Whole genome sequencing identifies a missense polymorphism in PADI6 associated with testicular/ovotesticular XX disorder of sex development in dogs DOI Creative Commons
Joanna Nowacka‐Woszuk, Monika Stachowiak, Izabela Szczerbal

et al.

Genomics, Journal Year: 2022, Volume and Issue: 114(4), P. 110389 - 110389

Published: May 18, 2022

Disorders of sex development (DSDs) are congenital malformations defined as discrepancies between chromosomes and phenotypical sex. Testicular or ovotesticular XX DSDs frequently observed in female dogs, while monogenic XY less frequent. Here, we applied whole genome sequencing (WGS) to search for causative mutations DSD females French Bulldogs (FB) American Staffordshire Terries (AST) Yorkshire (YT). The WGS results were validated by Sanger ddPCR. It was shown that a missense SNP the PADI6 gene, is significantly associated with (SRY-negative) phenotype AST (P = 0.0051) FB 0.0306). On contrary, did not find any variant YTs. Our study suggests genetic background may be more complex breed-specific.

Language: Английский

Multi-Stakeholder Opinion Statement on the Care of Individuals Born with Differences of Sex Development: Common Ground and Opportunities for Improvement DOI Creative Commons
Martine Cools, Earl Y. Cheng, J. Camille Hall

et al.

Hormone Research in Paediatrics, Journal Year: 2024, Volume and Issue: unknown, P. 1 - 17

Published: Feb. 8, 2024

In the last 15 years, care provided for individuals born with differences of sex development (DSD) has evolved, a strong emphasis on interdisciplinary approaches. However, these developments have not convinced some stakeholders to embrace current model care. This also paid insufficient attention socio-cultural and global inequalities.

Language: Английский

Citations

14
Oligogenic analysis across broad phenotypes of 46,XY differences in sex development associated with NR5A1/SF-1 variants: findings from the international SF1next study DOI Creative Commons
Chrysanthi Kouri, Idoia Martinez de la Piscina,

Rawda Naamneh-Elzenaty

et al.

EBioMedicine, Journal Year: 2025, Volume and Issue: 113, P. 105624 - 105624

Published: March 1, 2025

Oligogenic inheritance has been suggested as a possible mechanism to explain the broad phenotype observed in individuals with differences of sex development (DSD) harbouring NR5A1/SF-1 variants. We investigated genetic patterns oligogenicity cohort 30 variants and 46,XY DSD recruited from international SF1next study, using whole exome sequencing (WES) on family trios whenever available. WES data were analysed tailored filtering algorithm designed identify rare SF-1-related genes. Identified subsequently tested Resource for Variant Analysis (ORVAL) bioinformatics platform combined pathogenicity individual variant. In 73% (22/30) related DSD, we identified one seven additional variants, predominantly known DSD-related genes, that might contribute phenotype. found identical eight unrelated genes (e.g., TBCE, FLNB, GLI3 PDGFRA) different frequently associated CDH23, GLI2, KAT6B, MYO7A, PKD1, SPRY4 ZFPM2) 15 index cases. Our study also combinations novel candidate These findings highlight complex landscape NR5A1/SF-1, where several cases, use advanced testing specific algorithms machine learning tools revealed hits may Swiss National Science Foundation Boveri Zurich.

Language: Английский

Citations

1
Detection of cryptic balanced chromosomal rearrangements using high-resolution optical genome mapping DOI
Shuo Zhang, Zhenle Pei, Caixia Lei

et al.

Journal of Medical Genetics, Journal Year: 2022, Volume and Issue: 60(3), P. 274 - 284

Published: June 16, 2022

Chromosomal rearrangements have profound consequences in diverse human genetic diseases. Currently, the detection of balanced chromosomal (BCRs) mainly relies on routine cytogenetic G-banded karyotyping. However, cryptic BCRs are hard to detect by karyotyping, and risk miscarriage or delivering abnormal offspring with congenital malformations carrier couples is significantly increased. In present study, we aimed investigate potential single-molecule optical genome mapping (OGM) unravelling rearrangements.Eleven normal karyotypes that had abortions/affected unbalanced were enrolled. Ultra-high-molecular-weight DNA was isolated from peripheral blood cells processed via OGM. The assembly performed followed variant calling annotation. Meanwhile, multiple strategies, including FISH, long-range-PCR amplicon-based next-generation sequencing Sanger implemented confirm results obtained OGM.High-resolution OGM successfully detected reciprocal translocation all recruited couples, which consistent FISH sequencing. All high-confidence translocations confirmed analysis rearrangement breakpoints. Moreover, revealed additional complex events such as inverted aberrations, further refining interpretation.To best our knowledge, this first study wherein facilitate rapid robust clinical practice. With excellent performance, findings suggest well qualified an accurate, comprehensive first-line method for detecting testing.

Language: Английский

Citations

36
Towards a “Testis in a Dish”: Generation of Mouse Testicular Organoids that Recapitulate Testis Structure and Expression Profiles DOI Creative Commons

Aviya Stopel,

Cheli Lev,

Stav Dahari

et al.

International Journal of Biological Sciences, Journal Year: 2024, Volume and Issue: 20(3), P. 1024 - 1041

Published: Jan. 1, 2024

The testis is responsible for sperm production and androgen synthesis.Abnormalities in development function lead to disorders of sex male infertility.Currently, no vitro system exists modelling the testis.Here, we generated organoids from neonatal mouse primary testicular cells using transwell inserts show that these generate tubule-like structures cellular organization resembling vivo testis.Gene expression analysis demonstrates a profile recapitulates observed testis.Embryonic cells, but not adult are also capable forming organoids.These can be maintained culture 8-9 weeks shows signs entry into meiosis.We further developed defined media compositions promote immature versus mature Sertoli cell Leydig states, enabling organoid maturation vitro.These promising model basic research testes function, with translational applications elucidation treatment developmental infertility.

Language: Английский

Citations

7
Unveiling the roles of Sertoli cells lineage differentiation in reproductive development and disorders: a review DOI Creative Commons
Yang Gao,

Zican Wang,

Yue Long

et al.

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

Published: April 18, 2024

In mammals, gonadal somatic cell lineage differentiation determines the development of bipotential gonad into either ovary or testis. Sertoli cells, only cells in spermatogenic tubules, support spermatogenesis during development. During embryonic differentiation, relevant genes, including

Language: Английский

Citations

5
Molecular genetics and general management of androgen insensitivity syndrome DOI Open Access
Zhongzhong Chen, Pin Li, Yiqing Lyu

et al.

Intractable & Rare Diseases Research, Journal Year: 2023, Volume and Issue: 12(2), P. 71 - 77

Published: May 17, 2023

Androgen insensitivity syndrome (AIS) is a rare genetic disorder that affects the development of male reproductive system in individuals with 46,XY karyotype. In addition to physical impacts, patients AIS may face psychological distress and social challenges related gender identity acceptance. The major molecular etiology results from hormone resistance caused by mutations X-linked androgen receptor (AR) gene. Depending on severity resistance, wide spectrum can be divided into complete (CAIS), partial (PAIS), or mild (MAIS). Open issues treatment management include decisions about reconstructive surgery, counseling, assignment, timing gonadectomy, fertility physiological outcomes. Although new genomic approaches have improved understanding causes AIS, identification challenging, diagnosis often not achievable. relationship between genotype phenotype well established. Therefore, optimal remains uncertain. objective this review outline recent progress promote clinical manifestation, genetics expert multidisciplinary approach, an emphasis etiology.

Language: Английский

Citations

13
The genetic spectrum of a Chinese series of patients with 46, XY disorders of the sex development DOI
Wei Zhang, Jiangfeng Mao, Xi Wang

et al.

Andrology, Journal Year: 2023, Volume and Issue: 12(1), P. 98 - 108

Published: May 6, 2023

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

Language: Английский

Citations

12
Variants in SART3 cause a spliceosomopathy characterised by failure of testis development and neuronal defects DOI Creative Commons
Katie L. Ayers,

Stefanie Eggers,

Ben Rollo

et al.

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 9, 2023

Abstract Squamous cell carcinoma antigen recognized by T cells 3 ( SART3 ) is an RNA-binding protein with numerous biological functions including recycling small nuclear RNAs to the spliceosome. Here, we identify recessive variants in nine individuals presenting intellectual disability, global developmental delay and a subset of brain anomalies, together gonadal dysgenesis 46,XY individuals. Knockdown Drosophila orthologue reveals conserved role testicular neuronal development. Human induced pluripotent stem carrying patient show disruption multiple signalling pathways, upregulation spliceosome components demonstrate aberrant differentiation vitro. Collectively, these findings suggest that bi-allelic underlie spliceosomopathy which tentatively propose be termed INDYGON syndrome I ntellectual N eurodevelopmental defects D evelopmental 46,X Y GON adal dysgenesis). Our will enable additional diagnoses improved outcomes for born this condition.

Language: Английский

Citations

11
Two redundant transcription factor binding sites in a single enhancer are essential for mammalian sex determination DOI Creative Commons
Meshi Ridnik, Elisheva Abberbock,

Veronica Alipov

et al.

Nucleic Acids Research, Journal Year: 2024, Volume and Issue: 52(10), P. 5514 - 5528

Published: Feb. 29, 2024

Male development in mammals depends on the activity of two SOX gene: Sry and Sox9, embryonic testis. As deletion Enhancer 13 (Enh13) Sox9 gene results XY male-to-female sex reversal, we explored critical elements necessary for its function hence, testis male development. Here, demonstrate that while microdeletions individual transcription factor binding sites (TFBS) Enh13 lead to normal testicular development, combined just SRY/SOX motifs can alone fully abolish leading reversal. This suggests proper occur, these few nucleotides non-coding DNA must be intact. Interestingly, show depending nature TFBS mutations, dramatically different phenotypic outcomes providing a molecular explanation distinct clinical observed patients harboring variants same enhancer.

Language: Английский

Citations

4
A conserved NR5A1-responsive enhancer regulates SRY in testis-determination DOI Creative Commons
Denis Houzelstein, Caroline Eozénou, Carlos F. Lagos

et al.

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: March 30, 2024

Abstract The Y-linked SRY gene initiates mammalian testis-determination. However, how the expression of is regulated remains elusive. Here, we demonstrate that a conserved steroidogenic factor-1 (SF-1)/NR5A1 binding enhancer required for appropriate to initiate testis-determination in humans. Comparative sequence analysis 5’ regions mammals identified an evolutionary SF-1/NR5A1-binding motif within 250 bp region open chromatin located 5 kilobases upstream transcription start site. Genomic 46,XY individuals with disrupted testis-determination, including large multigenerational family, unique single-base substitutions highly residues element. In silico modelling and vitro assays properties NR5A1 motif. Deletion this hemizygous element by genome-editing, novel cellular model recapitulating human Sertoli cell formation, resulted significant reduction . Therefore, acts as regulatory switch between testis ovary development upregulating expression, role may predate eutherian radiation. We show disruption can phenocopy variants coding cause dysgenesis. Since disease causing enhancers are currently rare, regulation offers paradigm define activity key developmental process.

Language: Английский

Citations

4