Pharmacological, genetic and expression studies implicate N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia (SCZ). Similarly, several lines of evidence suggest that autism spectrum ...disorders (ASD) could be due to an imbalance between excitatory and inhibitory neurotransmission. As part of a project aimed at exploring rare and/or de novo mutations in neurodevelopmental disorders, we have sequenced the seven genes encoding for NMDA receptor subunits (NMDARs) in a large cohort of individuals affected with SCZ or ASD (n=429 and 428, respectively), parents of these subjects and controls (n=568). Here, we identified two de novo mutations in patients with sporadic SCZ in GRIN2A and one de novo mutation in GRIN2B in a patient with ASD. Truncating mutations in GRIN2C, GRIN3A and GRIN3B were identified in both subjects and controls, but no truncating mutations were found in the GRIN1, GRIN2A, GRIN2B and GRIN2D genes, both in patients and controls, suggesting that these subunits are critical for neurodevelopment. The present results support the hypothesis that rare de novo mutations in GRIN2A or GRIN2B can be associated with cases of sporadic SCZ or ASD, just as it has recently been described for the related neurodevelopmental disease intellectual disability. The influence of genetic variants appears different, depending on NMDAR subunits. Functional compensation could occur to counteract the loss of one allele in GRIN2C and GRIN3 family genes, whereas GRIN1, GRIN2A, GRIN2B and GRIN2D appear instrumental to normal brain development and function.
Autism spectrum disorder (ASD) and schizophrenia (SCZ) are two common neurodevelopmental syndromes that result from the combined effects of environmental and genetic factors. We set out to test the ...hypothesis that rare variants in many different genes, including de novo variants, could predispose to these conditions in a fraction of cases. In addition, for both disorders, males are either more significantly or more severely affected than females, which may be explained in part by X-linked genetic factors. Therefore, we directly sequenced 111 X-linked synaptic genes in individuals with ASD (n = 142; 122 males and 20 females) or SCZ (n = 143; 95 males and 48 females). We identified >200 non-synonymous variants, with an excess of rare damaging variants, which suggest the presence of disease-causing mutations. Truncating mutations in genes encoding the calcium-related protein IL1RAPL1 (already described in Piton et al. Hum Mol Genet 2008) and the monoamine degradation enzyme monoamine oxidase B were found in ASD and SCZ, respectively. Moreover, several promising non-synonymous rare variants were identified in genes encoding proteins involved in regulation of neurite outgrowth and other various synaptic functions (MECP2, TM4SF2/TSPAN7, PPP1R3F, PSMD10, MCF2, SLITRK2, GPRASP2, and OPHN1).
BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 ...mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.
We report a case of spinal cord toxoplasmosis occurring as a primary infection in a 31-year-old immunocompetent man. Exhaustive immunologic and genetic investigations did not identify any ...immunodeficiency. The causative agent was a typical type 2 strain. In cases of spinal cord lesions, toxoplasmosis should be considered, even in an immunocompetent patient.
The control of ceramic green parts dimensions produced by stereolithography is a central concern of the ceramic additive manufacturing industry. The presence of ceramic particles within the ...photopolymerizable system induces UV-laser beam scattering phenomenon, disrupting the polymerization process. This study focuses on the development of a numerical simulation model of the curing process, considering the scattering phenomenon. This paper presents each stages of the development of the numerical simulation model, supported and finally validated by experimentation on a commercial photopolymerizable alumina paste. Firstly, the numerical simulation model is presented. Then, a Greco-Latin square design of experiments is conducted to reduce the number of experiments. Subsequently, material-dependent parameters are identified through simulations and experimental measurements, and a scattering law is proposed. Finally, the simulation model enables to simulate easily and with accuracy the cure widths and the cure depth. It also provides visualization of the exposure distribution and the scattering phenomenon.
Abstract
Study question
What is the relevance to offer panels of infertility genes as a diagnostic tool for infertile patients?
Summary answer
Our results demonstrate the interest of custom designed ...panel to define the genetic etiology of infertile couple in up to 26% of cases.
What is known already
The etiology of infertility is very heterogeneous, and due to the complexity of the reproductive process, standard fertility examinations fail to identify an etiology in 15 to 30% of infertile couples. It is believed that about half of these cases could be explained by a genetic defect. Until recently, routine genetic tests in the field of infertility were restricted to karyotyping, Yq microdeletion, CFTR mutation screening and FMR1 gene screening. The improvement of high throughput sequencing (HTS) technologies has considerably modified the discovery of the genetic causes of diseases allowing the development of new genetic diagnostic tools.
Study design, size, duration
Since 2016, we have set up, within the genetic diagnostic service of the Strasbourg University Hospital (HUS), a gene panel assay of preselected genes for the genetic diagnosis of male and female non-syndromic infertility. Since 2016, reflecting the high level of the research in this field, we have upgraded our panel two times. Initially, our panel included 16 infertility genes, then 51. We are now offering a panel of 133 infertility genes.
Participants/materials, setting, methods
Three different infertility gene panels were used to analyse 205 infertile cases; 62 females and 143 males. Agilent-SureSelectQXT Target Enrichment system was used to prepare libraries from genomic DNA. Sequencing was performed on Illumina NextSeq 550 with 2x150bp reads. Variant analysis was achieved using VaRank tool. One control DNA with known genotype was used in the first run of each design for the quality control. Identity of each patient was confirmed by independent Taqman technology.
Main results and the role of chance
Our first custom designed infertility panel (V1) contained 16 genes; one female and 11 male samples were tested, one positive male sample was identified and resulted in a diagnostic yield of 8.3% (1/12). The second version of the panel (V2), encompassed 51 genes, 22 female and 91 male samples were analysed, allowing a diagnostic yield of 6.1% 7/113; diagnostic rate for female was 9% (2/22), diagnostic rate for male was 5.5% (5/91). The third version of our panel (V3) contains 133 infertility genes and so far the diagnostic yield is 26.3% (21/80). Among 80 samples analysed, 39 of them were female for whom we got a diagnostic rate of 17.9% (7/39) and 41 were male for whom we got a diagnostic rate of 34.1% (14/41). Concerning V2 panel, we analysed 69 azoospermic patients for whom the diagnosis was only based on semen analysis and we identified only 2 pathogenic variants (2.8%, 2/69). For the V3 panel, the analysis of 30 azoospermic samples among which 26 diagnosed via testicular biopsy and pathology report, leaded to a diagnostic yield of 33.3% (10/30). These results underline the importance of well-defined clinical data in the field of genetics of infertility.
Limitations, reasons for caution
The main limitation is the number of patients’ analysed so far. In order to fully challenge the clinical interest of such diagnostic tool, a larger group of patients needs to be analysed.
Wider implications of the findings
The precise molecular diagnostic is important for adapting the best treatment and counsel not only to patients but to their spouse and relatives. This study allows us to decipher the prevalence of mutations in identified genes for a specific infertility phenotype on our cohort of infertile patients.
Trial registration number
not applicable
Stereolithography is a process based on the photopolymerization of a UV-reactive system consisting of ceramic particles dispersion in a curable resin. A key issue of this process is the control of ...the rigidity of green parts, which are strongly related to UV light exposure. This work is focused on the numerical prediction of green part stiffness according to stereolithography manufacturing parameters. A first macroscopic approach, based on the modelling of ceramic suspension polymerization, makes it possible to establish a relationship between the exposure and the Young's modulus. A second microscopic approach, using a periodic homogenization technique based on the strain energy, is applied to a 2D finite element model to evaluate the effective elastic properties. Numerical results show that macroscopic model is able to provide a Young’s modulus with a good level of accuracy. The modelling results from the microscopic model demonstrate an acceptable convergence with the experimental Young’s modulus.
The role of de novo mutations (DNMs) in common diseases remains largely unknown. Nonetheless, the rate of de novo deleterious mutations and the strength of selection against de novo mutations are ...critical to understanding the genetic architecture of a disease. Discovery of high-impact DNMs requires substantial high-resolution interrogation of partial or complete genomes of families via resequencing. We hypothesized that deleterious DNMs may play a role in cases of autism spectrum disorders (ASD) and schizophrenia (SCZ), two etiologically heterogeneous disorders with significantly reduced reproductive fitness. We present a direct measure of the de novo mutation rate (μ) and selective constraints from DNMs estimated from a deep resequencing data set generated from a large cohort of ASD and SCZ cases (n = 285) and population control individuals (n = 285) with available parental DNA. A survey of ∼430 Mb of DNA from 401 synapse-expressed genes across all cases and 25 Mb of DNA in controls found 28 candidate DNMs, 13 of which were cell line artifacts. Our calculated direct neutral mutation rate (1.36 × 10−8) is similar to previous indirect estimates, but we observed a significant excess of potentially deleterious DNMs in ASD and SCZ individuals. Our results emphasize the importance of DNMs as genetic mechanisms in ASD and SCZ and the limitations of using DNA from archived cell lines to identify functional variants.
Les troubles schizophréniques (SCZ) ont une forte héritabilité, de l’ordre de 80%, mais, une très faible part du risque génétique a été identifiée. La plupart des études ont considéré l’implication ...de polymorphismes fréquents, chacun ayant un effet relativement faible individuellement, alors que les études de variants du nombre de copies (CNVs) ainsi que les études d’anomalies chromosomiques ont pointé l’implication possible de variants rares et de novo à une forte pénétrance. ;
Dans une première partie, nous présentons une synthèse sur les facteurs génétiques dans la SCZ, puis une revue des arguments en faveur de l’implication d’anomalies du système glutamatergique dans la SCZ, domaine sur lequel s’est centré notre travail.;
Notre travail s’inscrit dans un projet plus vaste, Synapse to Disease (S2D) ayant pour objectif de séquencer 1000 gènes synaptiques dans des cohortes de patients atteints de schizophrénie ou de troubles du spectre autistique. Nous avons exploré en particulier le système glutamatergique et les récepteurs NMDA. Dans un premier article, nous montrons une association d’une mutation troncante de novo de la kinésine 17, impliquée dans le transport de la sous-unité GRIN2B des récepteurs NMDA. Dans un second article, nous explorons les mutations rares et de novo dans les sous-unités des récepteurs NMDA et montrons l’association de mutation de novo dans GRIN2A et GRIN2B avec des cas de SCZ et d’autisme. Nos résultats renforcent l’idée qu’une part des cas de schizophrénie pourrait être due à l’implication de mutations rare à effet majeur, hypothèse alternative mais non exclusive à l’hypothèse d’interactions entre variants génétiques fréquents à effet mineur.
Schizophrenic disorders (SCZ) have high heritability (around 80%), but only a small part has been characterized. Most studies have focussed on common polymorphisms, each having small individual effect, whereas copy number variant and chromosomal abnormalities studies have pointed to the possible involvement of rare and de novo mutations with high penetrance.;
In the first part of this manuscript, we will present a synthesis on genetic factors of SCZ and then a review of the arguments supporting an involvement of glutamatergic system abnormalities in SCZ, which is the focus of our research.;
Our work is part of a global project, Synapse to Disease (S2D), that aimed to sequence 1000 synaptic genes in cohort of patients affected with schizophrenia or autism spectrum disorders. We focussed in particular on the glutamatergic system and NMDA receptors. In a first publication we show an association between SCZ and a de novo truncating mutation of kinesin 17, wich has been implicated in the transport of the GRIN2B subunit of NMDA receptors. In a second publication we explore rare and de novo mutations in NMDA receptor subunits. We show an association between de novo mutations in GRIN2A and GRIN2B with cases of SCZ and autism. Our results strengthen the idea that a portion of schizophrenia cases could be related to rare mutations having a high penetrance, an alternative but not contradictory explanation to the hypothesis for an interaction between common variants having a small effect.
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