GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’

Audí, Laura; Ahmed, S Faisal; Krone, Nils; Cools, Martine; McElreavey, Kenneth; Holterhus, Paul‐Martin; Greenfield, Andy; Bashamboo, Anu; Hiort, Olaf; Wudy, Stefan A.; McGowan, Ruth; _, _

doi:10.1530/eje-18-0256

Cited by 134 publications

(133 citation statements)

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“…Therefore, it was not possible to statistically associate the deletion with any specific form of equine cryptorchidism or other DSD. Our observations are consistent with those in humans where studies on DSDs and disorders of reproduction are more advanced and abundant [1][2][3][4], but face similar challenges for uncovering the genetic causes. One is the very nature of these conditions which prevents reproduction and transmission, making almost every case a singleton.…”

Section: Discussionsupporting

confidence: 89%

“…Mammalian disorders of sex development (DSDs) encompass a broad range of complex congenital conditions that affect sex determination, sexual differentiation, and the development and function of gonads [1][2][3][4][5][6]. The majority of DSDs are characterized by an atypical combination of chromosomal, gonadal and phenotypic sex and are broadly classified as XX and XY DSDs [5,7].…”

Section: Introductionmentioning

confidence: 99%

“…Earlier studies identified a large deletion in horse (Equus caballus, ECA) chromosome 29 (ECA29) that was found in two related Standardbred horses with SRY-positive XY DSDs and male pseudohermaphrodite phenotypes [22]. The deletion involves steroid hormone biosynthesis genes belonging to the aldo-keto reductase family 1 C (AKR1C), of which mutations have been associated with XY DSDs, such as cryptorchidism, undervirilized external genitalia, dihydrotestosterone (DHT) deficiency and sex reversal conditions in humans [1,3,4].…”

Section: Introductionmentioning

confidence: 99%

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Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Ghosh

Davis

Rosengren

et al. 2020

Genes

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Disorders of sex development (DSD) and reproduction are not uncommon among horses, though knowledge about their molecular causes is sparse. Here we characterized a ~200 kb homozygous deletion in chromosome 29 at 29.7–29.9 Mb. The region contains AKR1C genes which function as ketosteroid reductases in steroid hormone biosynthesis, including androgens and estrogens. Mutations in AKR1C genes are associated with human DSDs. Deletion boundaries, sequence properties and gene content were studied by PCR and whole genome sequencing of select deletion homozygotes and control animals. Deletion analysis by PCR in 940 horses, including 622 with DSDs and reproductive problems and 318 phenotypically normal controls, detected 67 deletion homozygotes of which 79% were developmentally or reproductively abnormal. Altogether, 8–9% of all abnormal horses were homozygous for the deletion, with the highest incidence (9.4%) among cryptorchids. The deletion was found in ~4% of our phenotypically normal cohort, ~1% of global warmblood horses and ponies, and ~7% of draught breeds of general horse population as retrieved from published data. Based on the abnormal phenotype of the carriers, the functionally relevant gene content, and the low incidence in general population, we consider the deletion in chromosome 29 as a risk factor for equine DSDs and reproductive disorders.

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Section: Discussionsupporting

confidence: 89%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Ghosh

Davis

Rosengren

et al. 2020

Genes

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“…46,XY DSD may include complete or partial gonadal dysgenesis due to disturbances in testis differentiation or undervirilization/undermasculinization as a result of aberrant androgen synthesis or action. The most common gene mutations associated with 46,XY DSD include ARX, ATRX, CBX2, DAX1, DHH, DMRT1, EMX2, ESR2, FGFR2, GATA4, HHAT, MAP3K1, NR5A1, SOX8, SOX9, SRY, TSPYL1, WNT4, WT1, ZFPM2, and ZNRF3 [2,19].…”

Section: Discussionmentioning

confidence: 99%

“…The etiological background of DSD is extremely heterogeneous as it can Electronic supplementary material The online version of this article (https ://doi.org/10.1007/s1103 3-019-04980 -8) contains supplementary material, which is available to authorized users. be induced by numerical or structural sex chromosome aberrations, variations of genes involved in the gonadal and/or genitalal development or steroidogenesis, maternal factors, hormonal disturbances and epigenetic modifications [2][3][4].…”

Section: Introductionmentioning

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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Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes

Abualsaud

Hashem

Alhashem

et al. 2020

American J of Med Genetics Pt A

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Disorders of sex development (DSD) are congenital conditions with atypical development of chromosomal, gonadal, or anatomical sex. The estimated incidence ranges from 1 in 4,500-5,500 for strictly defined "ambiguous genitalia" to 1 in 300 or higher when a broader definition is implemented. In this study, we aim to define DSD phenotypes encountered in a large heterogeneous cohort of molecularly characterized Mendelian disorders in a single center. Data were retrieved for patients with documented abnormal genitalia based on the 2006 consensus criteria. Out of 149 patients (129 families) with compatible human phenotype ontology, 76 patients (68 families) had an identified genetic cause and were included in our analysis. Potentially causal variants were identified in 42 genes, and two patients had a dual molecular diagnosis. Six genes have no associated phenotype in OMIM (PIANP, CELSR2, USP2, FAM179B, TXNDC15, and CCDC96). Thirteen genes have non-DSD OMIM phenotypes, thus we are expanding their phenotype to include DSD. We also highlight how certain disorders are under-recognized despite their established DSD phenotype in OMIM, especially CTU2-related DREAM-PL syndrome and TSPYL1-related sudden infant death with dysgenesis of the testes syndrome. In conclusion, this study of a large heterogeneous Mendelian cohort expands the list of genes and disorders beyond those classically DSD-linked. K E Y W O R D S ambiguous genitalia, differences in sex development, sex reversal 1 | INTRODUCTION Disorders of sex development (DSD) are defined as congenital conditions in which development of chromosomal, gonadal, or anatomical sex is atypical (Lee et al., 2016). The clinical phenotypes of these disorders are heterogenous and include micropenis, cryptorchidism, clitoromegaly and, in more severe cases, ambiguous genitalia. The exact incidence can be challenging to determine accurately due to discrepancy in the definition used by the different epidemiological studies and the changes in classification over time. However, it is estimated to be 1 in 4,500-5,500 for strictly defined "ambiguous genitalia" and increases to 1 in 300 or higher if a broader definition is used (

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GENETICS IN ENDOCRINOLOGY: Approaches to molecular genetic diagnosis in the management of differences/disorders of sex development (DSD): position paper of EU COST Action BM 1303 ‘DSDnet’

Cited by 134 publications

References 53 publications

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

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

Survey of disorders of sex development in a large cohort of patients with diverse Mendelian phenotypes

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