Human sex development: targeted technologies to improve diagnosis

Buonocore, Federica; Achermann, John C.

doi:10.1186/s13059-016-1128-4

Cited by 15 publications

(12 citation statements)

References 10 publications

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“…Copy number variants (CNV) affecting coding sequences or regulatory elements of critical dosage-sensitive genes, as well as single nucleotide variants (SNVs) in at least 75 genes involved in gonadal development and/or sex hormone biosynthesis/action are known causes of DSDs (Ahmed and Hughes, 2002;Vilain, E., 2010;Auchus and Miller, 2012;Buonocore and Achermann, 2016;Croft et al, 2018;Délot et al, 2017;Eggers and Sinclair, 2012;. Genetic etiology has been well established for many sex differentiation conditions.…”

Section: Genetics Of Dsdsmentioning

confidence: 99%

Translating genomics to the clinical diagnosis of disorders/differences of sex development

Parivesh

Barseghyan

Délot

et al. 2019

Current Topics in Developmental Biology

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The medical and psychosocial challenges faced by patients living with Disorders/Differences of Sex Development (DSD) and their families can be alleviated by a rapid and accurate diagnostic process. Clinical diagnosis of DSD is limited by a lack of standardization of anatomical and endocrine phenotyping and genetic testing, as well as poor genotype/phenotype correlation. Historically, DSD genes have been identified through positional cloning of disease-associated variants segregating in families and validation of candidates in animal and in vitro modeling of variant pathogenicity. Owing to the complexity of conditions grouped under DSD, genome-wide scanning methods are better suited for identifying disease causing gene variant(s) and providing a clinical diagnosis. Here, we review a number of established genomic tools (karyotyping, chromosomal microarrays and exome sequencing) used in clinic for DSD diagnosis, as well as emerging genomic technologies such as whole-genome (short-read) sequencing, long-read sequencing, and optical mapping used for novel DSD gene discovery. These, together with gene expression and epigenetic studies can potentiate the clinical diagnosis of DSD diagnostic rates and enhance the outcomes for patients and families.

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Section: Genetics Of Dsdsmentioning

confidence: 99%

Translating genomics to the clinical diagnosis of disorders/differences of sex development

Parivesh

Barseghyan

Délot

et al. 2019

Current Topics in Developmental Biology

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“…Testicular development was dependent on genes for testis determination and differentiation and on pathway of androgen metabolism and action. 5‐alpha‐reductase‐2 (SRD5A2) can convert testosterone to DHT; an activated form of testosterone and androgen receptor (AR) has a main role in 46,XY DSD (Arboleda, Sandberg, & Vilain, ; Buonocore & Achermann, ; Yatsenko & Witchel, ). Prevalence of genital anomalies is 1 in 300 births, and prevalence of genital ambiguity is approximately 1 in 4,500 to 5,000 births (Ahmed, Bashamboo, Lucas‐Herald, & McElreavey, ).…”

Section: Introductionmentioning

confidence: 99%

“…The key to achieving safety in affected families is to identify and diagnose the disorders properly. Only a minority of patients, comprising 20% of cases, clinically diagnosed with DSD pursue their genetic and molecular aetiology; therefore, a large gap exists in our understanding of prevalence, management and outcome in affected patients (Arboleda et al, ; Buonocore & Achermann, ).…”

Section: Introductionmentioning

confidence: 99%

Molecular investigation of mutations in androgen receptor and 5‐alpha‐reductase‐2 genes in 46,XY Disorders of Sex Development with normal testicular development

et al. 2019

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In this study, we aimed to determine androgen receptor (AR) and SRD5A2 gene mutations in 45 patients characterised by 46,XY Disorders of Sex Differentiation (DSD) signs with normal testicular development referred to the Children's Medical Center from February 2015 to September 2017. Karyotype and sex hormone analyses were performed. Cytogenetic investigation showed that seven patients were 46,XX DSD, six patients were chromosomal DSD and 32 patients were 46,XY DSD. Eight exons of the AR gene and five exons of the SRD5A2 gene were amplified. Two cases were affected with androgen insensitivity syndrome (AIS) (missense mutation on exon 7, position c.3637 G>A: p.R841H and position c.3610 G>A: p.R832Q), one case was affected with 5‐alpha‐reductase deficiency type 2 (missense mutation at c.578A>G: p.N193S on exon 4), and 22 cases (88%) did not demonstrate AIS or 5α‐RD2 gene abnormality. Due to the great impact of these disorders on human lifestyle, evaluation of genes involved can improve genetic counselling and therapeutic management. We focused on the AR and SRD5A2 genes in patients with 46,XY DSDs with normal testicular development referred to the Children's Medical Center from all over the country to eventually culminate in a reliable prenatal diagnosis protocol at this major referral centre giving service to a great number of families with consanguineous marriages.

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“…Recent advances in next-generation sequencing (NGS) techniques have enabled massive parallel sequencing of multiple genes. Targeted enrichment techniques have been developed to reduce genome complexity via targeted sequence captures and optimized the coverage of targeted regions for high throughput deep sequencing rather than whole exome sequencing (WES) or whole genome sequencing (WGS) [8]. Therefore, NGS techniques have changed how genetic research assesses genetically heterogeneous diseases.…”

Section: Introductionmentioning

confidence: 99%

Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

Kim

Seo

Kim

et al. 2018

Exp Clin Endocrinol Diabetes

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Human sex development: targeted technologies to improve diagnosis

Abstract: A new study of disorders of sex development presents an improved targeted next-generation sequencing approach for their diagnosis.Please see related Research article: http://genomebiology.biomedcentral.com/articles/10.1186/s13059-016-1105-y.

Cited by 15 publications

References 10 publications

Translating genomics to the clinical diagnosis of disorders/differences of sex development

Translating genomics to the clinical diagnosis of disorders/differences of sex development

Molecular investigation of mutations in androgen receptor and 5‐alpha‐reductase‐2 genes in 46,XY Disorders of Sex Development with normal testicular development

Targeted Gene Panel Sequencing for Molecular Diagnosis of Kallmann Syndrome and Normosmic Idiopathic Hypogonadotropic Hypogonadism

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