Diagnostic Application of Targeted Next-Generation Sequencing of 80 Genes Associated with Disorders of Sexual Development

Fan, Yanjie; Xia, Zhang; Wang, Lili; Wang, Ruifang; Huang, Zhuo; Sun, Yu; Yao, Rutao; Huang, Xiaodong; Ye, Jun; Han, Lianshu; Qiu, Wenjuan; Zhang, Huiwen; Liang, Lili; Gu, Xuefan; Yu, Yongguo

doi:10.1038/srep44536

Cited by 44 publications

(39 citation statements)

References 46 publications

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“…Overall, in this series of 352 patients, 138 pathogenic or likely pathogenic variants were identified, among which 26 CNVs, and 22 variants of uncertain significance. Our approach revealed to be a useful strategy, providing a molecular diagnosis in 35.2% of patients, similar to other heterogeneous conditions (50% for inborn errors of metabolism (Yubero et al, ), 47.3% for myopathies and muscular dystrophies (Stehlikova et al, ), 39% for intellectual disability (Martinez et al, ), 28.5% for epileptic encephalopathy (Kothur et al, ), 28.1% for disorders of sexual development (Fan et al, ), 24.5% for developmental eye disorders (Patel et al, ), 20% for primary arrhythmia syndrome and cardiomyopathy (Robyns et al, ), and 18% for inherited polyneuropathy (Wang et al, ). A 7.7% increase was observed in our diagnostic performance, compared to our previous workflow (diagnostic yield 27.5% before 2014, data not shown).…”

Section: Discussionsupporting

confidence: 58%

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

et al. 2019

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Congenital limb malformations (CLM) comprise many conditions affecting limbs and more than 150 associated genes have been reported. Due to this large heterogeneity, a high proportion of patients remains without a molecular diagnosis. In the last two decades, advances in high throughput sequencing have allowed new methodological strategies in clinical practice. Herein, we report the screening of 52 genes/regulatory sequences by multiplex high‐throughput targeted sequencing, in a series of 352 patients affected with various CLM, over a 3‐year period of time. Patients underwent a clinical triage by expert geneticists in CLM. A definitive diagnosis was achieved in 35.2% of patients, the yield varying considerably, depending on the phenotype. We identified 112 single nucleotide variants and 26 copy‐number variations, of which 52 are novel pathogenic or likely pathogenic variants. In 6% of patients, variants of uncertain significance have been found in good candidate genes. We showed that multiplex targeted high‐throughput sequencing works as an efficient and cost‐effective tool in clinical practice for molecular diagnosis of congenital limb malformations. Careful clinical evaluation of patients may maximize the yield of CLM panel testing.

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Section: Discussionsupporting

confidence: 58%

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

et al. 2019

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“…The presence of this hemizygous variant was confirmed in both brothers and heterozygous in their mother by Sanger sequencing at GENEWIZ (http://www.genecards.org) (Figure ). This variant is not reported in the three genomic databases studied, but has been found associated with Kallmann syndrome twice in the literature (Jiang et al ., ; Fan et al ., ). Therefore, we conclude that this is a pathogenic variant according to American College of Medical Genetics guidelines and the cause of Kallmann syndrome in this family.…”

Section: Resultsmentioning

confidence: 97%

“…It was subsequently reported in a study performing next‐generation sequencing of genes associated with disorders of sexual development (DSD) to identify novel disease‐causing variants. In this study, there were four patients with clinical hypogonadotropic hypogonadism and one was identified to have the c.1267C>T variant in ANOS1 (Fan et al ., ). Although our patients may fit into the spectrum of DSD, none of them fulfilled diagnostic criteria for autism on evaluation.…”

Section: Discussionmentioning

confidence: 97%

A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing

et al. 2017

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Kallmann syndrome is a rare genetic condition causing congenital hypogonadotropic hypogonadism. It presents with delayed puberty, anosmia, and infertility. Here, we set out to identify a causative DNA variant for Kallmann syndrome in two affected brothers of Hispanic ancestry. The male siblings presented with a clinical diagnosis of Kallmann syndrome (anosmia, delayed puberty, azoospermia, and undetectable luteinizing hormone and follicle stimulating hormone levels). Genetic variations were investigated by whole exome sequencing. Potentially pathogenic variants were filtered and prioritized followed by validation by Sanger sequencing in the two brothers and their mother. A pathogenic variant was identified in the ANOS1 gene on the X chromosome: c.1267C>T; both brothers were hemizygous, and their mother was heterozygous for the variant. The variant is a single nucleotide change that introduces a stop codon in exon 9 (p.R423*), likely producing a truncated variant of the protein. This variant has only been reported twice in the literature, in the setting of finding genetic causes for other conditions. This result supports the clinical value of whole exome sequencing for identification of genetic pathogenic variants. Genetic diagnosis is the essential first step for genetic counseling, preimplantation diagnosis, and research for a potential treatment.

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“…While we know the genetic aetiology of a small number of DSDs, up to as many as 75% of individuals with a DSD will remain without a genetic diagnosis (Arboleda et al 2014). Even with whole genome sequencing, it is often difficult to identify functional variants and causal mutations, rendering many sequencing approaches somewhat ineffective (Fan et al 2017). Gene expression levels, epigenetic modifiers and genetic background, along with the type of mutation and its functional consequence can all influence the resulting phenotype for both humans and mice.…”

Section: Discussionmentioning

confidence: 99%

The molecular pathways underlying early gonadal development

Yang

Workman

Wilson

2019

Journal of Molecular Endocrinology

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The body of knowledge surrounding reproductive development spans the fields of genetics, anatomy, physiology and biomedicine, to build a comprehensive understanding of the later stages of reproductive development in humans and animal models. Despite this, there remains much to learn about the bi-potential progenitor structure that the ovary and testis arise from, known as the genital ridge (GR). This tissue forms relatively late in embryonic development and has the potential to form either the ovary or testis, which in turn produce hormones required for development of the rest of the reproductive tract. It is imperative that we understand the genetic networks underpinning GR development if we are to begin to understand abnormalities in the adult. This is particularly relevant in the contexts of disorders of sex development (DSDs) and infertility, two conditions that many individuals struggle with worldwide, with often no answers as to their aetiology. Here, we review what is known about the genetics of GR development. Investigating the genetic networks required for GR formation will not only contribute to our understanding of the genetic regulation of reproductive development, it may in turn open new avenues of investigation into reproductive abnormalities and later fertility issues in the adult.

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Diagnostic Application of Targeted Next-Generation Sequencing of 80 Genes Associated with Disorders of Sexual Development

Cited by 44 publications

References 46 publications

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

Multiplex targeted high‐throughput sequencing in a series of 352 patients with congenital limb malformations

A rare ANOS1 variant in siblings with Kallmann syndrome identified by whole exome sequencing

The molecular pathways underlying early gonadal development

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