Search

Objectives: The screening of fetal aneuploidies and non-invasive prenatal diagnosis of monogenic diseases (NIPD-MD) both rely on the study of free fetal DNA in maternal circulation, but their respective rise was unequal. Development of NIPD-MD has taken longer as it represents a less attractive commercial dynamic for industry, but also because it usually involves the development of tailored tests specific to each pathogenic variant., Methods: We have carried out a review of the literature on the various indications and technologies involved in the use of NIPD-MM. We present its current implementation and its development in France., Results: To date, NIPD-MD has been routinely offered in France for several years by the laboratories of the French NIPD-MD network but remains mostly limited to the exclusion of paternal or de novo variants, the exclusion DPNI-MD. Indeed, it is still difficult to study the transmission of maternal variants from circulating free DNA analysis, due to its biological complexity: coexistence and predominance of similar DNA sequences of maternal origin. Different strategies, either direct or indirect, are being evaluated to establish fetal status regardless of the parental origin of the disease or its transmission mode. The emergence of commercial screening solutions for monogenic diseases complements the arsenal of prenatal exploration tools for these diseases., Conclusion: The multitude of existing technologies and protocols may complicate the information provided during antenatal consultations, but mastery of know-how and knowledge of ethical issues of NIPD-MD will ensure optimal service and better management of pregnancies at risk of transmitting monogenic disease., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

Sperm quality appears to be degrading over the past 40 years. Nowadays, more than 35 % of causes of male infertility are still idiopathic. More and more studies have suggested an impact of environment on sperm quality, essentially through epigenetic and hormonal changes. Recent studies in men with impaired sperm quality, have demonstrated epigenetic variations in sperm DNA. These modifications are responsible for modifications of the expression of transmissible genes to theiroffspring. Those transgenerational effects have been particularly illustrated in drosophila and caenorhabditis elegans. In humans, consequences of the environment on fertility have been studied in obese men, who present hypogonadotropic as well as hypergonadotropic hypogonadisms. Interestingly, recent studies have suggested a correlation between sperm quality and longevity. In summary, those environmental factors are the source of new causes of infertility., (© 2018 Elsevier Masson SAS. Tous droits réservés.)

The very high information density of DNA has prompted speculations on its use for information storage. The high costs of DNA synthesis and sequencing made this highly unpractical; however recent progress (notably array oligonucleotide synthesis) is changing the situation. A recent paper shows encoding and decoding of significant amounts of data (200 MB) with random access to individual files and faithful retrieval of content, at a cost that is still high but not extreme. Much progress remains to be achieved, but this use of DNA in now technically achievable and may eventually become practical., (© 2018 médecine/sciences – Inserm.)

Endometrial osseous metaplasia (EOM) is a rare condition characterised by the presence of bone in the uterine cavity. Some patients with this condition present with secondary infertility due to the presence of a foreign body in the endometrium. We report a case of a 39-year-old woman who presented with secondary infertility due to EOM. EOM is a rare cause of infertility that can be easily managed by hysteroscopic removal of the bony fragments., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

In September 2012, a batch of more than 30 articles presenting the results of the ENCODE (Encyclopaedia of DNA Elements) project was released. Many of these articles appeared in Nature and Science, the two most prestigious interdisciplinary scientific journals. Since that time, hundreds of other articles dedicated to the further analyses of the Encode data have been published. The time of hundreds of scientists and hundreds of millions of dollars were not invested in vain since this project had led to an apparent paradigm shift: contrary to the classical view, 80% of the human genome is not junk DNA, but is functional. This hypothesis has been criticized by evolutionary biologists, sometimes eagerly, and detailed refutations have been published in specialized journals with impact factors far below those that published the main contribution of the Encode project to our understanding of genome architecture. In 2014, the Encode consortium released a new batch of articles that neither suggested that 80% of the genome is functional nor commented on the disappearance of their 2012 scientific breakthrough. Unfortunately, by that time many biologists had accepted the idea that 80% of the genome is functional, or at least, that this idea is a valid alternative to the long held evolutionary genetic view that it is not. In order to understand the dynamics of the genome, it is necessary to re-examine the basics of evolutionary genetics because, not only are they well established, they also will allow us to avoid the pitfall of a panglossian interpretation of Encode. Actually, the architecture of the genome and its dynamics are the product of trade-offs between various evolutionary forces, and many structural features are not related to functional properties. In other words, evolution does not produce the best of all worlds, not even the best of all possible worlds, but only one possible world., (© 2015 médecine/sciences – Inserm.)

It was thought until recently that a new gene could only evolve from a previously existing gene, from recombination of genes, or from horizontal gene transfer. Recently a series of genomic and transcriptomic studies have led to the identification of non-coding DNA as a significant source of protein coding genes. The mechanism, which is probably universal since it has been identified in a wide array of eukaryotes, implies that a gradient of proto-genes, probably established by a balance between selection and genetic drift, exists between coding DNA and non-coding DNA. Therefore genome dynamics could account for the progressive formation of genes "out of the blue" thanks to the interplay of mutation and natural selection., (© 2014 médecine/sciences – Inserm.)

Aim of the Study: Current knowledge of the molecular basis of most blood groups enables genetic testing for blood groups to overcome the limitations of agglutination. A retrospective review was carried out on genotyping assays performed between 2011 and 2013., Methods and Patients: The Molecular Hematology Laboratory of the EFS Alpes-Méditerranée implements commercially available tools (BioArray, Gen-Probe) and other techniques (TaqMan, tetra-primer ARMS-PCR, sequencing). It provides a high-level of expertise in molecular biology, complying with regulatory requirements and standards., Results: A total of 2382 genotyping assays was performed including 764 extended typings and 115 large extended typings essentially in cases involving multiple transfusion and suspected rare blood type. Phenotype discrepancies linked to the RH system accounted for 1501 genotypings. Discrepancies linked to the D and E were mainly related to an allele coding for weak antigen (weak D type 1, 2, 3 and EIV) while those linked to C, c and e antigens were related to an allele coding for a partial antigen (RN, ces(340), ceMo). A high prevalence of (C)ces haplotype in trans of a DAR allele was observed in Afro-Caribbean (54/62)., Conclusion: In transfusion medicine, red-cell genotyping can overcome the limitations of hemagglutination. It must be used only in situations where it provides a benefit either for the patient or resource management. For implementation of appropriate transfusional practices, this technique requires a sound knowledge of the genetic characteristics of blood groups and clinically relevant variants. It also requires competency with molecular biology tools and continuously updated scientific data., (Copyright © 2014. Published by Elsevier SAS.)

The molecular basis of almost all antigens of the 33 blood group systems are known. These knowledge and the advent of the PCR technology have allowed the DNA-based genotyping in order to predict the presence or absence of a blood group antigen on the cell membrane of red blood cells. DNA genotyping is required in cases where red blood cells patient cannot be used for serological typing either after a recent transfusion or because of the presence of autoantibodies on the red blood cells. Numerous DNA assays are available to detect any nucleotide polymorphism on the genes encoding blood group antigens. The technologies have improved to answer quickly to any case of transfusion emergency and to limit the risk of DNA contamination in a molecular diagnostic laboratory. Some technologies are ready for high-throughput blood group genotyping. They will be used in the future to obtain a fully typed blood group card of each donor but also to detect blood donors with rare phenotypes to register them to the Banque Nationale de Sang de Phénotype Rare (BNSPR)., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Forensic examination is often requested when skeletal remains are discovered. Detailed visual observation can provide much information, such as the human or animal origin, sex, age, stature, and ancestry, and approximate time since death. New three-dimensional imaging techniques can provide further information (osteometry, facial reconstruction). Bone chemistry, and particularly measurement of stable or unstable carbon and nitrogen isotopes, yields information on diet and time since death, respectively. Genetic analyses of ancient DNA are also developing rapidly. Although seldom used in a judicial context, these modern anthropologic techniques are nevertheless available for the most complex cases.

In recent years, DNA profiling has been used regularly by the justice system, and has seen a number of improvements, with the need for fewer cells, more efficient DNA extraction and purification, and more rapid genotyping. These methods can now identify an individual more rapidly, from a corpse, blood stain, sperm or epithelial cells, by comparison with familial profiles. In France, DNA profiling can only be ordered by a judge.

Rat and mice are privileged tools for scientists. However, despite obvious advantages, such as a larger size, more faithful reproduction of human diseases, and utility for physiological and cognitive studies, rats have suffered from limited genetic technologies such as targeted mutagenesis. However, the gap between rat and mouse for genetic approaches will soon disappear with the recent advances of zinc finger nucleases applicable to early-stage rat embryos and the successful derivation of germ line competent rat ES cells, almost thirty years after murine ES cells. This will lead to new opportunities and to increase our capacity to model human pathologies.

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.

Aim of the Study: Free fetal DNA in maternal blood offers a non invasive method for prenatal diagnosis. The aim of this study is to perform fetal RHD genotyping by conventional PCR in D negative pregnant women of Moroccan origin., Patients and Methods: Plasma sample from 120 D negative pregnant women from 10 to 40 gestational weeks were tested by conventional PCR for the presence of exons 7 and 10 of RHD gene. The results were compared with the RhD phenotype of the newborns., Results: In this study, the positive and the negative predictive value of the fetal RhD status were 98.7 and 96.7%, respectively., Conclusion: These results demonstrate de feasibility of fetal RHD genotyping by conventional PCR in D negative pregnant women of Moroccan origin., (Copyright © 2010 Elsevier Masson SAS. All rights reserved.)

A complex system of molecular milestones ensures labelling of the genome, driving its organization and functions. These milestones correspond to particular marks associated to active and repressed genes, as well as to non-coding regions or those containing repetitive sequences. Most of these marks are chemical modifications of DNA, corresponding to cytosine methylation, or various posttranslational modifications of histones, the proteins which package the genome. These chemical modifications of DNA or histones are reversible and are catalysed and removed by enzymatic activities associated with factors ensuring critical cellular functions. Indeed, these enzymes are directly connected with signalling pathways, sensing extra- and intracellular environments. Altogether these mechanisms globally control the expression status of genes in each cell, meaning that certain genes are kept active, while most of the genome remains silent. Subtle metabolic changes or intra and extracellular modifications, by altering the marking associated to genes, can have long-term consequences on their expression status. Genes coding for essential regulators of cellular proliferation and differentiation could be among these genes, such as tumor suppressor genes for instance. Hence the knowledge of all these so-called "epigenetic" mechanisms will shed new light on the environmental impact on the control of gene expression and associated diseases, including malignant transformation. The understanding of these mechanisms will also pave the way for innovative therapeutic strategies to fight cancer. This review is aiming to give an overview to the reader of the relevance of epigenetic mechanisms for the understanding and treatment of cancer.

Background: Punctate palmoplantar keratoderma (PPPK), or Buschke-Fischer-Brauer's disease, is a rare form of genodermatosis with autosomal dominant transmission and with variable penetrance. Its molecular basis remains unknown. Two loci were found to be linked to this disease: one on 15q22 and the other on 8q24. We report the clinical and genetic characteristics of PPPK in a Tunisian family., Patients and Methods: A Tunisian family with PPPK was identified through a proband. As far as possible, history taking, physical examination, histopathological tests and blood sampling for DNA extraction were carried out for each patient., Results: Seventeen patients were included in this study. Age ranged from 15 to 81 years with a sex-ratio of 3.2 m/f. Lesions appeared between the ages of 10 and 65 years and at a mean of 28 years. Clinically, lesions ranged from few keratotic papules on the palms to coalescence of lesions in plaques over palmar and/or plantar surfaces. Hyperhydrosis, hypopigmented macules and nail dystrophy were frequently associated. In all patients, histopathological examination revealed thickening of the epidermis with compact orthohyperkeratosis overlying a small and sharply demarcated area of depressed epidermis. Mechanical measures and keratolytic ointments proved non-beneficial. Genotyping for chromosomes 8 and 15 as well as LOD scores confirmed genetic linkage with the suspected locus on chromosome 15q, with the interval of the locus in question reduced to 3.26 Mb. This region is flanked by markers D15S987 and D15S153., Conclusion: Our study of this family confirmed the classical characteristics of KPP-BFB as well as demonstrating several associated clinical signs of which the significance will be determined in subsequent studies. Further screening studies to identify mutated genes in the region of interest will help us to understand the molecular basis of this disease and hopefully to propose suitable treatment., (2010 Elsevier Masson SAS. All rights reserved.)

Gene therapy offers exciting opportunities for the treatment of innate or acquired genetic diseases. However, there is still a need for a safe and efficient strategy to deliver nucleic acids into cells while overcoming the current limitations faced with standard viral vectors. Intensive researches have been carried out over the past decade, focusing both on viral and non-viral (i.e. physical or chemical) strategies. Of these numerous attempts, magnetofection, defined as the combination of nucleic acid vectors with magnetic nanoparticles, holds the promise to achieve high transfection efficiency with reduced toxicity by magnetically focusing the genetic material to be delivered on its cellular target. In vitro as well as in vivo results already demonstrated that this strategy may become a valuable tool towards practical gene therapy.

The epigenetic marking of chromatin in the brain has recently been recognized as an essential mechanism for brain functions such as learning and memory formation. It allows nerve cells not only to respond to environmental stimuli and modulate their profile of gene expression, but also to establish and maintain their own identity. The epigenetic code is conferred by a set of covalent modifications on the basic elements of chromatin, DNA and histone proteins. These changes are catalyzed by specific enzymes and mechanisms, which include DNA methylation, and post-translational modifications of histone proteins such as acetylation, phosphorylation, methylation and ubiquitination. They are both stable and highly dynamic, and are triggered during stimulation of neuronal circuits but can also persist thereafter. Their study in animal models has demonstrated their importance, and revealed some of their modes of function., (© Société de Biologie, 2010.)

In order to accomplish its differentiation program, the nucleus of a multipotent cell must be sequentially reprogrammed to acquire and maintain new gene expression patterns. When a stem cell is committed to differentiate towards a given lineage, global genome reprogramming involves both repression of non-affiliated genes and selective activation of genes involved in the establishment of the lineage. Accumulating evidence indicates that lineage specific gene expression is determined not only by the availability of specific transcription factors, but also by epigenetic modifications including both local modifications of DNA and chromatin structure, as well as global topological changes in chromosomes and genes positioning in the nucleus. Combined, these different levels of gene regulation allow for fine controls that integrate environmental and intracellular signals to establish appropriate gene expression programs, and hence ultimately determine the identity of the cell. Therefore, epigenetic modifications most likely precede gene activation and play a critical role in the choices of a stem cell to continue to self-renew or to differentiate. However, the cause-effect relationship between chromatin structure, nuclear architecture and cell-fate decisions is still a matter of debate. The pericentromeric heterochromatin compartment will be presented as one of the best studied examples to understand the impact of and positioning of a gene on its transcription. We will set the influence of heterochromatin compartments in the context of hematopoietic differentiation of human multipotent progenitors., (© Société de Biologie, 2010.)

Primary ovarian insufficiency (POI) is characterised by the arrest of normal ovarian function before the age of 40 years and affects 1 % of all women. POI shows familial inheritance suggesting a genetic contribution. NR5A1 is nuclear receptor that regulates the transcription of many genes involved in sexual developmental and reproduction. 18 NR5A1 mutations have been published associated with either anomalies of adrenal or testis development. We have identified NR5A1 mutations associated with POI, including familial cases with affected 46,XY individuals. This demonstrates that NR5A1 plays an important role in ovarian development and function. However several questions remain. What is the incidence of NR5A1 mutations in POI? Is there a genotype/phenotype relationship? Are mutations associated with a progressive loss of reproductive function? Answering these questions will lead to a better understanding of ovarian function and dysfunction and could lead to new therapies for treating POI.

Hypertension is a common, modifiable and heritable cardiovascular risk factor. Some rare monogenic forms of hypertension have been described, but the majority of patients suffer from "essential" hypertension, for whom the underlying pathophysiological mechanism is not clear. Essential hypertension is a complex trait, involving multiple genes and environmental factors. Recently, progress in the identification of common genetic variants associated with blood pressure and hypertension has been made thanks to large-scale international collaborative projects involving geneticists, epidemiologists, statisticians and clinicians. In this article, we review some basic genetic concepts and the main research methods used to study the genetics of hypertension, as well as selected recent findings in this field.

In 1956, the number of chromosomes in humans is set at 46; in 1959, the link between a disability (mongolism) and a chromosomal anomaly (the Down syndrome) is established: human and medical cytogenetics were born. Since then, progress has been remarkable: the techniques of chromosomal and molecular cytogenetics can reach a resolution of the size of a single gene with a pangenomic scope. Practical applications are constantly expanded. The clinical impact is significant, from the genetic counselling in constitutional to the targeted therapies. Fifty years later, cytogenetics can be defined as the science which aims to detect chromosomal abnormalities, whether constitutional or acquired, using chromosomal or molecular techniques aiming to study the arrangement of genes in chromosomes, to quantify the number of gene copy and to look for the presence of gene fusion.

Nucleic acids offer an ample structural and functional plasticity enabling their industrial production and chemical diversification for therapeutic purposes as well as the establishment in vivo and in vitro of informational processes that did not spontaneously occur during evolution.

Recent genomic studies have led to an inventory of the genes encoding their immune receptors. Some have been submitted to great diversification by duplication in the germline. In some families like LRR and IgSF several species of vertebrates and invertebrates diversify further the receptors by individual somatic processes demanding cellular control and selection that can lead to the genesis of adaptive systems. At all levels many convergences reveal even better than conservations the intensity of pressure exerted on the immune systems to diversify their immunoreceptors in front of the changing environment.