The Role of Copy Number Variants in Disorders of Sex Development

Croft, Brittany; Ohnesorg, Thomas; Sinclair, Andrew H.

doi:10.1159/000481896

Cited by 40 publications

(32 citation statements)

References 74 publications

(97 reference statements)

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“…In our cohort of patients with SRY ‐negative 46,XX (ovo)testicular DSD, NR5A1 variants contribute to 15% (4/26) of cases. This is comparable to SOX9 enhancer duplications, which underlie 19% (5/26) of cases in this cohort (Croft et al., ; Ohnesorg et al., ). Consequently, NR5A1 gene variants should be considered an important cause underlying cases of SRY ‐negative 46,XX (ovo)testicular DSDs.…”

Section: Discussionsupporting

confidence: 74%

“…Up to 90% of 46,XX testicular DSDs (McElreavey, Vilain, & Abbas, ) and 10% of 46,XX ovotesticular DSDs (Vilain et al., ) are caused by translocation of the Sex‐determining region Y ( SRY ) gene, the initiating gene for testis differentiation, onto the X chromosome ( SRY ‐positive 46,XX DSD). Another common cause is ectopic SRY‐box 9 ( SOX9 ) expression, often caused by duplications in the upstream enhancer (Croft, Ohnesorg, & Sinclair, ). Loss of function variants in ovarian pathway genes (e.g., R‐Spondin 1 [ RSPO1 ]) have been identified in a small subset of syndromic 46,XX (ovo)testicular DSDs (Bashamboo et al., ; Parma et al., ; Tomaselli et al., ).…”

Section: Introductionmentioning

confidence: 99%

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NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

et al. 2018

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Several recent reports have described a missense variant in the gene NR5A1 (c.274C>T; p.Arg92Trp) in a significant number of 46,XX ovotesticular or testicular disorders of sex development (DSDs) cases. The affected residue falls within the DNA‐binding domain of the NR5A1 protein, however the exact mechanism by which it causes testicular development in 46,XX individuals remains unclear. We have screened a cohort of 26 patients with 46,XX (ovo)testicular DSD and identified three unrelated individuals with this NR5A1 variant (p.Arg92Trp), as well as one patient with a novel NR5A1 variant (c.779C>T; p.Ala260Val). We examined the functional effect of these changes, finding that while protein levels and localization were unaffected, variant NR5A1 proteins repress the WNT signaling pathway and have less ability to upregulate the anti‐testis gene NR0B1 . These findings highlight how NR5A1 variants impact ovarian differentiation across multiple pathways, resulting in a switch from ovarian to testis development in genetic females.

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Section: Discussionsupporting

confidence: 74%

Section: Introductionmentioning

confidence: 99%

NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

et al. 2018

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“…Since 2011, copy number variants (CNVs) located within the 2 Mb putative SOX9 upstream regulatory region, denoted XYSR and RevSex have been increasingly identified by array comparative genomic hybridisation (CGH) or multiplex ligation-dependant probe amplification (MLPA) in several isolated 46,XX and 46,XY DSDs (reviewed in [37]). The refined analysis of these genomic regions has allowed the identification of two putative enhancers 5 of SOX9, named Sex Reversal Enhancer-A (eSR-A) and Sex Reversal Enhancer-B (eSR-B) [38].…”

Section: The Sry/sox Family: New Concepts In Gene Dosage and Regulationmentioning

confidence: 99%

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

Gomes

Chetty

Jørgensen

et al. 2020

IJMS

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Disorders (or differences) of sex development (DSD) are a heterogeneous group of congenital conditions with variations in chromosomal, gonadal, or anatomical sex. Impaired gonadal development is central to the pathogenesis of the majority of DSDs and therefore a clear understanding of gonadal development is essential to comprehend the impacts of these disorders on the individual, including impacts on future fertility. Gonadal development was traditionally considered to involve a primary ‘male’ pathway leading to testicular development as a result of expression of a small number of key testis-determining genes. However, it is increasingly recognized that there are several gene networks involved in the development of the bipotential gonad towards either a testicular or ovarian fate. This includes genes that act antagonistically to regulate gonadal development. This review will highlight some of the novel regulators of gonadal development and how the identification of these has enhanced understanding of gonadal development and the pathogenesis of DSD. We will also describe the impact of DSDs on fertility and options for fertility preservation in this context.

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“…To date, more than 40 NR5A1 heterozygous mutations have been described in 46,XY GD [12] with no clear genotype-phenotype relationships established. In contrast to nucleotide sequence mutations, CNVs are extremely rarely detected in 46,XY DSD individuals [21,22]. Significant numbers of urogenital defects are associated with major congenital malformations or minor abnormalities, which is highly suggestive of chromosomal alterations as etiological factors [23].…”

Section: Discussionmentioning

confidence: 99%

The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development

Nagy

Kárteszi²,

Hartwig³

et al. 2019

Mol Biol Rep

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Gonadal dysgenesis (GD) is a rare cause of differences of sex development (DSD) with highly variable clinical and genetic conditions. Although identification of the causative genetic alterations can offer a clearer prognosis and personalized management to patients, more than 50% of the DSD cases still do not have an accurate genetic diagnosis. NR5A1 (previously known as SF-1), is a transcriptional regulator of genes required for normal development and functional maintenance of the gonads and the adrenal glands. Nucleotide sequence variants of the NR5A1 gene have been reported in numerous patients with GD with or without adrenal failure, however, microdeletion or partial deletion in the NR5A1 gene have been described only in a few GD cases. In this case study, we present a subject with female phenotype, mild clitoromegaly, partial GD and normal adrenal function. Cytogenetic analysis revealed a 46,XY SRY + karyotype. Microarray analysis did not identify pathogenic copy number variations, nor did panel sequencing of the most common DSD genes. Subsequently, multiplex ligationdependent probe amplification (MLPA) was performed to test for small deletion/duplication of the most frequently affected genes associated with GD. Using this method, we have identified a novel heterozygous deletion involving exons 5 and 6 of the NR5A1 gene as the cause of abnormal sexual development of the patient. This report expands our knowledge about the range and pathogenetic role of NR5A1 mutations associated with partial gonadal dysgenesis in 46,XY DSD. Furthermore, our data emphasises the indispensable role of MLPA in the diagnosis of DSD with unclear etiology.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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The Role of Copy Number Variants in Disorders of Sex Development

Cited by 40 publications

References 74 publications

NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

NR5A1 gene variants repress the ovarian-specific WNT signaling pathway in 46,XX disorders of sex development patients

Disorders of Sex Development—Novel Regulators, Impacts on Fertility, and Options for Fertility Preservation

The importance of the multiplex ligation-dependent probe amplification in the identification of a novel two-exon deletion of the NR5A1 gene in a patient with 46,XY differences of sex development

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