Exome Sequencing for the Diagnosis of 46,XY Disorders of Sex Development

Baxter, Ruth; Arboleda, Valerie A.; Lee, Hane; Barseghyan, Hayk; Adam, Margaret P; Fechner, Patricia Y.; Bargman, Renee; Keegan, Catherine E.; Travers, Sharon H.; Schelley, Susan; Hudgins, Louanne; Mathew, Revi P.; Stalker, Heather J.; Zori, Roberto T.; Gordon, Ora; Ramos‐Platt, Leigh; Pawlikowska-Haddal, Anna; Eskin, Ascia; Nelson, Stanley F.; Délot, Emmanuèle C.; Vilain, Éric

doi:10.1210/jc.2014-2605

Cited by 184 publications

(202 citation statements)

References 41 publications

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“…The inability to provide a genetic diagnosis for the majority of individuals with a DSD has led to the development of more robust diagnostic tests to screen large regions of the genome for potential disease-causing mutations, including exome sequencing and copy number variation arrays (White et al, 2011;Arboleda et al, 2013;Baxter et al, 2015). This approach has revealed non-coding mutations upstream of SOX9 that result in DSDs (Kim et al, 2015).…”

Section: Regulatory Sites May Harbor Non-coding Mutations That Cause mentioning

confidence: 99%

Genome-wide identification of regulatory elements in Sertoli cells

et al. 2017

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A current goal of molecular biology is to identify transcriptional networks that regulate cell differentiation. However, identifying functional gene regulatory elements has been challenging in the context of developing tissues where material is limited and cell types are mixed. To identify regulatory sites during sex determination, we subjected Sertoli cells from mouse fetal testes to DNaseI-seq and ChIP-seq for H3K27ac. DNaseI-seq identified putative regulatory sites around genes enriched in Sertoli and pregranulosa cells; however, active enhancers marked by H3K27ac were enriched proximal to only Sertoli-enriched genes. Sequence analysis identified putative binding sites of known and novel transcription factors likely controlling Sertoli cell differentiation. As a validation of this approach, we identified a novel Sertoli cell enhancer upstream of Wt1, and used it to drive expression of a transgenic reporter in Sertoli cells. This work furthers our understanding of the complex genetic network that underlies sex determination and identifies regions that potentially harbor non-coding mutations underlying disorders of sexual development.

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Section: Regulatory Sites May Harbor Non-coding Mutations That Cause mentioning

confidence: 99%

Genome-wide identification of regulatory elements in Sertoli cells

et al. 2017

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“…1,7 Nextgeneration-sequencing-based approaches such as wholeexome sequencing improve the identification of causal genetic defects, and the discovery of new genes and signaling pathways implicated in sex development. 8,9 Elucidating the underlying causes of DSD can facilitate sex assignment and lead to improved management, a better prognosis and a more accurate evaluation of gonadal function and gonadal germ cell cancer risk. 10 So far, mutations in genes encoding nuclear receptors, such as NR5A1 (also known as the steroidogenic factor 1 gene, or SF1) 11 and the androgen receptor NR3C4 gene 12 have been implicated in DSD pathogenesis as well as the duplication of the nuclear receptor subfamily 0 group B member 1 gene (NR0B1, DAX1).…”

Section: Introductionmentioning

confidence: 99%

Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development

Baetens

Güran

Mendonça

et al. 2018

Genetics in Medicine

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Purpose: Disorders or differences of sex development (DSDs) are rare congenital conditions characterized by atypical sex development. Despite advances in genomic technologies, the molecular cause remains unknown in 50% of cases.Methods: Homozygosity mapping and whole-exome sequencing revealed an ESR2 variant in an individual with syndromic 46,XY DSD. Additional cases with 46,XY DSD underwent whole-exome sequencing and targeted next-generation sequencing of ESR2. Functional characterization of the identified variants included luciferase assays and protein structure analysis. Gonadal ESR2 expression was assessed in human embryonic data sets and immunostaining of estrogen receptor-β (ER-β) was performed in an 8-week-old human male embryo.

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“…Новые молекулярно-генетические технологии в диагностике нарушений формирования пола, полового развития и репродукции Наиболее эффективно новые методы анализа ге-нома могут быть использованы в исследовании причин и в диагностике моногенных и гетерогенных генных заболеваний, микроделеционных и микродупликаци-онных синдромов, в том числе с поражением развития или функции репродуктивной системы [20,40,41].…”

Section: пациентыunclassified

“…Молекулярный анализ гена SRY (Sex-determining Region Y) позволяет выявить его делеции и мутации у 10-15 % пациентов с XY-дисгенезией гонад, наличие этого гена у 85-90 % пациентов с 46, ХХ-тес-тикулярной формой НФП (синдромом де ля Шаппеля / 46,ХХ-мужчина). Еще в 10-15 % случаев НПФ, не свя-занных с цитогенетическими аномалиями половых хромосом, причину заболевания возможно установить с помощью молекулярного анализа «частых» генов (на-пример, SOX9, DAX1/NR0B1, AR/HUMARA), вовлеченных в половую дифференцировку у человека [41]. Однако в большинстве (65-70 %) случаев НФП, не связанных с аномалиями кариотипа, рутинное генетическое об-следование оказывается неэффективным.…”

Section: пациентыunclassified