Female-to-male sex reversal associated with unique Xp21.2 deletion disrupting genomic regulatory architecture of the dosage-sensitive sex reversal region

Dangle, Pankaj P.; Touzon, Maria Sol; Reyes‐Múgica, Miguel; Witchel, Selma F.; Rajkovic, Aleksandar; Schneck, Francis X.; Yatsenko, Svetlana A.

doi:10.1136/jmedgenet-2016-104128

Cited by 19 publications

(18 citation statements)

References 20 publications

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“…We initially utilized a custom‐designed oligonucleotide CGH microarray (Yatsenko et al., ) to examine for pathologic genomic imbalances involving both X‐linked and autosomal genes associated with HH. This oligonucleotide‐based 180K CGH microarray has been designed to achieve high‐resolution detection of losses and gains for 397 gonadal genes which include known and candidate genes implicated in gonadal dysgenesis, HH, steroidogenesis, and ovarian and testicular differentiation derived from studies in humans and animal models (Dangle et al., ). In addition to covering the autosomal regions of the genome, this microarray platform densely covers X chromosome to achieve a resolution of ~0.3–3 kb.…”

Section: Resultsmentioning

confidence: 99%

Functional study of a novel missense single‐nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency

Ren

Diao

Katari

et al. 2018

Molec Gen & Gen Med

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BackgroundHypergonadotropic hypogonadism (HH) is a genetically heterogeneous disorder that usually presents with amenorrhea, atrophic ovaries, and low estrogen. Most cases of HH are idiopathic and nonsyndromic. Nucleoporin 107 (NUP107), a protein involved in transport between cytoplasm and nucleus with putative roles in meiosis/mitosis progression, was recently implicated as a cause of HH. We identified a NUP107 genetic variant in a nonconsanguineous family with two sisters affected with primary amenorrhea and HH, and generated a mouse model that carried the human variant.MethodsWe performed a high‐resolution X‐chromosome microarray and whole exome sequencing on parents and two sisters with HH to identify pathogenic variants. We generated a mouse model of candidate NUP107 variant using CRISPR/Cas9.ResultsWhole exome sequencing identified a novel and rare missense variant in the NUP107 gene (c.1063C>T, p.R355C) in both sisters with HH. In order to determine functional significance of this variant, we used CRISPR/Cas9 to introduce the human variant into the mouse genome. Mice with the homolog of the R355C variant, as well as the nine base pairs deletion in Nup107 had female subfertility.ConclusionsOur findings indicate that NUP107 R355C variant falls in the category of variant of unknown significance as the cause of HH and infertility.

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Section: Resultsmentioning

confidence: 99%

Functional study of a novel missense single‐nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency

Ren

Diao

Katari

et al. 2018

Molec Gen & Gen Med

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“…Distribution of rare-shared and POI-unique CNVs along the X chromosome in POI patients Copy-number alterations of a few genes on the X chromosome are known to be implicated in sex differentiation, such as duplications and deletions surrounding the NR0B1 (MIM *300473) gene. [25][26][27] We hypothesized that fertile women are less likely to have CNVs in the regions that are involved in sexual development and gonadal differentiation. We constructed a high-resolution CNV map to assess distribution of observed gains and losses along the X chromosome in fertile females (Fig.…”

Section: Encode Annotations Of the Noncoding Genomic Intervalsmentioning

confidence: 99%

A high-resolution X chromosome copy-number variation map in fertile females and women with primary ovarian insufficiency

Yatsenko

Wood-Trageser

Chu

et al. 2019

Genetics in Medicine

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Sex-biased expression of genes on the X chromosome is accomplished by a complex mechanism of dosage regulation that leads to anatomical and physiological differences between males and females. Copy-number variations (CNVs) may impact the human genome by either affecting gene dosage or disturbing a chromosome structural and/or functional integrity. Methods: We performed a high-resolution CNV profiling to investigate the X chromosome integrity in cohorts of 269 fertile females and 111 women affected with primary ovarian insufficiency (POI) and assessed CNVs impact into functional and nonfunctional genomic elements. Results: In POI patients, we observed a 2.5-fold enrichment for rare CNVs comprising ovary-expressed genes, and genes implicated in autoimmune response and apoptotic signaling. Moreover, there was a higher prevalence of deletions encompassing genes that escape X inactivation, noncoding RNAs, and intergenic DNA sequences among POI females, highlighting structural differences between X chromosomes of fertile and POI females. Furthermore, we discovered a~4% carrier incidence for X-linked disorders among fertile women. Conclusion: We constructed a high-resolution map of femalespecific CNVs that provides critical insights into the spectrum of human genetic variation, sex-specific disease risk factors, and reproductive potential. We discovered novel CNVs associated with ovarian dysfunction and support polygenic models for POI.

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“…The best examples are the many deletions that include the NR0B1 gene and surrounding region that result in adrenal hypoplasia [Barbaro et al, 2007[Barbaro et al, , 2008White et al, 2011;Rojek et al, 2016;Dangle et al, 2017]. A duplication of FGF9 and the surrounding genomic region has also been identified in this manner [Chiang et al, 2013].…”

Section: Cnvs Affecting Coding Sequences Of Dsd Genesmentioning

confidence: 99%

The Role of Copy Number Variants in Disorders of Sex Development

Croft

Ohnesorg

Sinclair

2017

Sex Dev

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Despite considerable research effort and significant advances in sequencing technologies, the majority of disorders of sex development (DSD) cases still lack a molecular genetic diagnosis. While coding variants have been discovered in known and candidate DSD genes, comparatively little is known about copy number variations (CNVs) affecting both coding and noncoding regions. Due to rapidly falling costs of whole genome sequencing, many more CNVs in individuals with DSD will be identified. These CNVs may explain a significant number of hitherto undiagnosed cases of DSD. In this review, we provide an overview of CNVs that are known to cause DSD and discuss approaches to identify and verify causative CNVs.

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Female-to-male sex reversal associated with unique Xp21.2 deletion disrupting genomic regulatory architecture of the dosage-sensitive sex reversal region

Abstract: Duplication of the DSS region containing the and genes has been implicated in testis repression and sex reversal. Identification of this microdeletion highlights the importance of genomic integrity in the regulation and interaction of sex determining genes during gonadal development.

Cited by 19 publications

References 20 publications

Functional study of a novel missense single‐nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency

Functional study of a novel missense single‐nucleotide variant of NUP107 in two daughters of Mexican origin with premature ovarian insufficiency

A high-resolution X chromosome copy-number variation map in fertile females and women with primary ovarian insufficiency

The Role of Copy Number Variants in Disorders of Sex Development

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