The genetic diagnosis of rare endocrine disorders of sex development and maturation : a survey among Endo-ERN centres

Differences of sex development and maturation (SDM) represent a heterogeneous puzzle of rare conditions with a large genetic component whose management and treatment could be improved by an accurate classification of underlying molecular conditions, and next-generation sequencing (NGS) should represent the most appropriate approach. Therefore, we conducted a survey dedicated to the use and potential outcomes of NGS for SDM disorders diagnosis among the 53 health care providers (HCP) of the European Reference Network for rare endocrine conditions. The response rate was 49% with a total of 26 HCPs from 13 countries. All HCPs, except 1, performed NGS investigations for SDM disorders on 6720 patients, 3764 (56%) with differences of sex development (DSD), including 811 unexplained primary ovarian insufficiency, and 2956 (44%) with congenital hypogonadotropic hypogonadism (CHH). The approaches varied from targeted analysis of custom gene panels (range: 11-490 genes) in 81.5% of cases or whole exome sequencing with the extraction of a virtual panel in the remaining cases. These analyses were performed for diagnostic purposes in 21 HCPs, supported by the National Health Systems in 16 cases. The likelihood of finding a variant ranged between 7 and 60%, mainly depending upon the number of analysed genes or criteria used for reporting, most HCPs also reporting variants of uncertain significance. These data illustrate the status of genetic diagnosis of DSD and CHH across Europe. In most countries, these analyses are performed for diagnostic purposes, yielding highly variable results, thus suggesting the need for harmonization and general improvements of NGS approaches.publishersversionPeer reviewe

EDIR.tar.zip.001

The files (EDIR.tar.ZIP.001 -003) have to be merged into a signle file by using for instance 7-zip. After uncompressing the merged file, please specify the path in the PATH parameter in the gene_lookup function.</p

Cadherins and epithelial-to-mesenchymal transition

Epithelial–mesenchymal transition (EMT) is a process whereby epithelial cells are transcriptionally reprogrammed, resulting in decreased adhesion and enhanced migration or invasion. EMT occurs during different stages of embryonic development, including gastrulation and neural crest cell delamination, and is induced by a panel of specific transcription factors. These factors comprise, among others, members of the Snail, ZEB, and Twist families, and are all known to modulate cadherin expression and, in particular, E-cadherin. By regulating expression of the cadherin family of proteins, EMTinducing transcription factors dynamically modulate cell adhesion, allowing many developmental processes to take place. However, during cancer progression EMT can be utilized by cancer cells to contribute to malignancy. This is also reflected at the level of the cadherins, where the cadherin switch between E- and N-cadherins is a classical example seen in cancer-related EMT. In this chapter, we give a detailed overview of the entanglement between EMT-inducing transcription factors and cadherin modulation during embryonic development and cancer progression. We describe how classical cadherins such as E- and N-cadherins are regulated during EMT, as well as cadherin 7, -6B, and 11

Genetic diagnosis of subfertility – the impact of meiosis and maternal effects

During reproductive age, approximately one in seven couples are confronted with fertility problems. While the etiology is diverse, including infections, metabolic diseases, hormonal imbalances and iatrogenic effects, it is becoming increasingly clear that genetic factors have a significant contribution. Due to the complex nature of infertility which often hints at a multifactorial cause, the search for potentially causal gene mutations in idiopathic infertile couples has remained difficult. Idiopathic infertility patients with a suspicion of an underlying genetic cause can be expected to have mutations in genes which do not readily affect general health, but are only essential in certain processes connected to fertility. In this review, we specifically focus on genes involved in meiosis, a process which plays a pivotal role in fertility, and genes critical for maternal effect processes. We give an overview of genes which have been linked to infertility, as well as genes which are good candidates. Finally, we propose a phenotypic range in which we expect an optimal diagnostic yield of a meiotic/maternal effect gene panel

Intra‐amniotic levothyroxine infusions in a case of fetal goiter due to novel Thyroglobulin gene variants

Indications and administration of intra-amniotic infusions of L-thyroxine in the context of non-immune fetal hypothyroidism with goiter lack of standardization. Systematic follow-up of clinical features related to thyroid hormonal homeostasis may be useful to evaluate their efficiency and develop standardized management guidelines

Evolutionary functional analysis and molecular regulation of the ZEB transcription factors

ZEB1 and ZEB2, which are members of the ZEB family of transcription factors, play a pivotal role in the development of the vertebrate embryo. However, recent evidence shows that both proteins can also drive the process of epithelial-mesenchymal transition during malignant cancer progression. The understanding of how both ZEBs act as transcription factors opens up new possibilities for future treatment of advanced carcinomas. This review gives insight into the molecular mechanisms that form the basis of the multitude of cellular processes controlled by both ZEB factors. By using an evolutionary approach, we analyzed how the specific organization of the different domains and regulatory sites in ZEB1 and ZEB2 came into existence. On the basis of this analysis, a detailed overview is provided of the different cofactors and post-translational mechanisms that are associated with ZEB protein functionality

Sertoli Cell-Only Syndrome: Behind the Genetic Scenes

Sertoli cell-only syndrome is defined by the complete absence of germ cells in testicular tissues and always results in male infertility. The aetiology often remains unknown. In this paper, we have investigated possible causes of Sertoli cell-only syndrome with a special focus on genetic causes. Our results show that, for a large part of the patients (&gt;23% in an unselected group), the sex chromosomes are involved. The majority of patients had a Klinefelter syndrome, followed by patients with Yq microdeletions. Array comparative genomic hybridization in a selected group of &quot;idiopathic patients&quot; showed no known infertility related copy number variations

Sertoli Cell-Only Syndrome: Behind the Genetic Scenes

Sertoli cell-only syndrome is defined by the complete absence of germ cells in testicular tissues and always results in male infertility. The aetiology often remains unknown. In this paper, we have investigated possible causes of Sertoli cell-only syndrome with a special focus on genetic causes. Our results show that, for a large part of the patients (>23% in an unselected group), the sex chromosomes are involved. The majority of patients had a Klinefelter syndrome, followed by patients with Yq microdeletions. Array comparative genomic hybridization in a selected group of “idiopathic patients” showed no known infertility related copy number variations

Novel inactivating follicle-stimulating hormone receptor mutations in a patient with premature ovarian insufficiency identified by next-generation sequencing gene panel analysis

Objective: To find the genetic etiology of premature ovarian insufficiency (POI) in a patient with primary amenorrhea and hypergonadotropic hypogonadism. Design: Case report. Setting: University hospital. Patient(s): A Belgian woman aged 32 years with POI at the age of 17, her parents, and her sister whose POI was diagnosed at age 29. Intervention(s): Analysis of a panel of 31 genes implicated in POI (POIGP) using next-generation sequencing (NGS), Sanger sequencing, and in vitro functional study. Main Outcome Measure(s): Gene variants, family mutational segregation, and in vitro functional impact of the mutant proteins. Result(s): The analysis of the gene panel using NGS identified the presence of two novel follicle-stimulating hormone receptor (FSHR) missense mutations at a compound heterozygous state in the affected patient: c.646 G>A, p.Gly216Arg, and c.1313C>T, p.Thr438Ile. Sanger sequencing showed the presence of each mutation at heterozygous state in the patient's parents and at heterozygous compound state in the affected sister. Both substituted amino acids (Gly216 and Thr438) were conserved in FSHR of several vertebrate species as well as in other glycoproteins receptors (TSHR and LHCGHR), suggesting a potentially important role in glycoprotein receptor function. An in vitro functional study showed similar results for both variants with more than 90% reduction of their cell surface expression and a 55% reduction of their FSH-induced cyclic adenosine 3′:5′ monophosphate (cAMP) production compared with the wild-type FSHR. Conclusion(s): The analysis of a gene panel of 31 genes implicated in POI allowed us to identify two novel partially inactivating mutations of FSHR that are likely responsible for the POI phenotype of the proband and of her affected sister.SCOPUS: ar.jinfo:eu-repo/semantics/publishe