A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor‐1 (<i>WT1</i>) pathogenic variant

Gomes, Nathália Lisboa; Paula, Leila Cristina Pedroso de; Silva, Juliana M; Silva, Thatiana E.; Lerário, Antônio M.; Nishi, Mirian Yumie; Batista, Rafael Loch; Júnior, José Antônio Diniz Faria; Moraes, Daniela; Costa, Elaine Maria Frade; Hemesath, Tatiana Prade; Guaragna-Filho, Guilherme; Leite, Júlio César Loguercio; Carvalho, Clarissa Gutiérrez; Domenice, Sorahia; Costa, Eduardo Corrêa; Mendonca, Berenice B.

doi:10.1111/cge.13459

Cited by 30 publications

(32 citation statements)

References 22 publications

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“…Structural protein remodeling suggests an increased activation of target genes, mainly NR5A1. However, these assumptions remain to be experimentally validated [70].…”

Section: Nr5a1 (Sf1) and Wt1: Old Genes New Mechanismsmentioning

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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“…Structural protein remodeling suggests an increased activation of target genes, mainly NR5A1. However, these assumptions remain to be experimentally validated [70].…”

Section: Nr5a1 (Sf1) and Wt1: Old Genes New Mechanismsmentioning

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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“…Furthermore, great interest has been paid in methods for predicting protein pathogenicity and structure based on amino acid sequence, which have become more accessible through advancements in bioinformatics tools (Touma et al, ). Pathogenic and structural analysis of rare mutations can be predicted using various computational methods (Gomes et al, ). For an accurate diagnosis of a rare mutation, it is essential to know how the mutation may affect the function of the gene to result in pathogenic effects through a combination of sequence and structure‐based algorithms.…”

Section: Introductionmentioning

confidence: 99%

Analysis of deletional hereditary persistence of fetal hemoglobin/δβ‐thalassemia and δ‐globin gene mutations in Southerwestern China

Zhang

Yang

et al. 2019

Molec Gen & Gen Med

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Background Deletional hereditary persistence of fetal hemoglobin (HPFH)/δβ‐thalassemia and δ‐thalassemia are rare inherited disorders which may complicate the diagnosis of β‐thalassemia. The aim of this study was to reveal the frequency of these two disorders in Southwestern China. Methods A total of 33,596 subjects were enrolled for deletional HPFH/δβ‐thalassemia, and positive individuals with high fetal hemoglobin (Hb F) level were diagnosed by multiplex ligation‐dependent probe amplification (MLPA). A total of 17,834 subjects were analyzed for mutations in the δ‐globin gene. Positive samples with low Hb A2 levels were confirmed by δ‐globin gene sequencing. Furthermore, the pathogenicity and construction of a selected δ‐globin mutation were analyzed. Results A total of 92 suspected cases with Hb F ≥5.0% were further characterized by MLPA. Eight different deletional HPFH/δβ‐thalassemia were observed at a frequency of 0.024%. In addition, 195 cases suspected to have a δ‐globin gene mutation (Hb A2 ≤2.0%) were characterized by molecular analysis. δ‐Globin gene mutation was found at a frequency of 0.49% in Yunnan. The pathogenicity and construction for a selected δ‐globin mutation was predicted. Conclusion Screening of these two disorders was analyzed in Southwestern China, which could define the molecular basis of these conditions in this population.

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“…The variant was located in the highly conserved fourth zinc finger DNA‐binding domain of WT1 required for testis formation (Eozenou et al, 2020) (Table 4). Similarly, Gomes et al (2019) reported a patient with 46,XX testicular DSD who had a novel heterozygous p.Arg485Glyfs*14 pathogenic variant of WT1 , located in the fourth zinc finger of the protein. WT1 (OMIM # 194070) encodes a zinc finger DNA‐binding protein that has a role in transcriptional activation or repression depending on chromosomal context.…”

Section: Discussionmentioning

confidence: 90%

Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development

Mazen

Mekkawy²,

Kamel³

et al. 2021

American J of Med Genetics Pt A

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Disorders/differences of sex development (DSD) comprise a group of congenital disorders that affect the genitourinary tract and usually involve the endocrine and reproductive system. The aim of this work was to identify genetic variants responsible for disorders of human urogenital development in a cohort of Egyptian patients. This three‐year study included 225 patients with various DSD forms, referred to the genetic DSD and endocrinology clinic, National Research Centre, Egypt. The patients underwent thorough clinical examination, hormonal and imaging studies, detailed cytogenetic and fluorescence in situ hybridization analysis, and molecular sequencing of genes known to commonly cause DSD including AR, SRD5A2, 17BHSD3, NR5A1, SRY, and WT1. Whole exome sequencing (WES) was carried out for 18 selected patients. The study revealed a high rate of sex chromosomal DSD (33%) with a wide array of cytogenetic abnormalities. Sanger sequencing identified pathogenic variants in 33.7% of 46,XY patients, while the detection rate of WES reached 66.7%. Our patients showed a different mutational profile compared with that reported in other populations with a predominance of heritable DSD causes. WES identified rare and novel pathogenic variants in NR5A1, WT1, HHAT, CYP19A1, AMH, AMHR2, and FANCA and in the X‐linked genes ARX and KDM6A. In addition, digenic inheritance was observed in two of our patients and was suggested to be a cause of the phenotypic variability observed in DSD.

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A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor‐1 (WT1) pathogenic variant

Cited by 30 publications

References 22 publications

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

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

Analysis of deletional hereditary persistence of fetal hemoglobin/δβ‐thalassemia and δ‐globin gene mutations in Southerwestern China

Advances in genomic diagnosis of a large cohort of Egyptian patients with disorders of sex development

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