Showing papers by "Jean-Louis Mandel published in 2022"

Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization

Abstract: Background and Objectives Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. Methods A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. Results We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B, EIF2B5, POLR3A, and PLP1, and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. Discussion Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance.

Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

Abstract: Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

AAV‐delivered diacylglycerol kinase DGKk achieves long‐term rescue of fragile X syndrome mouse model

Abstract: Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA‐binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1‐KO mouse model. Here we show that adeno‐associated viral vector delivery of a modified and FMRP‐independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS‐relevant behavioral phenotypes in the Fmr1‐KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.

Neurocognitive and neurobehavioral characterization of two frequent forms of neurodevelopmental disorders: the DYRK1A and the Wiedemann–Steiner syndromes

Abstract: DYRK1A and Wiedemann–Steiner syndromes (WSS) are two genetic conditions associated with neurodevelopmental disorders (NDDs). Although their clinical phenotype has been described, their behavioral phenotype has not systematically been studied using standardized assessment tools. To characterize the latter, we conducted a retrospective study, collecting data on developmental history, autism spectrum disorder (ASD), adaptive functioning, behavioral assessments, and sensory processing of individuals with these syndromes (n = 14;21). In addition, we analyzed information collected from families (n = 20;20) using the GenIDA database, an international patient‐driven data collection aiming to better characterize natural history of genetic forms of NDDs. In the retrospective study, individuals with DYRK1A syndrome showed lower adaptive behavior scores compared to those with WSS, whose scores showed greater heterogeneity. An ASD diagnosis was established for 57% (8/14) of individuals with DYRK1A syndrome and 24% (5/21) of those with WSS. Language and communication were severely impaired in individuals with DYRK1A syndrome, which was also evident from GenIDA data, whereas in WSS patients, exploration of behavioral phenotypes revealed the importance of anxiety symptomatology and ADHD signs, also flagged in GenIDA. This study, describing the behavioral and sensorial profiles of individuals with WSS and DYRK1A syndrome, highlighted some specificities important to be considered for patients' management.

GenIDA: an international participatory database to gain knowledge on health issues related to genetic forms of neurodevelopmental disorders

Abstract: Intellectual disability with or without manifestations of autism and/or epilepsy affects 1-2% of the population, and it is estimated that more than 30-50% of these cases have a single genetic cause. More than 1000 genes and recurrent chromosomal abnormalities are involved in these genetic forms of neurodevelopmental disorders, which often remain insufficiently described in terms of clinical spectrum, associated medical problems, etc., due to their rarity and the often-limited number of patients' phenotypes reported. GenIDA is an international online participatory database that aims to better characterise the clinical manifestations and natural histories of these rare diseases. Clinical information is reported by parents of affected individuals using a structured questionnaire exploring physical parameters, cognitive and behavioural aspects, the presence or absence of neurological disorders or problems affecting major physiological functions, as well as autonomy and quality of life. This strengthens the implication in research of the concerned families. GenIDA aims to construct international cohorts of significant size of individuals affected by a given condition. As of July 2022, GenIDA counts some 1545 documented patient records from over 60 nationalities and collaborates with clinicians and researchers around the world who have access to the anonymized data collected to generate new, medically meaningful information to improve patient care. We present the GenIDA database here, together with an overview of the possibilities it offers to affected individuals, their families, and professionals in charge of the management of genetic forms of neurodevelopmental disorders. Finally, case studies of cohorts will illustrate the usefulness of GenIDA.

The impact of lockdown on young people with genetic neurodevelopmental disabilities: a study with the international participatory database GenIDA

Abstract: Previous publications suggested that lockdown is likely to impact daily living issues of individuals with intellectual disabilities. The authors notably suspected an intensification of behavioural, eating and sleep problems.To test these hypotheses, we conducted an international online survey about the impact of COVID-19-associated first lockdown on people with genetic neurodevelopmental disorders. This survey was carried out using GenIDA, an international participatory database collecting medical information on genetic neurodevelopmental disorders. Patients' relatives took part in this online survey from 30/04/2020 to 09/06/2020. This survey adapted from GenIDA standard questionnaire requested information on diagnosis, lifestyle and was based on yes/no answers to questions regarding behaviour, diet, and sleep, in the 6-months period before lockdown and during lockdown. We also asked relatives to evaluate the intensity of these problems by severity level. Finally, relatives could freely comment in open fields on the medical and/or quality of life problems they had encountered during lockdown.In total 199 participants-144 children and 45 adults-with neurodevelopmental disorders (intellectual disability (79.4%) and/or autism spectrum disorder (21.6%)) of various genetic origins, with near-equal male/female (96/103) contribution and originating mainly from Europe and Northern America, were included. The average lockdown duration at time of the survey was 57 days. We did not find differences in the frequency of behavioural, eating and sleep problems before and during lockdown. Moreover, there was no apparent difference in the intensity of eating and sleep disorders between both periods. However, for persons with behavioural problems at both periods, relatives reported an increase in aggressivity, self-aggressivity, depressiveness, stereotypies, and restricted interests during lockdown, all of which might be interpreted as consequences of a lack of stimulation or a reaction to unexpected changes in daily habits.Our results support previous studies that suggest that the negative impact of lockdown does not depend on the intellectual disability per se but on the associated comorbidities such as behavioural disorders. This study addresses the need for prevention of behavioural disturbance in the vulnerable population with genetic neurodevelopmental disabilities.

Systematic analysis and prediction of genes associated with disorders on chromosome X

Abstract: Disease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using a neural network trained to distin-guish disease-associated from dispensable genes, we classify 235 genes, including 121 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.

Molecular consequences of PQBP1 deficiency, involved in the X-linked Renpenning syndrome

Abstract: Mutations in the PQBP1 gene (polyglutamine-binding protein 1) are responsible for a syndromic X-linked form of intellectual disability (XLID), the Renpenning syndrome. PQBP1 encodes a protein that plays a role in the regulation of gene expression, splicing and mRNA translation. To investigate the consequences of variants in PQBP1, we performed transcriptomic studies in 1) patients’ lymphoblastoid cell lines (LCL) carrying pathogenic variants in PQBP1 and 2) in human neural stem cells (hNSC) knocked-down (KD) for PQBP1. This led to the identification of a hundred dysregulated genes. In particular, we identified an increase in the expression of a non-canonical isoform of another XLID gene, UPF3B. UPF3B plays a crucial role during neurodevelopment by coding for an important actor of the nonsense mRNA mediated decay (NMD) system involved in regulation of protein translation, however, the exact function of the non-canonical isoform,UPF3B_S, is currently unknown. In order to investigate the role of UPF3B_S isoform, we compared the protein interactome of UPF3B_S to the canonical isoform (UPF3B_L). We confirmed that, on the contrary to UPF3B_L, UPF3B_S does not interact with the UPF2/UPF1 complex while it still interacts with exon junction complexes (EJC). However, no notable decrease of NMD pathways was observed in patient’s LCL or in hNSC KD for PQBP1. We identified several additional protein interactors specific to UPF3B_S. Moreover, we used the increase of UPF3B_S mRNA as a molecular marker to test the pathogenicity of variants of unknown clinical significance identified in individuals with ID in PQPB1. We analyzed patients’ LCL mRNA as well as blood mRNA samples and performed complementation studies in HeLa cells by overexpressing Wild-type and mutant PQBP1 cDNA. We showed that all these three approaches were efficient to test the effect of variants, at least for variants affecting the CTD domain of the protein. In conclusion, our study provides information on how PQBP1 deficiency may affect the expression of genes and isoforms, such as UPF3B. This informs about the pathological mechanisms involved in Renpenning syndrome but also allows to propose a functional test for variants of unknown significance identified in PQBP1.