Genetic control of typical and atypical sex development

Reyes, Alejandra P; León, Nayla Y; Frost, Emily R; Harley, Vincent R.

doi:10.1038/s41585-023-00754-x

Cited by 20 publications

(11 citation statements)

References 226 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent insights have been gained in understanding the genetic background of DSD, especially 46,XY DSD with the use of new tools like WES having been more and more introduced in clinical practice. A growing body of research is focused on understanding the future genes involved in typical and atypical sex development and in improving our understanding of DSD [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Prenatal Features of MIRAGE Syndrome—Case Report and Review of the Literature

Panaitescu,

Huluță,

Gorecki

et al. 2024

Children

View full text Add to dashboard Cite

MIRAGE syndrome is a recently described congenital condition characterized genetically by heterozygous gain-of-function missense mutations in the growth repressor sterile alpha domain containing 9 (SAMD9) located on the arm of chromosome 7 (7q21.2). The syndrome is rare and is usually diagnosed in newborns and children with myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy, hence the acronym MIRAGE. The aims of this paper are (1) to present fetal ultrasound features in a case where MIRAGE syndrome was diagnosed prenatally and (2) to review the existing literature records on prenatal manifestations of MIRAGE syndrome. In our case, the fetus had severe early fetal growth restriction (FGR) with normal Doppler studies, atypical genitalia, oligohydramnios, and hyperechogenic bowel at the routine mid-gestation anomaly scan. Amniocentesis excluded infections and numeric or structural chromosomal abnormalities while whole exome sequencing (WES) of the fetal genetic material identified the specific mutation. Targeted testing in parents was negative, suggesting the “de novo” mutation in the fetus. We could not identify other specific case reports in the literature on the prenatal diagnosis of MIRAGE syndrome. In cases reported in the literature where the diagnosis of MIRAGE syndrome was achieved postnatally, there are mentions related to the marked FGR on prenatal ultrasound. Severe early-onset FGR with no other apparent cause seems to be a central prenatal feature in these babies, and WES should be offered, especially if there are other structural abnormalities. Prenatal diagnosis of MIRAGE syndrome is possible, allowing for reproductive choices, improved counseling of parents, and better preparation of neonatal care.

show abstract

Section: Discussionmentioning

confidence: 99%

Prenatal Features of MIRAGE Syndrome—Case Report and Review of the Literature

Panaitescu,

Huluță,

Gorecki

et al. 2024

Children

View full text Add to dashboard Cite

show abstract

“…Differences/Disorders of Sex Development (DSDs) are a heterogenous group of congenital conditions in which the development of chromosomal, gonadal and/or anatomic sex is atypical ( Hughes et al, 2006 ). A notable subset of DSDs is 46, XY DSD, where individuals possess a 46, XY chromosome complement but present with atypical male or even female external genitalia, with or without Müllerian duct derived structures (female internal genitalia) ( Wisniewski et al, 2019 ; Reyes et al, 2023 ). 46, XY DSD is associated with genetic mutations in key genes involved in testis development, such as the testis-determining gene SRY , SOX9 , NR5A1 , MAP3K1 , and DHX37 ( Eggers et al, 2016 ; Xu et al, 2019 ; Reyes et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

“…A notable subset of DSDs is 46, XY DSD, where individuals possess a 46, XY chromosome complement but present with atypical male or even female external genitalia, with or without Müllerian duct derived structures (female internal genitalia) ( Wisniewski et al, 2019 ; Reyes et al, 2023 ). 46, XY DSD is associated with genetic mutations in key genes involved in testis development, such as the testis-determining gene SRY , SOX9 , NR5A1 , MAP3K1 , and DHX37 ( Eggers et al, 2016 ; Xu et al, 2019 ; Reyes et al, 2023 ). Despite advancements in genomic technologies, many 46, XY DSD patients lack a clinical genetic diagnosis, and numerous genes contributing to DSD remain unidentified.…”

Section: Introductionmentioning

confidence: 99%

A role for TRPC3 in mammalian testis development

Ming,

Bagheri-Fam,

Frost

et al. 2024

Front. Cell Dev. Biol.

Self Cite

View full text Add to dashboard Cite

SOX9 is a key transcription factor for testis determination and development. Mutations in and around the SOX9 gene contribute to Differences/Disorders of Sex Development (DSD). However, a substantial proportion of DSD patients lack a definitive genetic diagnosis. SOX9 target genes are potentially DSD-causative genes, yet only a limited subset of these genes has been investigated during testis development. We hypothesize that SOX9 target genes play an integral role in testis development and could potentially be causative genes in DSD. In this study, we describe a novel testicular target gene of SOX9, Trpc3. Trpc3 exhibits high expression levels in the SOX9-expressing male Sertoli cells compared to female granulosa cells in mouse fetal gonads between embryonic day 11.5 (E11.5) and E13.5. In XY Sox9 knockout gonads, Trpc3 expression is markedly downregulated. Moreover, culture of E11.5 XY mouse gonads with TRPC3 inhibitor Pyr3 resulted in decreased germ cell numbers caused by reduced germ cell proliferation. Trpc3 is also expressed in endothelial cells and Pyr3-treated E11.5 XY mouse gonads showed a loss of the coelomic blood vessel due to increased apoptosis of endothelial cells. In the human testicular cell line NT2/D1, TRPC3 promotes cell proliferation and controls cell morphology, as observed by xCELLigence and HoloMonitor real-time analysis. In summary, our study suggests that SOX9 positively regulates Trpc3 in mouse testes and TRPC3 may mediate SOX9 function during Sertoli, germ and endothelial cell development.

show abstract

“…Gonadal Sex determination is the genetic decision that directs the bipotential gonads to differentiate either as a testis or an ovary while sex differentiation refers to the process in which factors produced by the gonads drive the development of the phenotypic sex. (Reyes et al 2023) The disruption of one or both processes lead to /Variants of sex development (VSD) (Biason-Lauber 2010).VSD encompass a diverse group of conditions characterized by atypical chromosomal, gonadal, or anatomical sex development. (P. A.…”

Section: Introductionmentioning

confidence: 99%

Maximizing the Benefits of WES Data for Clinical Diagnosis of individuals with Differences/Variations of Sex Development

Decken,

Gutiérrez,

Sproll

et al. 2024

Preprint

View full text Add to dashboard Cite

Variations of Sex Development (VSD) are conditions where genetic and anatomical features do not align with typical male or female characteristics, often due to sex chromosome differences, hormonal imbalances, or other genetic factors. Diagnosing the genetic etiology of VSD can be challenging due to the complex and variable nature of the condition. We developed a whole exome sequencing (WES) pipeline, demonstrating WES as an all-in-one genetic testing tool. It offers reliable karyotyping and SRY gene detection, potentially replacing costly and time-consuming karyotyping and FISH assays. Our pipeline tests all known and candidate VSD genes simultaneously, avoiding the need for single-gene tests. A customized filtering system, including a blacklist of variants from healthy controls, enhances variant detection. Among 171 subjects with a VSD diagnosis of unresolved etiology, our pipeline provided probable genetic diagnoses for 50 patients, identifying two chromosomal aberrations, one SRY translocation missed by initial FISH-assay, and 47 point mutations in known VSD genes, 18 of which are novel. Overall, WES consolidates multiple genetic tests into one, making it a more accessible and cost-effective diagnostic tool for clinics, usable by non-experts.

show abstract

Genetic control of typical and atypical sex development

Cited by 20 publications

References 226 publications

Prenatal Features of MIRAGE Syndrome—Case Report and Review of the Literature

Prenatal Features of MIRAGE Syndrome—Case Report and Review of the Literature

A role for TRPC3 in mammalian testis development

Maximizing the Benefits of WES Data for Clinical Diagnosis of individuals with Differences/Variations of Sex Development

Contact Info

Product

Resources

About