recommended, taking into account the risk of masculinization during the puberty and estrogen therapy initiation in this period. If the diagnosis of 17HSD3 deficiency is established during puberty, when virilization manifests, the therapeutic strategy is based on the results of comprehensive psychological testing and gender identity of a patient. In patients with more pronounced masculinization or diagnosis established shortly after birth, who are assigned at birth and raise as male, testosterone therapy is used to achieve a male phenotype. The 17HSD3 deficiency and virilization often result in a change of gender identity during puberty. The article presents a clinical case of 17-βhydroxysteroid dehydrogenase type 3 deficiency with late diagnosis due to parental will. The diagnostic approaches and management of the disease are also described.

The genetic spectrum of a Chinese series of patients with 46, XY disorders of the sex development.

The etiology of 46, XY disorders of sex development (46, XY DSD) is complex, and studies have shown that different series of patients with 46, XY DSD has different genetic spectrum. In this study, we aimed to investigate the underlying genetic etiology in a Chinese series of patients with 46, XY DSD by whole exome sequencing (WES). Seventy patients with 46, XY DSD were enrolled from the Peking Union Medical College Hospital (Beijing, China). The detailed clinical characteristics were evaluated, and peripheral blood was collected for WES to find the patients' rare variants (RVs) of genes related to 46, XY DSD. The clinical significance of the RVs was annotated according to American College of Medical Genetics and Genomics (ACMG) guidelines. A total of 57 RVs from nine genes were identified in 56 patients with 46, XY DSD, which include 21 novel RVs and 36 recurrent RVs. Based on the American ACMG guidelines, 43 variants were classified as pathogenic(P) or likely pathogenic (LP) variants and 14 variants were defined as variants of uncertain significance (VUS). P or LP variants were identified in 64.3% (45/70) patients of the series. Thirty-nine, 14, and 4 RVs were involved in the process of androgen synthesis and action, testicular determination and developmental process, and syndromic 46, XY DSD, respectively. The top three genes most frequently affected to cause 46, XY DSD were AR, SRD5A2, and NR5A1. Seven patients were found harboring RVs of the 46, XY DSD pathogenic genes identified in recent years, namely DHX37 in four patients, MYRF in two patients, and PPP2R3C in one patient. We identified 21 novel RVs of nine genes, which extended the genetic spectrum of 46, XY DSD pathogenic variants. Our study showed that 60% of the patients were caused by AR, SRD5A2 or NR5A1 P/LP variants. Therefore, polymerase chain reaction (PCR) amplification and Sanger sequencing of these three genes could be performed first to identify the pathogeny of the patients. For those patients whose pathogenic variants had not been found, whole-exome sequencing could be helpful in determining the etiology.

46 xy disorders of sex development (dsd): a case report

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

46 XY disorder of sex development: Case report

Disorders of sexual differentiation in 46, XY patients cover a wide spectrum of clinical pictures (female phenotype, posterior hypospadias, cryptorchidism). Their causes are varied and affect the stages of testicular determination (gonadal dysgenesis) or defects in testosterone production or action (testosterone secretion abnormalities, androgen insensitivity, 5⍺-reductase deficiency). They require rational and rapid management, within a multidisciplinary team. We report a rare case of this disorder in a patient of 18 years with the therapeutic obstacles that we faced in its management.

DHX37 and NR5A1 Variants Identified in Patients with 46,XY Partial Gonadal Dysgenesis.

The group of disorders known as 46,XY gonadal dysgenesis (GD) is characterized by anomalies in testis determination, including complete and partial GD (PGD) and testicular regression syndrome (TRS). Several genes are known to be involved in sex development pathways, however approximately 50% of all cases remain elusive. Recent studies have identified variants in DHX37, a gene encoding a putative RNA helicase essential in ribosome biogenesis and previously associated with neurodevelopmental disorders, as a cause of PGD and TRS. To investigate the potential role of DHX37 in disorders of sexual development (DSD), 25 individuals with 46,XY DSD were analyzed and putative pathogenic variants were found in four of them. WES analyses were performed on these patients. In DHX37, the variant p.(Arg308Gln), recurrent associated with DSD, was identified in one patient; the p.(Leu467Val), predicted to be deleterious, was found together with an NR5A1 loss-of-function variant in patient 2; and, the p.(Val999Met) was identified in two unrelated patients, one of whom (patient 3) also carried a pathogenic NR5A1 variant. For both patients carrying DHX37 and NR5A1 pathogenic variants, a digenic inheritance is suggested. Our findings support the importance of DHX37 variants as a cause of disorders of sex development, implying a role in testis development.

A novel c.64G > T (p.G22C) NR5A1 variant in a Chinese adolescent with 46,XY disorders of sex development: a case report

BackgroundAdolescents with 46,XY disorders of sex development (DSD) face additional medical and psychological challenges. To optimize management and minimize hazards, correct and early clinical and molecular diagnosis is necessary.Case presentationWe report a 13-year-old Chinese adolescent with absent Müllerian derivatives and suspected testis in the inguinal area. History, examinations, and assistant examinations were available for clinical diagnosis of 46,XY DSD. The subsequent targeting specific disease‐causing genes, comprising 360 endocrine disease-causing genes, was employed for molecular diagnosis. A novel variation in nuclear receptor subfamily 5 group A member 1 (NR5A1) [c.64G > T (p.G22C)] was identified in the patient. In vitro functional analyses of the novel variant suggested no impairment to NR5A1 mRNA or protein expression relative to wild-type, and immunofluorescence confirmed similar localization of NR5A1 mutant to the cell nucleus. However, we observed decreased DNA-binding affinity by the NR5A1 variant, while dual-luciferase reporter assays showed that the mutant effectively downregulated the transactivation capacity of anti-Müllerian hormone. We described a novel NR5A1 variant and demonstrated its adverse effects on the functional integrity of the NR5A1 protein resulting in serious impairment of its modulation of gonadal development.ConclusionsThis study adds one novel NR5A1 variant to the pool of pathogenic variants and enriches the adolescents of information available about the mutation spectrum of this gene in Chinese population.