scholarly journals Disorders of sex development: advances in genetic diagnosis and challenges in management

2015 ◽  
pp. 165 ◽  
Author(s):  
Faisal Ahmed ◽  
Andreas Kyriakou ◽  
Edward Tobias ◽  
Angela Lucas-Herald ◽  
Ruth McGowan
Keyword(s):  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Sex Development

WT1 Pathogenic Variants are Associated with a Broad Spectrum of Differences in Sex Development Phenotypes and Heterogeneous Progression of Renal Disease

2021 ◽  
pp. 1-9
Author(s):  
Maria T.M. Ferrari ◽  
Andreia Watanabe ◽  
Thatiane E. da Silva ◽  
Nathalia L. Gomes ◽  
Rafael L. Batista ◽  
...  
Keyword(s):  
Kidney Development ◽  
Wilms Tumor ◽  
Genetic Diagnosis ◽  
Germ Cell Tumors ◽  
Disorders Of Sex Development ◽  
Medical Attention ◽  
Primary Amenorrhea ◽  
Normal Female ◽  
Sex Development ◽  
Pathogenic Variants

Wilms’ tumor suppressor gene 1 (<i>WT1</i>) plays an essential role in urogenital and kidney development. Heterozygous germline pathogenic allelic variants of <i>WT1</i> have been classically associated with Denys–Drash syndrome (DDS) and Frasier syndrome (FS). Usually, exonic pathogenic missense variants in the zinc finger region are the cause of DDS, whereas pathogenic variants affecting the canonic donor lysine-threonine-serine splice site in intron 9 cause FS. Phenotypic overlap between <i>WT1</i> disorders has been frequently observed. New <i>WT1</i> variant-associated phenotypes, such as 46,XX testicular/ovarian-testicular disorders of sex development (DSD) and primary ovarian insufficiency, have been reported. In this report, we describe the phenotypes and genotypes of 7 Brazilian patients with pathogenic <i>WT1</i> variants. The molecular study involved Sanger sequencing and massively parallel targeted sequencing using a DSD-associated gene panel. Six patients (5 with a 46,XY karyotype and 1 with a 46,XX karyotype) were initially evaluated for atypical genitalia, and a 46,XY patient with normal female genitalia sought medical attention for primary amenorrhea. Germ cell tumors were identified in 2 patients, both with variants affecting alternative splicing of <i>WT1</i> between exons 9 and 10. Two pathogenic missense <i>WT1</i> variants were identified in two 46,XY individuals with Wilms’ tumors; both patients were &#x3c;1 year of age at the time of diagnosis. A novel <i>WT1</i> variant<i>,</i> c.1453_1456 (p.Arg485Glyfs*14), was identified in a 46,XX patient with testicular DSD. Nephrotic proteinuria was diagnosed in all patients, including 3 who underwent renal transplantation after progressing to end-stage kidney disease. The expanding phenotypic spectrum associated with <i>WT1</i> variants in XY and XX individuals confirms their pivotal role in gonadal and renal development as well as in tumorigenesis, emphasizing the clinical implications of these variants in genetic diagnosis.

scholarly journals Modern opportunities and indications for genetic diagnosis of male infertility

2019 ◽  
pp. 3-15
Author(s):  
Т.М. Сорокина ◽  
О.А. Соловова ◽  
В.Б. Черных
Keyword(s):  
Male Infertility ◽  
Recurrent Miscarriage ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Gene Mutations ◽  
Genomic Analysis ◽  
Copy Number Variations ◽  
Genetic Causes ◽  
Sex Development ◽  
Genetic Examination

Тяжелые формы мужского и женского бесплодия, привычного невынашивания беременности, аномалий формирования пола часто обусловлены генетическими причинами или связаны с генетическими факторами. Медико-генетическое обследование и консультирование пациентов с нарушением репродукции зачастую ограничивается использованием стандартных рутинных исследований, поэтому не позволяет выявить многие наследственные формы репродуктивной патологии. Методы геномного анализа позволяют повысить эффективность диагностики генетически обусловленных нарушений репродукции, вызванных генными мутациями и вариациями числа копий (CNV), но их пока широко не используют в практическое медицине. В статье рассмотрены современные возможности медико-генетического обследования мужчин с нарушением фертильности, а также приведены показания и алгоритмы диагностики генетических причин мужского бесплодия, связанного с различными формами патозооспермии. Evere forms of male and female infertility, recurrent miscarriage, abnormalities in disorders of sex development are often due to genetic causes or are associated with genetic factors. Genetic examination and counseling of patients with reproductive problems is often limited to the use of standard routine techniques, therefore, it is not possible to identify many hereditary forms of reproductive pathology. Genomic analysis methods can improve the diagnosis of genetic reproductive disorders caused by gene mutations and copy number variations (CNVs), but they are not yet widely used in practical medicine. The article discusses the modern possibilities of medical-genetic examination of infertile men with, as well as the indications and diagnostic algorithms for the genetic causes of male infertility associated with various forms of pathozoospermia.

scholarly journals Cis-Regulatory Control of Mammalian Sex Determination

2021 ◽  
pp. 1-18
Author(s):  
Meshi Ridnik ◽  
Stefan Schoenfelder ◽  
Nitzan Gonen
Keyword(s):  
Sex Determination ◽  
Cell Fate ◽  
Developmental Disorders ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Regulatory Elements ◽  
Regulatory Control ◽  
Male Factor ◽  
Cis Acting ◽  
Sex Development

Sex determination is the process by which an initial bipotential gonad adopts either a testicular or ovarian cell fate. The inability to properly complete this process leads to a group of developmental disorders classified as disorders of sex development (DSD). To date, dozens of genes were shown to play roles in mammalian sex determination, and mutations in these genes can cause DSD in humans or gonadal sex reversal/dysfunction in mice. However, exome sequencing currently provides genetic diagnosis for only less than half of DSD patients. This points towards a major role for the non-coding genome during sex determination. In this review, we highlight recent advances in our understanding of non-coding, cis-acting gene regulatory elements and discuss how they may control transcriptional programmes that underpin sex determination in the context of the 3-dimensional folding of chromatin. As a paradigm, we focus on the <i>Sox9</i> gene, a prominent pro-male factor and one of the most extensively studied genes in gonadal cell fate determination.

Targeting the Non-Coding Genome for the Diagnosis of Disorders of Sex Development

2021 ◽  
pp. 1-19
Author(s):  
Gabby Atlas ◽  
Rajini Sreenivasan ◽  
Andrew Sinclair
Keyword(s):  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Regulatory Elements ◽  
Gonadal Development ◽  
Comparative Genomic ◽  
Enhancer Activity ◽  
Sex Development ◽  
Genomic Regions

Disorders of sex development (DSD) are a complex group of conditions with highly variable clinical phenotypes, most often caused by failure of gonadal development. DSD are estimated to occur in around 1.7% of all live births. Whilst the understanding of genes involved in gonad development has increased exponentially, approximately 50% of patients with a DSD remain without a genetic diagnosis, possibly implicating non-coding genomic regions instead. Here, we review how variants in the non-coding genome of DSD patients can be identified using techniques such as array comparative genomic hybridization (CGH) to detect copy number variants (CNVs), and more recently, whole genome sequencing (WGS). Once a CNV in a patient’s non-coding genome is identified, putative regulatory elements such as enhancers need to be determined within these vast genomic regions. We will review the available online tools and databases that can be used to refine regions with potential enhancer activity based on chromosomal accessibility, histone modifications, transcription factor binding site analysis, chromatin conformation, and disease association. We will also review the current in vitro and in vivo techniques available to demonstrate the functionality of the identified enhancers. The review concludes with a clinical update on the enhancers linked to DSD.

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

2015 ◽  
Vol 100 (2) ◽  
pp. E333-E344 ◽  
Author(s):  
Ruth M. Baxter ◽  
Valerie A. Arboleda ◽  
Hane Lee ◽  
Hayk Barseghyan ◽  
Margaret P. Adam ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Single Gene ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Clinical Samples ◽  
Sequencing Data ◽  
Sex Development ◽  
Genetic Level ◽  
Clinical Conditions ◽  
Clinical Genomic

Abstract Context: Disorders of sex development (DSD) are clinical conditions where there is a discrepancy between the chromosomal sex and the phenotypic (gonadal or genital) sex of an individual. Such conditions can be stressful for patients and their families and have historically been difficult to diagnose, especially at the genetic level. In particular, for cases of 46,XY gonadal dysgenesis, once variants in SRY and NR5A1 have been ruled out, there are few other single gene tests available. Objective: We used exome sequencing followed by analysis with a list of all known human DSD-associated genes to investigate the underlying genetic etiology of 46,XY DSD patients who had not previously received a genetic diagnosis. Design: Samples were either submitted to the research laboratory or submitted as clinical samples to the UCLA Clinical Genomic Center. Sequencing data were filtered using a list of genes known to be involved in DSD. Results: We were able to identify a likely genetic diagnosis in more than a third of cases, including 22.5% with a pathogenic finding, an additional 12.5% with likely pathogenic findings, and 15% with variants of unknown clinical significance. Conclusions: Early identification of the genetic cause of a DSD will in many cases streamline and direct the clinical management of the patient, with more focused endocrine and imaging studies and better-informed surgical decisions. Exome sequencing proved an efficient method toward such a goal in 46,XY DSD patients.

scholarly journals Clinical Approach for Evaluation and Manage¬ment of Disorders of Sex Development

2017 ◽  
Vol 1 (3) ◽  
Author(s):  
Najya Abdullah Attia
Keyword(s):  
Genetic Diagnosis ◽  
Tumor Development ◽  
Disorders Of Sex Development ◽  
External Genitalia ◽  
Ambiguous Genitalia ◽  
Rapid Progression ◽  
Clinical Approach ◽  
Sex Development ◽  
Special Approach ◽  
Atypical Development

"It's a boy" and "It's a girl" are words that are heard every second of every day all around the world. However, it is very distressing when the birth attendants are unable to make such a pronouncement because of disorders of sex development (DSD). DSD are congenital conditions associated with an atypical development of chromosomal, gonadal or anatomical sex. Normal sex development progresses in steps from conception to the complete development of the fetal external genitalia; any disturbance in any of these steps can lead to DSD. Ambiguous genitalia are the most common type of DSD and it is a challenging clinical diagnosis for the pediatric endocrinologist. A newborn baby with ambiguous genitalia is often a surprise for both the medical team and the parents, frequently described as an emergency. The condition needs a special approach in terms of counseling the parents appropriately, evaluation and management. The Chicago Conference (2006) recommended new nomenclature and a classification for DSD, as the old nomenclature was confusing for doctors and parents, and sometimes pejorative. The new classification is based on karyotyping and gonadal structure, improving understanding of the underlying pathogenic mechanisms. The rapid progression of genetic diagnosis of DSD using advanced techniques such as next-generation sequencing (NGS) allows more appropriate diagnosis and genetic counseling for families. The focus of the article is a review of normal sex development, DSD classification, clinical approach, genetic assessment, sex assignment, surgical management and risk of germ cell tumor development.

scholarly journals OR27-01 Combining Clinical and Genetic Approaches in Diagnosing a Large Brazilian Cohort of Patients with 46,XY Differences/Disorders of Sex Development (DSD)

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Nathalia Lisboa Rosa Almeida Gomes ◽  
Rafael Loch Batista ◽  
Mirian Yumie Nishi ◽  
Antonio Marcondes Lerario ◽  
Thatiana Evilen Silva ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Massively Parallel Sequencing ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Androgen Insensitivity Syndrome ◽  
Unknown Etiology ◽  
Androgen Synthesis ◽  
Sex Development ◽  
Liquid Chromatography Tandem Mass ◽  
Phenotype Heterogeneity

Abstract Background: It is recommended a multidisciplinary approach consisted of clinical, hormonal and genetic workups for diagnosing 46,XY DSD. However, no previous study has quantified how useful is this combined approach. Objectives: To retrospectively review the clinical and genetic findings for diagnosing a large cohort of patients with 46,XY DSD from a single Brazilian center. Methods: 247 non-syndromic 46,XY DSD individuals (159 sporadic and 88 familial cases from 39 families) were studied. Clinical and hormonal data were collected from medical files. Testosterone (T), androstenedione (A) were measured by immunoradiometric or immunofluorimetric assays and dihydrotestosterone (DHT) by RIA after celite chromatography or by liquid chromatography tandem mass spectrometry; T/DHT and T/A ratios were calculated. Analysis of sensitivity (SE), specificity (SP) of T/DHT was performed, being the molecular diagnosis considered the gold standard for diagnosing SRD5A2 deficiency. A T/A&gt;0.8 was considered indicative of 17ß-HSDB3 deficiency. The patients were clinically classified into four subgroups: 1) androgen insensitivity syndrome (AIS), 2) gonadal dysgenesis (GD); 3) defects in androgen synthesis (DAS) and 4) DSD of unknown etiology. Molecular studies were performed by Sanger sequencing and/ or massively parallel sequencing (MPS). Results: The median age at first visit was 14 years (range 0.1 to 59 years). The molecular diagnosis was established in 96.5% of the cases with AIS (n=28/29), in 96% of the subjects with DAS (n=46/48), in 36% of the patients with GD (n=21/57) and in 26.7% (n=15/56) with DSD of unknown etiology. The best cut-off for T/DHT in basal state and hCG stimulated was 12.5 (SE=100%; SP=78.57%) and 24 (SE=87.5%; SP=95.7%) respectively. A T/A&lt;0.8 was observed in 13/16 (81%) of the patients with molecular diagnosis of 17ß-HSDB3 deficiency and also in 1/49 patients with other diagnose. Classification according to the phenotype matched with the genetic diagnosis in most cases. The molecular evaluation allowed that 16% (9/56) of the patients that were classified as DSD of unknow etiology had a definitive diagnosis, including six GD cases, two individuals with SRD5A2 deficiency and one with 17ß-HSDB3 deficiency. A clear AIS phenotype of five patients allowed us to consider and prove the pathogenicity of two synonymous and one promoter region variants as the cause of AIS. The combination of clinical and molecular diagnosis led to an increase in 8% the diagnosis in a total of 116 index-cases (58.5%) with a molecular diagnosis. Conclusion: Considering the phenotype heterogeneity, pitfalls of the hormonal assessment and number of genes involved, it is reasonable to consider MPS as a first test for diagnosing patients with 46,XY DSD. However, the combination of clinical and molecular diagnosis is more accurate than either strategies alone in diagnosing 46,XY DSD.

scholarly journals The laboratory in the multidisciplinary diagnosis of differences or disorders of sex development (DSD)

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Maria Luisa Granada ◽  
Laura Audí
Keyword(s):  
Multidisciplinary Team ◽  
Molecular Genetic ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Gonadal Development ◽  
Abnormal Development ◽  
Sex Characteristics ◽  
Fetal Life ◽  
Sex Development ◽  
Male Sex

Abstract Objectives The development of female or male sex characteristics occurs during fetal life, when the genetic, gonadal, and internal and external genital sex is determined (female or male). Any discordance among sex determination and differentiation stages results in differences/disorders of sex development (DSD), which are classified based on the sex chromosomes found on the karyotype. Content This chapter addresses the physiological mechanisms that determine the development of female or male sex characteristics during fetal life, provides a general classification of DSD, and offers guidance for clinical, biochemical, and genetic diagnosis, which must be established by a multidisciplinary team. Biochemical studies should include general biochemistry, steroid and peptide hormone testing either at baseline or by stimulation testing. The genetic study should start with the determination of the karyotype, followed by a molecular study of the 46,XX or 46,XY karyotypes for the identification of candidate genes. Summary 46,XX DSD include an abnormal gonadal development (dysgenesis, ovotestes, or testes), an androgen excess (the most frequent) of fetal, fetoplacental, or maternal origin and an abnormal development of the internal genitalia. Biochemical and genetic markers are specific for each group. Outlook Diagnosis of DSD requires the involvement of a multidisciplinary team coordinated by a clinician, including a service of biochemistry, clinical, and molecular genetic testing, radiology and imaging, and a service of pathological anatomy.

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