Evaluation of an Updated Gene Panel as a Diagnostic Tool for Both Male and Female Infertility.

In recent years, an increasing number of genes associated with male and female infertility have been identified. The genetics of infertility is no longer limited to the analysis of karyotypes or specific genes, and it is now possible to analyse several dozen infertility genes simultaneously. Here, we present the diagnostic activity over the past two years including 140 patients (63 women and 77 men). Targeted sequencing revealed causative variants in 17 patients, representing an overall diagnostic rate of 12.1%, with prevalence rates in females and males of 11% and 13%, respectively. The gene-disease relationship (GDR) was re-evaluated for genes due to the addition of new patients and/or variants in the actual study. Five genes changed categories: two female genes (MEIOB and TBPL2) moved from limited to moderate; two male genes (SOHLH1 and GALNTL5) moved from no evidence to strong and from limited to moderate; and SEPTIN12, which was unable to classify male infertility, was reclassified as limited. Many infertility genes have yet to be identified. With the increasing integration of genetics in reproductive medicine, the scope of intervention extends to include other family members, in addition to individual patients or couples. Genetic counselling consultations and appropriate staffing will need to be established in fertility centres. Trial registration number: Not applicable.

Parental stress and mental health outcomes following very preterm birth: A systematic review of recent findings.

BACKGROUND: In recent years, there has been a wide array of research studies published on parental mental health and stress following very preterm birth. This review aims at reviewing the prevalence and risk factors of long-term parental depression, anxiety, post-traumatic stress symptoms and parenting stress following very preterm birth. METHODS: We searched PubMed, PsychINFO and Web of Science for descriptive, cross-sectional and longitudinal studies published between January 2013 and August 2022. RESULTS: 45 studies met our inclusion criteria. In the first two years, depression, anxiety, post-traumatic stress symptoms and parenting stress were present in ∼20 % of mothers of extreme and very low birth weight (E/VLBW) infants. Long-term psychological distress symptoms could be observed, although few studies have focused on symptoms into school age and longer. Fathers of VLBW infants might experience more psychological distress as well, however, they were only included in ten studies. We found that parental distress is more common when the co-parent is struggling with mental health symptoms. Many risk factors were identified such as social risk, history of mental illness, interpersonal factors (i.e. social support) and child-related factors (i.e. intraventricular hemorrhage, disability, use of medical equipment at home). LIMITATIONS: Several studies have methodological issues, such as a lack of control of known confounders and there is a large variety of measures employed. CONCLUSION: Important risk factors for stress and mental health symptoms were identified. More evidence is needed to determine if long-term symptoms persist into school age. Research should focus on taking a family-based approach in order to identify preventive strategies and resilience factors in parents of VLBW infants.

Screening preterm-born infants for autistic traits may help to identify social communication difficulties at five years of age.

AIM: This study compared neurodevelopmental screening questionnaires completed when preterm-born children reached 2 years of corrected age with social communication skills at 5.5 years of age. METHODS: Eligible subjects were born in 2011 at 24-34 weeks of gestation, participated in a French population-based epidemiological study and were free of motor and sensory impairment at 2 years of corrected age. The Ages and Stages Questionnaire (ASQ) and the Modified Checklist for Autism in Toddlers (M-CHAT) were used at 2 years and the Social Communication Questionnaire (SCQ) at 5.5 years of age. RESULTS: We focused on 2119 children. At 2 years of corrected age, the M-CHAT showed autistic traits in 20.7%, 18.5% and 18.2% of the children born at 24-26, 27-31 and 32-34 weeks of gestation, respectively (p = 0.7). At 5.5 years of age, 12.6%, 12.7% and 9.6% risked social communication difficulties, with an SCQ score ≥90th percentile (p = 0.2). A positive M-CHAT score at 2 years was associated with higher risks of social communication difficulties at 5.5 years of age (odds ratio 3.46, 95% confidence interval 2.04-5.86, p < 0.001). Stratifying ASQ scores produced similar results. CONCLUSION: Using parental neurodevelopmental screening questionnaires for preterm-born children helped to identify the risk of later social communication difficulties.

[Neurodevelopment and neuroprotection in young children]. / Le neurodéveloppement et la neuroprotection du jeune enfant.

In France, the most pessimistic estimates put the prevalence of neurodevelopmental disorders (NDD) at 15 % of births. The two largest populations of newborns at highest risk of NDD are premature babies and babies born into siblings with one or more infants who already have an autism spectrum disorder or another NDD. The high prevalence of these disorders justifies a health promotion policy, centred on the child and his or her family. Prevention is based on the early identification of high-risk factors, by informing families and training pregnancy and early childhood professionals, and implementing perinatal prevention protocols for high-risk newborns (antenatal corticosteroid therapy and magnesium sulfate for women at risk of preterm delivery before 32 weeks, developmental care, therapeutic hypothermia for full-term infants with early neonatal encephalopathy presumed to be anoxic). Preventing the severity of NDD depends on their early identification, as early as possible in the highest plastic "1000 days" developmental window, a smooth flow of diagnosis and care for mothers and children, and the establishment of an ecosystem that includes multi-modal early intervention, at the best in multi-disciplinary teams such as the early medical and social action centres, support for families through guidance programs and inclusion in the community, first in day-care centers and then in nursery schools.

Methanediol from cloud-processed formaldehyde is only a minor source of atmospheric formic acid.

Atmospheric formic acid is severely underpredicted by models. A recent study proposed that this discrepancy can be resolved by abundant formic acid production from the reaction (1) between hydroxyl radical and methanediol derived from in-cloud formaldehyde processing and provided a chamber-experiment-derived rate constant, k1 = 7.5 × 10-12 cm3 s-1. High-level accuracy coupled cluster calculations in combination with E,J-resolved two-dimensional master equation analyses yield k1 = (2.4 ± 0.5) × 10-12 cm3 s-1 for relevant atmospheric conditions (T = 260-310 K and P = 0-1 atm). We attribute this significant discrepancy to HCOOH formation from other molecules in the chamber experiments. More importantly, we show that reversible aqueous processes result indirectly in the equilibration on a 10 min. time scale of the gas-phase reaction [Formula: see text] (2) with a HOCH2OH to HCHO ratio of only ca. 2%. Although HOCH2OH outgassing upon cloud evaporation typically increases this ratio by a factor of 1.5-5, as determined by numerical simulations, its in-cloud reprocessing is shown using a global model to strongly limit the gas-phase sink and the resulting production of formic acid. Based on the combined findings in this work, we derive a range of 1.2-8.5 Tg/y for the global HCOOH production from cloud-derived HOCH2OH reacting with OH. The best estimate, 3.3 Tg/y, is about 30 times less than recently reported. The theoretical equilibrium constant Keq (2) determined in this work also allows us to estimate the Henry's law constant of methanediol (8.1 × 105 M atm-1 at 280 K).

Assessing of executive functions in daily life in preterm children aged 3-4 years old from the "Behavior Rating Inventory of Executive Function-Preschool version" questionnaire.

Background: Executive functions (EFs) are a set of neuropsychological skills permitting solving problems in a new situation by regulating action, behavior, and emotional response. As cerebral maturation remains vulnerable in preterm children, a higher risk of developing cognitive disorders including EFs exist compared to term children. Aims: The aim of this study was to estimate the incidence of preschool EF impairments through proxy reports in children born preterm before 34 weeks of gestational age using the Behavior Rating Inventory of Executive Function-Preschool (BRIEF-P) version. Secondary aims were to report neonatal, child, or socioeconomic factors associated with EF disorders. Results: Parents of 357 children born preterm aged 3-4 years old completed the BRIEF-P version. Impairment in EFs was clinically significant for 13.5% of preterm children (n = 47; 95% CI = 0.10-0.18) compared to 5.1% in term children. A low parental socioeconomic level was significantly associated with impaired parent-rated EF (19.1% vs. 5.3%, p = 0.003). Conclusions: Proxy reports of EF impairment are about twice as frequent as in term children. EF difficulties are not related to neonatal or child severity factors in contrast with the parental socioeconomic level. Using a parent-rated questionnaire may be a useful and easy tool to identify early the daily life impact of EF disorders on clinical follow-up of preterm children.This study was recorded in the Clinical Trials Register under identifier NCT03700463.

Assisted reproductive techniques do not impact late neurodevelopmental outcomes of preterm children.

Objective: Assisted reproductive technology (ART) increases the rate of preterm births, though few studies have analyzed outcomes for these infants. No data are available on 4-year-old children born prematurely after ART. The objective was to investigate whether ART affect the neurodevelopmental outcomes at 4 years in preterm infants born before 34 weeks of gestational age (GA). Methods and results: A total of 166 ART and 679 naturally conceived preterm infants born before 34 weeks GA between 2013 and 2015 enrolled in the Loire Infant Follow-up Team were included. Neurodevelopment was assessed at 4 years using the age and stage questionnaire (ASQ) and the need for therapy services. The association between the socio-economic and perinatal characteristics and non-optimal neurodevelopment at 4 years was estimated. After adjustment, the ART preterm group remained significantly associated with a lower risk of having at least two domains in difficulty at ASQ: adjusted odds ratio (aOR) 0.34, 95% confidence interval (CI) (0.13-0.88), p = 0.027. The factors independently associated with non-optimal neurodevelopment at 4 years were male gender, low socio-economic level, and 25-30 weeks of GA at birth. The need for therapy services was similar between groups (p = 0.079). The long-term neurodevelopmental outcomes of preterm children born after ART are very similar, or even better than that of the spontaneously conceived children.

Assessing Behavioral Disorders with SDQ in Very Preterm Children at 5 Years of Age in LIFT Cohort.

BACKGROUND: Preterm-born children are at risk of behavioral disorders and the systematic assessment of these disorders remains a challenge. Questions remain about the accuracy of self-reported parent questionnaires and the real everyday life behavior of the child. AIM: To evaluate the association between SDQ reported by parents in the preterm and behavioral difficulties in the everyday school life environment reported by teacher. METHODS: All children born before 33 weeks and who followed-up in the LIFT (Loire Infant Follow-up team) network were included. The Strengths and Difficulties Parental Questionnaire (SDQ), completed at 5 years, was used to check for behavioral difficulties and identified three groups: "normal", "borderline" and "abnormal". Then, the SDQ results were compared to the Global School Adaptation Score (GSA) at 5 years. RESULTS: Out of the 1825 children followed in the cohort at the age of 5, 1397 questionnaires were analyzed. A total of 11.1% of children had an abnormal score, and 9.7% had a borderline score. Male gender and a lower birth weight z-score were significantly associated with the "abnormal SDQ" group. There is a significant relationship between the probability of being in the "abnormal SDQ" group at 5 years and with difficulty in global school adaptation at 5 years, as well as an SDQ borderline score in the preterm (p < 0.001). CONCLUSIONS: SDQ abnormal and borderline scores are associated with behavioral difficulties in the classroom and everyday life behavior. In preterm children, one should be alerted even by a borderline SDQ score.

From ecological functions to ecosystem services: linking coastal lagoons biodiversity with human well-being.

In this review we highlight the relevance of biodiversity that inhabit coastal lagoons, emphasizing how species functions foster processes and services associated with this ecosystem. We identified 26 ecosystem services underpinned by ecological functions performed by bacteria and other microbial organisms, zooplankton, polychaetae worms, mollusks, macro-crustaceans, fishes, birds, and aquatic mammals. These groups present high functional redundancy but perform complementary functions that result in distinct ecosystem processes. Because coastal lagoons are located in the interface between freshwater, marine and terrestrial ecosystems, the ecosystem services provided by the biodiversity surpass the lagoon itself and benefit society in a wider spatial and historical context. The species loss in coastal lagoons due to multiple human-driven impacts affects the ecosystem functioning, influencing negatively the provision of all categories of services (i.e., supporting, regulating, provisioning and cultural). Because animals' assemblages have unequal spatial and temporal distribution in coastal lagoons, it is necessary to adopt ecosystem-level management plans to protect habitat heterogeneity and its biodiversity, ensuring the provision of services for human well-being to multi-actors in the coastal zone.

WGS Revealed Novel BBS5 Pathogenic Variants, Missed by WES, Causing Ciliary Structure and Function Defects.

Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy that affects multiple organs, leading to retinitis pigmentosa, polydactyly, obesity, renal anomalies, cognitive impairment, and hypogonadism. Until now, biallelic pathogenic variants have been identified in at least 24 genes delineating the genetic heterogeneity of BBS. Among those, BBS5 is a minor contributor to the mutation load and is one of the eight subunits forming the BBSome, a protein complex implied in protein trafficking within the cilia. This study reports on a European BBS5 patient with a severe BBS phenotype. Genetic analysis was performed using multiple next-generation sequencing (NGS) tests (targeted exome, TES and whole exome, WES), and biallelic pathogenic variants could only be identified using whole-genome sequencing (WGS), including a previously missed large deletion of the first exons. Despite the absence of family samples, the biallelic status of the variants was confirmed. The BBS5 protein's impact was confirmed on the patient's cells (presence/absence and size of the cilium) and ciliary function (Sonic Hedgehog pathway). This study highlights the importance of WGS and the challenge of reliable structural variant detection in patients' genetic explorations as well as functional tests to assess a variant's pathogenicity.

Clinical utility of periodic reinterpretation of CNVs of uncertain significance: an 8-year retrospective study.

BACKGROUND: Array-CGH is the first-tier genetic test both in pre- and postnatal developmental disorders worldwide. Variants of uncertain significance (VUS) represent around 10~15% of reported copy number variants (CNVs). Even though VUS reanalysis has become usual in practice, no long-term study regarding CNV reinterpretation has been reported. METHODS: This retrospective study examined 1641 CGH arrays performed over 8 years (2010-2017) to demonstrate the contribution of periodically re-analyzing CNVs of uncertain significance. CNVs were classified using AnnotSV on the one hand and manually curated on the other hand. The classification was based on the 2020 American College of Medical Genetics (ACMG) criteria. RESULTS: Of the 1641 array-CGH analyzed, 259 (15.7%) showed at least one CNV initially reported as of uncertain significance. After reinterpretation, 106 of the 259 patients (40.9%) changed categories, and 12 of 259 (4.6%) had a VUS reclassified to likely pathogenic or pathogenic. Six were predisposing factors for neurodevelopmental disorder/autism spectrum disorder (ASD). CNV type (gain or loss) does not seem to impact the reclassification rate, unlike the length of the CNV: 75% of CNVs downgraded to benign or likely benign are less than 500 kb in size. CONCLUSIONS: This study's high rate of reinterpretation suggests that CNV interpretation has rapidly evolved since 2010, thanks to the continuous enrichment of available databases. The reinterpreted CNV explained the phenotype for ten patients, leading to optimal genetic counseling. These findings suggest that CNVs should be reinterpreted at least every 2 years.

The AnnotSV webserver in 2023: updated visualization and ranking.

Much of the human genetics variant repertoire is composed of single nucleotide variants (SNV) and small insertion/deletions (indel) but structural variants (SV) remain a major part of our modified DNA. SV detection has often been a complex question to answer either because of the necessity to use different technologies (array CGH, SNP array, Karyotype, Optical Genome Mapping…) to detect each category of SV or to get an appropriate resolution (Whole Genome Sequencing). Thanks to the deluge of pangenomic analysis, Human geneticists are accumulating SV and their interpretation remains time consuming and challenging. The AnnotSV webserver (https://www.lbgi.fr/AnnotSV/) aims at being an efficient tool to (i) annotate and interpret SV potential pathogenicity in the context of human diseases, (ii) recognize potential false positive variants from all the SV identified and (iii) visualize the patient variants repertoire. The most recent developments in the AnnotSV webserver are: (i) updated annotations sources and ranking, (ii) three novel output formats to allow diverse utilization (analysis, pipelines), as well as (iii) two novel user interfaces including an interactive circos view.

Contamination of tea leaves by anthraquinone: The atmosphere as a possible source.

The detection of anthraquinone in tea leaves has raised concerns due to a potential health risk associated with this species. This led the European Union to impose a maximum residue limit (MRL) of 0.02 mg/kg for anthraquinone in dried tea leaves. As atmospheric contamination has been identified as one of the possible sources of anthraquinone residue, this study investigates the contamination resulting from the deposition of atmospheric anthraquinone using a global chemical transport model that accounts for the emission, atmospheric transport, chemical transformation, and deposition of anthraquinone on the surface. The largest contribution to the global atmospheric budget of anthraquinone is from residential combustion followed by the secondary formation from oxidation of anthracene. Simulations suggest that atmospheric anthraquinone deposition could be a substantial source of the anthraquinone found on tea leaves in several tea-producing regions, especially near highly industrialized and populated areas of southern and eastern Asia. The high level of anthraquinone deposition in these areas may result in residues in tea products exceeding the EU MRL. Additional contamination could also result from local tea production operations.

A biallelic loss of function variant in HORMAD1 within a large consanguineous Turkish family is associated with spermatogenic arrest.

STUDY QUESTION: Can the analysis of a large Turkish consanguineous family via whole exome sequencing (WES) identify novel causative genetic variation responsible for nonobstructive azoospermia (NOA) characterized by arrest at primary spermatocyte stage? SUMMARY ANSWER: WES analysis revealed a homozygous nonsense variant in HORMAD1 in three affected brothers of a Turkish family. WHAT IS KNOWN ALREADY: Studying patient cohorts in small or large consanguineous families using high-throughput sequencing allows the identification of genetic causes of different pathologies, including infertility. Over the last two decades, a number of genes involved in human male infertility have been discovered, but only 14 genes have been identified as being at least moderately linked to isolated NOA or oligozoospermia in men. STUDY DESIGN, SIZE, DURATION: The study included a Turkish family comprising three brothers with NOA. Two brothers had a normal karyotype, normal hormonal levels and no Yq microdeletion. The testicular histopathology analysis revealed the complete arrest of spermatogenesis at the primary spermatocyte stage. PARTICIPANTS/MATERIALS, SETTING, METHODS: We recruited a consanguineous Turkish family where parents were first-degree cousins and had seven children; three sons who had NOA, two sons who were fertile and two daughters for whom no information was available. Saliva samples from the index patient, his two affected brothers, parents and two nonaffected brothers (seven samples in total) were collected. Prior to WES, the index patient underwent targeted genetic testing using an infertility panel, which includes 133 infertility genes. No pathogenic variations were identified. WES was then performed on the DNA of the seven family members available. Bioinformatics analysis was performed using an in-house pipeline. Detected variants were scored and ranked, and copy number variants were called and annotated.The consequences of mutation on protein expression and localization were investigated by cell transfection followed by immunofluorescence or immunoblotting. MAIN RESULTS AND THE ROLE OF CHANCE: WES revealed a homozygous nonsense variant chr1:150675797G>A; HORMAD1 (NM_032132.5): c.1021C>T, p.Gln341* in exon 13, which was confirmed in all three affected brothers. HORMAD1 encodes the HORMA domain-containing protein 1. The parents as well as the two fertile brothers were carriers of this variant. This variant may lead to the production of a truncated protein lacking the nuclear localization signal; therefore, human cells were transfected with the wild-type and mutated form, in fusion with green fluorescent protein. Immunoblotting experiments confirmed the production of a truncated HORMAD1 protein, and immunofluorescence microscopy revealed that the mutated protein displayed cytoplasmic localization while the wild type protein located to the nucleus. Altogether, our findings validate HORMAD1 as an essential genetic factor in the meiotic process in human. LIMITATIONS, REASONS FOR CAUTION: According to one scoring system used to evaluate the clinical validity of male infertility genes, this study would classify HORMAD1 as displaying limited clinical evidence of being involved in male infertility. However, such a score is the maximum possible when only one family is analyzed and the addition of one patient showing a pathogenic or likely pathogenic variant would immediately change this classification to 'moderate'. Thus, this report should prompt other researchers to screen patients with NOA for this genetic variant. WIDER IMPLICATIONS OF THE FINDINGS: Identification of new genetic factors involved in the human meiosis process will contribute to an improvement of our knowledge at the basic level, which in turn will allow the management of better care for infertile patients. Since Hormad1-/- knock-out female mice are also infertile, HORMAD1 could also be involved in human female infertility. Our findings have direct implications for the genetic counseling of patients and their family members. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by Fondation Maladies Rares (High Throughput Sequencing and Rare Diseases-2018, 'GenOmics of rare diseases'). The authors declare that they have no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Euphol from Tapinanthus sp. Induces Apoptosis and Affects Signaling Proteins in Glioblastoma and Prostate Cancer Cells

BACKGROUND: Plants play an important role in cancer therapy. They are source of natural molecules which can induce apoptosis in cancer cells by affecting molecular mechanisms implicated in cancer progression. The MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways are two classical signaling pathways implicated in cancer progression and constitute therapeutic targets against cancer. This study aimed to evaluate the effect of euphol on MAP Kinase/ERK1/2 and PI3K/AKT signaling pathways in glioblastoma and prostate cancer cells. Euphol is a tetracyclique triterpene alcohol isolated from Tapinanthus sp. which is a hemi parasitic plant belonging to Loranthaceae family. METHODS: Plant powder was extracted by maceration and euphol was isolated and described using respectively column chromatography separation on silica gel and spectroscopic data. Cytotoxic effect of euphol was evaluated using XTT assay and its effect on MAP Kinase/ERK1/2 and PI3K/AKT protein expression was investigated by Western immunoblot analysis. Apotosis was analyzed by evaluating caspase-3/7 activity. RESULTS: Our investigations demonstrated that this compound has an important cytotoxic effect on C6 and U87 MG glioblastoma (GBM) cells and PC-3 prostate cancer cells. Furthermore, euphol-induced apoptosis revealed by elevated caspase 3/7 activity, was correlated with a significant inhibition of MAP kinase/Erk 1/2 and PI3K/Akt signaling pathway in glioblastoma U87 MG cells. The reverse effect was observed in C6 glioblastoma cells, where apoptosis was correlated with a long-lasting activation of Erk 1/2.  In PC-3 cells, euphol had no or limited effect on Erk 1/2 and Akt activity. CONCLUSION: These results indicate that euphol induces cell death in glioblastoma and prostate cancer cells and regulates significantly Erk1/2 and Akt activity in glioblastoma cells.

Spray-Deposited Anisotropic Assemblies of Plasmonic Nanowires for Direction-Sensitive Strain Measurement.

The development of nanoscale composites with hierarchical architecture and complex anisotropies enables the fabrication of new classes of devices. Stretchable strain sensors have been developed in the past for applications in various fields such as wearable electronics and soft robotics, yet the sensing capacities of most of these sensors are independent of the direction of deformation. In the present work, we report on the preparation of a direction-sensitive strain sensor using the anisotropic optical properties of a monolayer of oriented plasmonic 1D nano-objects. Grazing incidence spraying (GIS) is used for depositing a monolayer of in-plane aligned silver nanowires with a controlled density on a deformable and transparent substrate. Using the selective excitation of transverse and longitudinal localized plasmon resonance modes of silver nanowires by polarized UV-visible-NIR spectroscopy, we show that the macroscopic anisotropic properties of the monolayer upon stretching are highly dependent on the stretching direction and light polarization. Measuring the polarized optical properties of the anisotropic thin films upon stretching thus allow for retrieving both the local strain and the direction of the deformation using a simple model.

A correlation between Magnetic Resonance Spectroscopy (1-H MRS) and the neurodevelopment of two-year-olds born preterm in an EPIRMEX cohort study.

Background: Preterm infants are at risk of neurodevelopmental impairments. At present, proton magnetic resonance spectroscopy (1H-MRS) is currently used to evaluate brain metabolites in asphyxiated term infants. The purpose of this study was to identify in the preterm EPIRMEX cohort any correlations between (1H-MRS) metabolites ratio at term equivalent age (TEA) and neurodevelopmental outcomes at 2 years. Methods: Our study included EPIRMEX eligible patients who were very preterm infants (gestational age at birth ≤32 weeks) and who underwent a brain MRI at TEA and 1H-MRS using a monovoxel technique. The volumes of interest (VOI) were periventricular white matter posterior area and basal ganglia. The ratio of N Acetyl Aspartate (NAA) to Cho (Choline), NAA to Cr (creatine), Cho to Cr, and Lac (Lactate) to Cr were measured. Neurodevelopment was assessed at 24 months TEA with ASQ (Ages and Stages Questionnaire). Results: A total of 69 very preterm infants had a 1H-MRS at TEA. In white matter there was a significant correlation between a reduction in the NAA/Cho ratio and a total ASQ and/or abnormal communication score, and an increase in the Lac/Cr ratio and an abnormality of fine motor skills. In the gray nuclei there was a trend correlation between the reduction in the NAA/Cho ratio and sociability disorders; and the increase in the Lac/Cr ratio and an anomaly in problem-solving. Conclusions: Using NAA as a biomarker, the vulnerability of immature oligodendrocytes in preterm children at TEA was correlated to neurodevelopment at 2 years. Similarly, the presence of lactate at TEA was associated with abnormal neurodevelopment at 2 years in the preterm brain.

A Prospective Observational Study to Assess Attachment Representations With Regard to Neurocognitive and Behavioral Outcomes in Children Born Very Prematurely in the Loire Infant Follow-Up Team (LIFT Cohort).

Context and purpose: Prematurity is a situation that can disrupt parent-child interactions. We hypothesize that establishing relationships with parents in a context of extreme prematurity can alter the development of secure attachment representations in the child. Furthermore, we hypothesize that secure maternal representations and their possible interactions with prematurity factors prevent the development of insecure or disorganized attachment in the child. In addition, maternal representations and their possible interactions with factors related to prematurity may prevent or accentuate the development of an insecure or disorganized attachment in the child. Methods and analysis: This is a longitudinal, prospective, exploratory, and bi-centric study. Children born in the neonatal intensive care units of Angers or Nantes University Hospitals with a gestational age of up to 28 weeks will be included in the study. The main objective is to describe the attachment representations at 3 and 5 years through the Attachment Story Completion Task scales and to analyze them in regard to the children's neurocognitive and behavioral outcomes as well as maternal attachment and mental health. Ethics: The study file received a favorable opinion for the implementation of this research on February 18, 2020 - ID-RCB no. 2019-A03352-55 (File 2-20-007 id6699) 2°HPS. This study has received authorization from the French Data Protection Authority (CNIL) under no. 920229. Discussion: A better understanding of attachment representations in extreme prematurity and their possible associations with children's neurocognitive and behavioral outcomes as well as maternal attachment and mental health could pave the way for individualized care at an early stage, or even interventions during the neonatal period to improve the outcome of these vulnerable newborns. Trial registration: [ClinicalTrials.gov], identifier [NCT04304846].

SLITRK2 variants associated with neurodevelopmental disorders impair excitatory synaptic function and cognition in mice.

SLITRK2 is a single-pass transmembrane protein expressed at postsynaptic neurons that regulates neurite outgrowth and excitatory synapse maintenance. In the present study, we report on rare variants (one nonsense and six missense variants) in SLITRK2 on the X chromosome identified by exome sequencing in individuals with neurodevelopmental disorders. Functional studies showed that some variants displayed impaired membrane transport and impaired excitatory synapse-promoting effects. Strikingly, these variations abolished the ability of SLITRK2 wild-type to reduce the levels of the receptor tyrosine kinase TrkB in neurons. Moreover, Slitrk2 conditional knockout mice exhibited impaired long-term memory and abnormal gait, recapitulating a subset of clinical features of patients with SLITRK2 variants. Furthermore, impaired excitatory synapse maintenance induced by hippocampal CA1-specific cKO of Slitrk2 caused abnormalities in spatial reference memory. Collectively, these data suggest that SLITRK2 is involved in X-linked neurodevelopmental disorders that are caused by perturbation of diverse facets of SLITRK2 function.

The Economic, Medical and Psychosocial Consequences of Whole Genome Sequencing for the Genetic Diagnosis of Patients With Intellectual Disability: The DEFIDIAG Study Protocol.

Introduction: Like other countries, France has invested in a national medical genomics program. Among the four pilot research studies, the DEFIDIAG project focuses on the use of whole genome sequencing (WGS) for patients with intellectual disability (ID), a neurodevelopmental condition affecting 1-3% of the general population but due to a plethora of genes. However, the access to genomic analyses has many potential individual and societal issues in addition to the technical challenges. In order to help decision-makers optimally introduce genomic testing in France, there is a need to identify the socio-economic obstacles and leverages associated with the implementation of WGS. Methods and Analysis: This humanities and social sciences analysis is part of the DEFIDIAG study. The main goal of DEFIDIAG is to compare the percentage of causal genetic diagnoses obtained by trio WGS (including the patient and both parents) (WGST) to the percentage obtained using the minimal reference strategy currently used in France (Fragile-X testing, chromosomal microarray analysis, and gene panel strategy including 44 ID genes) for patients with ID having their first clinical genetics consultation. Additionally, four complementary studies will be conducted. First, a cost-effectiveness analysis will be undertaken in a subsample of 196 patients consulting for the first time for a genetic evaluation; in a blinded fashion, WGST and solo (index case, only) genomic analysis (WGSS) will be compared to the reference strategy. In addition, quantitative studies will be conducted: the first will estimate the cost of the diagnostic odyssey that could potentially be avoidable with first-line WGST in all patients previously investigated in the DEFIDIAG study; the second will estimate changes in follow-up of the patients in the year after the return of the WGST analysis compared to the period before inclusion. Finally, through semi-directive interviews, we will explore the expectations of 60 parents regarding genomic analyses. Discussion: Humanities and social sciences studies can be used to demonstrate the efficiency of WGS and assess the value that families associate with sequencing. These studies are thus expected to clarify trade-offs and to help optimize the implementation of genomic sequencing in France. Ethics Statement: The protocol was approved by the Ethics Committee Sud Méditerranée I (June 2019)-identification number: 2018-A00680-55 and the French data privacy commission (CNIL, authorization 919361). Clinical Trial Registration: (ClinicalTrials.gov), identifier (NCT04154891).