Worldwide cohort study of 46, XY differences/disorders of sex development genetic diagnoses: geographic and ethnic differences in variants

Frontiers in Genetics, Journal Year: 2024, Volume and Issue: 15

Published: June 10, 2024

Differences/disorders of sex development (DSDs) in individuals with a 46, XY karyotype are group congenital disorders that manifest as male gonadal hypoplasia or abnormalities the external genitalia. Approximately 50% patients DSDs cannot obtain molecular diagnosis. The aims this paper were to review most common causative genes and rare DSDs, analyze global diagnostic cohorts for prevalence geographic distribution genes, identify factors affecting cohort detection results. Although spectrum genetic variants varies across regions severity clinical phenotype patients, next-generation sequencing (NGS), commonly used method, can still reveal aid A comparison rates various modalities revealed whole-exome (WES) facilitates greater rate diagnosis disease than panel sequencing. Whole-genome (WGS), third-generation sequencing, algorithm advancements will contribute improvement efficiency. mutated associated androgen synthesis action AR , SR5A2 HSD17B3 involved formation NR5A1 MAP3K1. Detection results affected by differences enrollment criteria technologies.

Language: Английский

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The Importance of Clinical Categorization for a Successful Etiologic Diagnosis of Monogenic Disorders in 46,XY DSD

The Journal of Clinical Endocrinology & Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 13, 2025

Journal Article Corrected proof The Importance of Clinical Categorization for a Successful Etiologic Diagnosis Monogenic Disorders in 46,XY DSD Get access Sofía Suco Valle, Valle Centro de Investigaciones Endocrinológicas "Dr. César Bergadá" (CEDIE), CONICET—FEI—División Endocrinología, Hospital Niños Ricardo Gutiérrez, C1425EFD Buenos Aires, Argentina https://orcid.org/0009-0000-4061-8700 Search other works by this author on: Oxford Academic Google Scholar Rodolfo A Rey ArgentinaFacultad Medicina, Departamento Histología, Embriología, Biología Celular y Genética, Universidad C1121ABG Correspondence: A. Rey, MD, PhD, Gallo 1330, Argentina. Email: [email protected]. https://orcid.org/0000-0002-1100-3843 Endocrinology & Metabolism, dgaf054, https://doi.org/10.1210/clinem/dgaf054 Published: 13 February 2025 history Received: 03 January Editorial decision: 27 and typeset:

Language: Английский

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

Orphanet Journal of Rare Diseases, Journal Year: 2025, Volume and Issue: 20(1)

Published: April 17, 2025

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

Language: Английский

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Role of the pediatrician in the initial management of a newborn with Differences of Sex Development or hypospadias

European Journal of Pediatrics, Journal Year: 2025, Volume and Issue: 184(5)

Published: April 22, 2025

Language: Английский

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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

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(17), P. 10026 - 10026

Published: Sept. 2, 2022

The 17-beta-hydroxysteroid dehydrogenase type 3 (17-β-HSD3) enzyme converts androstenedione to testosterone and is encoded by the HSD17B3 gene. Homozygous or compound heterozygous mutations block synthesis of in fetal testis, resulting a Disorder Sex Development (DSD). We describe child raised as female whom discovery testes inguinal canals led genetic study whole exome sequencing (WES) identification mutation gene (c.608C>T, p.Ala203Val, c.645A>T, p.Glu215Asp). Furthermore, we review all published so far cases 17-β-HSD3 deficiency. A total 70 different have been reported 239 patients from 187 families. 118 families had homozygous mutations, 63 six undetermined genotypes. Mutations occurred 11 exons were missense (55%), splice-site (29%), small deletions insertions (7%), nonsense (5%), multiple exon duplications (2%). Several recurrent at codon 80 c.277+4A>T each represented 17% mutated alleles. These findings may be useful those involved clinical management diagnosis this disorder.

Language: Английский

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Fair and Safe Eligibility Criteria for Women's Sport: The Proposed Testing Regime Is Not Justified, Ethical, or Viable

Scandinavian Journal of Medicine and Science in Sports, Journal Year: 2024, Volume and Issue: 34(11)

Published: Nov. 1, 2024

In an invited editorial, Tucker et al. [1] addressed the eligibility controversy regarding Paris 2024 Olympic boxing competition. They cited Lundberg [2] concerning in/eligibility of transgender women for female sports category and identified performance differences between males females alongside studies involving testosterone suppression. Several authors present letter also co-authored stand by that paper, but declined co-authorship al.'s editorial here, with additional collaborators, challenges to editorial. First, did not acknowledge absence high-quality scientific data sport advantage athletes XY sex development (DSDs). Furthermore, individuals DSDs possess one or more numerous rare genetic mutations [3], causing wide variability in pubertal physical relevant within different DSDs. Consequently, no primary evidence base currently exists demonstrating athletic justify testing regulation entire population competitors. Second, despite lacuna, propose mandatory women's worldwide "early", sub-elite Figure 2 includes high-performing teenage athletes. If consistent their thesis, "early" must therefore include minors. Mandatory was abandoned 1999 due concerns about validity, financial cost, practicality, as well trauma stigmatization many [4]. All these remain are amplified vastly increased number younger tested under proposal. The gives impression such tests straightforward, "individual consent, confidentiality, dignity… simple cheek swab… standard medical care", assurances ignore enormous problems a regime would generate. Individual voluntary consent is core principle [5]. Under proposed rather than healthcare, young be presented genuine choice. Consent only coercive offer: comply test never participate competitive girls' sport, even at level. ethically responsible counseling ensures people understand potential consequences receiving results before consenting [6] provides comprehensive professional follow-up [7]. Who fund produce this army expertise? For those undergoing clinical examination genome sequencing (only providing diagnosis ~50% cases [8]), how devastation athletes' personal identity self-esteem, alarm caused families [9], managed? resultant duty care will fall federations mandating assessments, without any realistic prospect being fulfilled. What, precisely, does involve? say "standard care". do state transparently it begins assess clitoromegaly, symmetry external genital structures, presence/absence breast development, extent sexual hair, involves palpation genitalia, so forth [9]. Indeed, part "Level 1 Assessment", World Athletics regulations [10] require gynecologists physicians following current guidance outlined above apply regulations, affect small proportion have undergo invasive potentially humiliating editorial's We agree criticism approach some sports, which "invites targeted based on allegation, suspicion, subjective assessment, bias" broad discussion required develop appropriate regulations. However, all girls justified evidence, has limited ethical defensibility, operationally viable proposition. like make joint conflict interest statement we declare following: received payment provide expert testimony related topic and/or served pro bono witnesses proceedings Court Arbitration Sport. work organisations. travel accommodation expenses speaking engagements topic. spoken mainstream media research funding from organisations including International Committee, Anti-Doping Agency US Agency. Data sharing applicable article new were created analyzed study.

Language: Английский

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Nuclear Receptor Gene Variants Underlying Disorders/Differences of Sex Development through Abnormal Testicular Development

Biomolecules, Journal Year: 2023, Volume and Issue: 13(4), P. 691 - 691

Published: April 19, 2023

Gonadal development is the first step in human reproduction. Aberrant gonadal during fetal period a major cause of disorders/differences sex (DSD). To date, pathogenic variants three nuclear receptor genes (NR5A1, NR0B1, and NR2F2) have been reported to DSD via atypical testicular development. In this review article, we describe clinical significance NR5A1 as introduce novel findings from recent studies. are associated with 46,XY 46,XX testicular/ovotesticular DSD. Notably, both caused by show remarkable phenotypic variability, which digenic/oligogenic inheritances potentially contribute. Additionally, discuss roles NR0B1 NR2F2 etiology acts an anti-testicular gene. Duplications containing result DSD, whereas deletions encompassing can underlie has recently causative gene for possibly although role unclear. The knowledge about these receptors provides insights into molecular networks involved fetuses.

Language: Английский

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Pathological characteristics of SRY-negative 38,XX-DSD pigs: a family case report

Animal Reproduction Science, Journal Year: 2024, Volume and Issue: 270, P. 107579 - 107579

Published: Aug. 17, 2024

Language: Английский

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Gonadal tumors in a contemporary cohort of patients with differences in sex development undergoing surgery – A multi-site study from the Pediatric Urologic Oncology Working Group of the societies for pediatric urology

Journal of Pediatric Urology, Journal Year: 2023, Volume and Issue: 19(4), P. 399.e1 - 399.e8

Published: April 13, 2023

Language: Английский

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Genetic reanalysis of patients with a difference of sex development carrying the NR5A1/SF-1 variant p.Gly146Ala has discovered other likely disease-causing variations

PLoS ONE, Journal Year: 2023, Volume and Issue: 18(7), P. e0287515 - e0287515

Published: July 11, 2023

NR5A1/ SF-1 (Steroidogenic factor-1) variants may cause mild to severe differences of sex development (DSD) or be found in healthy carriers. The NR5A1 /SF-1 c.437G>C/p.Gly146Ala variant is common individuals with a DSD and has been suggested act as susceptibility factor for adrenal disease cryptorchidism. Since the allele frequency high general population, functional testing p.Gly146Ala revealed inconclusive results, disease-causing effect this questioned. However, role modifier still possible given that oligogenic inheritance described patients variants. Therefore, we performed next generation sequencing (NGS) 13 harboring search other DSD-causing clarify function phenotype Panel whole-exome was performed, data were analyzed filtering algorithm detecting - DSD-related genes. studied ranged from scrotal hypospadias ambiguous genitalia 46,XY opposite both 46,XX. In nine subjects identified either clearly pathogenic gene (e.g. AR ) one four potentially deleterious likely explain observed alone FGFR3 , CHD7 ). Our study shows most carrying variant, harbor at least which can phenotype. This finding confirms not contribute pathogenesis qualifies benign polymorphism. Thus, individuals, whom underlying genetic their past, should re-evaluated NGS method reveal real diagnosis.

Language: Английский

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