Publications by authors named "Richard Redon"

96 Publications

Targeting the Microtubule EB1-CLASP2 Complex Modulates Na1.5 at Intercalated Discs.

Circ Res 2021 Jun 7. Epub 2021 Jun 7.

Clinical and Experimental Cardiology, Amsterdam UMC, NETHERLANDS.

Loss-of-function of the cardiac sodium channel Na1.5 causes conduction slowing and arrhythmias. Na1.5 is differentially distributed within subcellular domains of cardiomyocytes, with sodium current (I) being enriched at the intercalated discs (ID). Various pathophysiological conditions associated with lethal arrhythmias display ID-specific I reduction, but the mechanisms underlying microdomain-specific targeting of Na1.5 remain largely unknown. To investigate the role of the microtubule (MT) plus-end tracking proteins end binding protein 1 (EB1) and CLIP-associated protein 2 (CLASP2) in mediating Na1.5 trafficking and subcellular distribution in cardiomyocytes. EB1 overexpression in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) resulted in enhanced whole-cell I, increased action potential (AP) upstroke velocity (V), and enhanced Na1.5 localization at the plasma membrane as detected by multi-color stochastic optical reconstruction microscopy (STORM). Fluorescence recovery after photobleaching (FRAP) experiments in HEK293A cells demonstrated that EB1 overexpression promoted Na1.5 forward trafficking. Knockout of MAPRE1 in hiPSC-CMs led to reduced whole-cell I, decreased V and AP duration (APD) prolongation. Similarly, acute knockout of the MAPRE1 homolog in zebrafish (mapre1b) resulted in decreased ventricular conduction velocity and V as well as increased APD. STORM imaging and macropatch I measurements showed that subacute treatment (2-3 hours) with SB216763 (SB2), a GSK3β inhibitor known to modulate CLASP2-EB1 interaction, reduced GSK3β localization and increased Na1.5 and I preferentially at the ID region of wild type murine ventricular cardiomyocytes. By contrast, SB2 did not affect whole cell I or Na1.5 localization in cardiomyocytes from Clasp2-deficient mice, uncovering the crucial role of CLASP2 in SB2-mediated modulation of NaV1.5 at the ID. Our findings demonstrate the modulatory effect of the MT plus-end tracking protein EB1 on Na1.5 trafficking and function, and identify the EB1-CLASP2 complex as a target for preferential modulation of I within the ID region of cardiomyocytes.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.318643DOI Listing
June 2021

Missense variants in DPYSL5 cause a neurodevelopmental disorder with corpus callosum agenesis and cerebellar abnormalities.

Am J Hum Genet 2021 May 23;108(5):951-961. Epub 2021 Apr 23.

Service de Génétique, Centre Hospitalier Universitaire, 86021 Poitiers, France; Equipe d'Accueil 3808, Université de Poitiers, 86034 Poitiers, France.

The collapsin response mediator protein (CRMP) family proteins are intracellular mediators of neurotrophic factors regulating neurite structure/spine formation and are essential for dendrite patterning and directional axonal pathfinding during brain developmental processes. Among this family, CRMP5/DPYSL5 plays a significant role in neuronal migration, axonal guidance, dendrite outgrowth, and synapse formation by interacting with microtubules. Here, we report the identification of missense mutations in DPYSL5 in nine individuals with brain malformations, including corpus callosum agenesis and/or posterior fossa abnormalities, associated with variable degrees of intellectual disability. A recurrent de novo p.Glu41Lys variant was found in eight unrelated patients, and a p.Gly47Arg variant was identified in one individual from the first family reported with Ritscher-Schinzel syndrome. Functional analyses of the two missense mutations revealed impaired dendritic outgrowth processes in young developing hippocampal primary neuronal cultures. We further demonstrated that these mutations, both located in the same loop on the surface of DPYSL5 monomers and oligomers, reduced the interaction of DPYSL5 with neuronal cytoskeleton-associated proteins MAP2 and βIII-tubulin. Our findings collectively indicate that the p.Glu41Lys and p.Gly47Arg variants impair DPYSL5 function on dendritic outgrowth regulation by preventing the formation of the ternary complex with MAP2 and βIII-tubulin, ultimately leading to abnormal brain development. This study adds DPYSL5 to the list of genes implicated in brain malformation and in neurodevelopmental disorders.
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http://dx.doi.org/10.1016/j.ajhg.2021.04.004DOI Listing
May 2021

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
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http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia.

Arterioscler Thromb Vasc Biol 2021 01 19;41(1):e63-e71. Epub 2020 Nov 19.

Hospices Civils de Lyon, UF Dyslipidémies Service de Biochimie et de Biologie Moléculaire Grand Est, Bron, France (X.V., D.C., O.M., E.D., M.D.F.).

Objective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the (apolipoprotein B) and genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, <0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia.

Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients.
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http://dx.doi.org/10.1161/ATVBAHA.120.315491DOI Listing
January 2021

Infanticide vs. inherited cardiac arrhythmias.

Europace 2021 Mar;23(3):441-450

Istituto Auxologico Italiano, IRCCS, Center for Cardiac Arrhythmias of Genetic Origin, Via Pier Lombardo, 22, 20135 Milan, Italy.

Aims: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children's deaths as part of an inquiry into the mother's convictions.

Methods And Results: Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children.

Conclusion: A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.
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http://dx.doi.org/10.1093/europace/euaa272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947592PMC
March 2021

Genome-wide association study of intracranial aneurysms identifies 17 risk loci and genetic overlap with clinical risk factors.

Nat Genet 2020 12 16;52(12):1303-1313. Epub 2020 Nov 16.

Department of Research, Innovation and Education, Division of Clinical Neuroscience, Oslo University Hospital, Oslo, Norway.

Rupture of an intracranial aneurysm leads to subarachnoid hemorrhage, a severe type of stroke. To discover new risk loci and the genetic architecture of intracranial aneurysms, we performed a cross-ancestry, genome-wide association study in 10,754 cases and 306,882 controls of European and East Asian ancestry. We discovered 17 risk loci, 11 of which are new. We reveal a polygenic architecture and explain over half of the disease heritability. We show a high genetic correlation between ruptured and unruptured intracranial aneurysms. We also find a suggestive role for endothelial cells by using gene mapping and heritability enrichment. Drug-target enrichment shows pleiotropy between intracranial aneurysms and antiepileptic and sex hormone drugs, providing insights into intracranial aneurysm pathophysiology. Finally, genetic risks for smoking and high blood pressure, the two main clinical risk factors, play important roles in intracranial aneurysm risk, and drive most of the genetic correlation between intracranial aneurysms and other cerebrovascular traits.
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http://dx.doi.org/10.1038/s41588-020-00725-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116530PMC
December 2020

A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome.

Clin Genet 2021 Feb 14;99(2):318-324. Epub 2020 Nov 14.

Laboratoire de Génétique Médicale, Institut de génétique médicale d'Alsace IGMA, INSERM U1112, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg UMRS_1112, Strasbourg, France.

Bardet-Biedl syndrome (BBS) is a ciliopathy characterized by retinitis pigmentosa, obesity, polydactyly, cognitive impairment and renal failure. Pathogenic variants in 24 genes account for the molecular basis of >80% of cases. Toward saturated discovery of the mutational basis of the disorder, we carefully explored our cohorts and identified a hominid-specific SINE-R/VNTR/Alu type F (SVA-F) insertion in exon 13 of BBS1 in eight families. In six families, the repeat insertion was found in trans with c.1169 T > G, p.Met390Arg and in two families the insertion was found in addition to other recessive BBS loci. Whole genome sequencing, de novo assembly and SNP array analysis were performed to characterize the genomic event. This insertion is extremely rare in the general population (found in 8 alleles of 8 BBS cases but not in >10 800 control individuals from gnomAD-SV) and due to a founder effect. Its 2435 bp sequence contains hallmarks of LINE1 mediated retrotransposition. Functional studies with patient-derived cell lines confirmed that the BBS1 SVA-F is deleterious as evidenced by a significant depletion of both mRNA and protein levels. Such findings highlight the importance of dedicated bioinformatics pipelines to identify all types of variation.
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http://dx.doi.org/10.1111/cge.13878DOI Listing
February 2021

Mutation Type and a Genetic Risk Score Associate Variably With Brugada Syndrome Phenotype in Families.

Circ Genom Precis Med 2020 12 9;13(6):e002911. Epub 2020 Nov 9.

National Cerebral and Cardiovascular Center, Osaka, Japan (S.O., T.I., W.S., N.M., T.A.).

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- is the most common mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and mutation type on BrS phenotype in BrS families with mutations.

Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles).

Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45-11.85]; =0.0078). Among -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89-6.22]; =0.0846). In -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84-269.30]; =0.0146). Among E1784K- positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93-13.62]; =0.0011).

Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a mutation and severity of loss of function.
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http://dx.doi.org/10.1161/CIRCGEN.120.002911DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748043PMC
December 2020

Location of intracranial aneurysms is the main factor associated with rupture in the ICAN population.

J Neurol Neurosurg Psychiatry 2021 02 23;92(2):122-128. Epub 2020 Oct 23.

Department of Diagnostic and Therapeutic Neuroradiology, University Hospital of Nantes, L'institut du thorax, Inserm 1087, CNRS, UNIV Nantes, Nantes, Pays de la Loire, FR, University Hospital Centre Nantes, Nantes, Pays de la Loire, France

Background And Purpose: The ever-growing availability of imaging led to increasing incidentally discovered unruptured intracranial aneurysms (UIAs). We leveraged machine-learning techniques and advanced statistical methods to provide new insights into rupture intracranial aneurysm (RIA) risks.

Methods: We analysed the characteristics of 2505 patients with intracranial aneurysms (IA) discovered between 2016 and 2019. Baseline characteristics, familial history of IA, tobacco and alcohol consumption, pharmacological treatments before the IA diagnosis, cardiovascular risk factors and comorbidities, headaches, allergy and atopy, IA location, absolute IA size and adjusted size ratio (aSR) were analysed with a multivariable logistic regression (MLR) model. A random forest (RF) method globally assessed the risk factors and evaluated the predictive capacity of a multivariate model.

Results: Among 994 patients with RIA (39.7%) and 1511 patients with UIA (60.3 %), the MLR showed that IA location appeared to be the most significant factor associated with RIA (OR, 95% CI: internal carotid artery, reference; middle cerebral artery, 2.72, 2.02-3.58; anterior cerebral artery, 4.99, 3.61-6.92; posterior circulation arteries, 6.05, 4.41-8.33). Size and aSR were not significant factors associated with RIA in the MLR model and antiplatelet-treatment intake patients were less likely to have RIA (OR: 0.74; 95% CI: 0.55-0.98). IA location, age, following by aSR were the best predictors of RIA using the RF model.

Conclusions: The location of IA is the most consistent parameter associated with RIA. The use of 'artificial intelligence' RF helps to re-evaluate the contribution and selection of each risk factor in the multivariate model.
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http://dx.doi.org/10.1136/jnnp-2020-324371DOI Listing
February 2021

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

Genet Med 2021 01 7;23(1):47-58. Epub 2020 Sep 7.

Member of the European Reference Network for rare, low prevalence and/or complex diseases of the heart: ERN GUARD-Heart, Amsterdam, Netherlands.

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate.

Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants.

Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency.

Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing.
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http://dx.doi.org/10.1038/s41436-020-00946-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7790744PMC
January 2021

Prediction of Unruptured Intracranial Aneurysm Evolution: The UCAN Project.

Neurosurgery 2020 07;87(1):150-156

CHU Nantes, Neuroradiology Department, Nantes, France.

Background: Management of small (<7 mm) unruptured intracranial aneurysms (UIA) remains controversial. Retrospective studies have suggested that post gadolinium arterial wall enhancement (AWE) of UIA on magnetic resonance imaging (MRI) may reflect aneurysm wall instability, and hence may highlight a higher risk of UIA growth. This trial aims at exploring wall imaging findings of UIAs with consecutive follow-up to substantiate these assumptions.

Objective: To develop diagnostic and predictive tools for the risk of IA evolution. Our aim is to demonstrate in clinical practice the predictive value of AWE for UIA growth. The growth will be determined by any modification of the UIA measurement. UIA growth and the UIA wall enhancement will be assessed in consensus by 2 expert neuroradiologists.

Methods: The French prospective UCAN project is a noninterventional international wide and multicentric cohort. UIA of bifurcation between 3 and 7 mm for whom a clinical and imaging follow-up without occlusion treatment was scheduled by local multidisciplinary staff will be included. Extensive clinical, biological, and imaging data will be recorded during a 3-yr follow-up.

Expected Outcomes: Discovering to improve the efficiency of UIA follow-up by identifying additional clinical, imaging, biological, and anatomic risk factors of UIA growth.

Discussion: A prospective nationwide recruitment allows for the inclusion of a large cohort of patients with UIA. It will combine clinical phenotyping and specific imaging with AWE screening. It will enable to exploit metadata and to explore some pathophysiological pathways by crossing clinical, genetic, biological, and imaging information.
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http://dx.doi.org/10.1093/neuros/nyaa093DOI Listing
July 2020

Correction: The genetic history of France.

Eur J Hum Genet 2020 Jul;28(7):988

Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41431-020-0604-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316808PMC
July 2020

Genetic Association Analyses Highlight , , and As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis.

Circ Genom Precis Med 2019 10 15;12(10):e002617. Epub 2019 Oct 15.

l'institut du thorax, INSERM, CNRS, UNIV Nantes, Nantes, France (C.D., S.L.S., R.C., S.R., F.S., A.-S.B., S.L., E.B., S.B., M.K., E.C., I.F., J.-C.R., V.P., R. Redon, T.L.T., J.-J.S.).

Background: Calcific aortic valve stenosis (CAVS) is a frequent and life-threatening cardiovascular disease for which there is currently no medical treatment available. To date, only 2 genes, and , have been identified as causal for CAVS. We aimed to identify additional susceptibility genes for CAVS.

Methods: A GWAS (genome-wide association study) meta-analysis of 4 cohorts, totaling 5115 cases and 354 072 controls of European descent, was performed. A TWAS (transcriptome-wide association study) was completed to integrate transcriptomic data from 233 human aortic valves. A series of post-GWAS analyses were performed, including fine-mapping, colocalization, phenome-wide association studies, pathway, and tissue enrichment as well as genetic correlation with cardiovascular traits.

Results: In the GWAS meta-analysis, 4 loci achieved genome-wide significance, including 2 new loci: (interleukin 6) on 7p15.3 and (alkaline phosphatase) on 1p36.12. A TWAS integrating gene expression from 233 human aortic valves identified (neuron navigator 1) on 1q32.1 as a new candidate causal gene. The CAVS risk alleles were associated with higher mRNA expression of in valve tissues. Fine-mapping identified rs1800795 as the most likely causal variant in the locus. The signal identified colocalizes with the expression of the RNA antisense in various tissues. Phenome-wide association analyses in the UK Biobank showed colocalized associations between the risk allele at the lead variant and higher eosinophil count, pulse pressure, systolic blood pressure, and carotid artery procedures, implicating modulation of the IL6 pathways. The risk allele at the lead variant colocalized with higher pulse pressure and higher prevalence of carotid artery stenosis. Association results at the genome-wide scale indicated genetic correlation between CAVS, coronary artery disease, and cardiovascular risk factors.

Conclusions: Our study implicates 3 new genetic loci in CAVS pathogenesis, which constitute novel targets for the development of therapeutic agents.
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http://dx.doi.org/10.1161/CIRCGEN.119.002617DOI Listing
October 2019

The genetic history of France.

Eur J Hum Genet 2020 07 10;28(7):853-865. Epub 2020 Feb 10.

Université de Nantes, CHU Nantes, CNRS, INSERM, l'institut du thorax, F-44000, Nantes, France.

The study of the genetic structure of different countries within Europe has provided significant insights into their demographic history and population structure. Although France occupies a particular location at the western part of Europe and at the crossroads of migration routes, few population genetic studies have been conducted so far with genome-wide data. In this study, we analyzed SNP-chip genetic data from 2184 individuals born in France who were enrolled in two independent population cohorts. Using FineSTRUCTURE, six different genetic clusters of individuals were found that were very consistent between the two cohorts. These clusters correspond closely to geographic, historical, and linguistic divisions of France, and contain different proportions of ancestry from Stone and Bronze Age populations. By modeling the relationship between genetics and geography using EEMS, we were able to detect gene flow barriers that are similar across the two cohorts and correspond to major rivers and mountain ranges. Estimations of effective population sizes also revealed very similar patterns in both cohorts with a rapid increase of effective population sizes over the last 150 generations similar to other European countries. A marked bottleneck is also consistently seen in the two datasets starting in the 14 century when the Black Death raged in Europe. In conclusion, by performing the first exhaustive study of the genetic structure of France, we fill a gap in genetic studies of Europe that will be useful to medical geneticists, historians, and archeologists.
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http://dx.doi.org/10.1038/s41431-020-0584-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7316781PMC
July 2020

RPL13 Variants Cause Spondyloepimetaphyseal Dysplasia with Severe Short Stature.

Am J Hum Genet 2019 11 17;105(5):1040-1047. Epub 2019 Oct 17.

INSERM U1149/ERL 8252, Inflammation Research Center, 75018 Paris, France; AP-HP, Service d'Hématologie Biologique, Hôpital R. Debré, Université Paris 7 Denis Diderot, Sorbonne Paris Cité, 75019 Paris, France.

Variants in genes encoding ribosomal proteins have thus far been associated with Diamond-Blackfan anemia, a rare inherited bone marrow failure, and isolated congenital asplenia. Here, we report one de novo missense variant and three de novo splice variants in RPL13, which encodes ribosomal protein RPL13 (also called eL13), in four unrelated individuals with a rare bone dysplasia causing severe short stature. The three splice variants (c.477+1G>T, c.477+1G>A, and c.477+2 T>C) result in partial intron retention, which leads to an 18-amino acid insertion. In contrast to observations from Diamond-Blackfan anemia, we detected no evidence of significant pre-rRNA processing disturbance in cells derived from two affected individuals. Consistently, we showed that the insertion-containing protein is stably expressed and incorporated into 60S subunits similar to the wild-type protein. Erythroid proliferation in culture and ribosome profile on sucrose gradient are modified, suggesting a change in translation dynamics. We also provide evidence that RPL13 is present at high levels in chondrocytes and osteoblasts in mouse growth plates. Taken together, we show that the identified RPL13 variants cause a human ribosomopathy defined by a rare skeletal dysplasia, and we highlight the role of this ribosomal protein in bone development.
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http://dx.doi.org/10.1016/j.ajhg.2019.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6849359PMC
November 2019

Fryns type mesomelic dysplasia of the upper limbs caused by inverted duplications of the HOXD gene cluster.

Eur J Hum Genet 2020 03 7;28(3):324-332. Epub 2019 Oct 7.

Service de Génétique, Hôpital Bretonneau, CHU, Tours, France.

The HoxD cluster is critical for vertebrate limb development. Enhancers located in both the telomeric and centromeric gene deserts flanking the cluster regulate the transcription of HoxD genes. In rare patients, duplications, balanced translocations or inversions misregulating HOXD genes are responsible for mesomelic dysplasia of the upper and lower limbs. By aCGH, whole-genome mate-pair sequencing, long-range PCR and fiber fluorescent in situ hybridization, we studied patients from two families displaying mesomelic dysplasia limited to the upper limbs. We identified microduplications including the HOXD cluster and showed that microduplications were in an inverted orientation and inserted between the HOXD cluster and the telomeric enhancers. Our results highlight the existence of an autosomal dominant condition consisting of isolated ulnar dysplasia caused by microduplications inserted between the HOXD cluster and the telomeric enhancers. The duplications likely disconnect the HOXD9 to HOXD11 genes from their regulatory sequences. This presumptive loss-of-function may have contributed to the phenotype. In both cases, however, these rearrangements brought HOXD13 closer to telomeric enhancers, suggesting that the alterations derive from the dominant-negative effect of this digit-specific protein when ectopically expressed during the early development of forearms, through the disruption of topologically associating domain structure at the HOXD locus.
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http://dx.doi.org/10.1038/s41431-019-0522-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028936PMC
March 2020

RRAD mutation causes electrical and cytoskeletal defects in cardiomyocytes derived from a familial case of Brugada syndrome.

Eur Heart J 2019 10;40(37):3081-3094

Division of Cardiovascular Medicine, Department of Medicine, Stanford Cardiovascular Institute, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.

Aims: The Brugada syndrome (BrS) is an inherited cardiac disorder predisposing to ventricular arrhythmias. Despite considerable efforts, its genetic basis and cellular mechanisms remain largely unknown. The objective of this study was to identify a new susceptibility gene for BrS through familial investigation.

Methods And Results: Whole-exome sequencing performed in a three-generation pedigree with five affected members allowed the identification of one rare non-synonymous substitution (p.R211H) in RRAD, the gene encoding the RAD GTPase, carried by all affected members of the family. Three additional rare missense variants were found in 3/186 unrelated index cases. We detected higher levels of RRAD transcripts in subepicardium than in subendocardium in human heart, and in the right ventricle outflow tract compared to the other cardiac compartments in mice. The p.R211H variant was then subjected to electrophysiological and structural investigations in human cardiomyocytes derived from induced pluripotent stem cells (iPSC-CMs). Cardiomyocytes derived from induced pluripotent stem cells from two affected family members exhibited reduced action potential upstroke velocity, prolonged action potentials and increased incidence of early afterdepolarizations, with decreased Na+ peak current amplitude and increased Na+ persistent current amplitude, as well as abnormal distribution of actin and less focal adhesions, compared with intra-familial control iPSC-CMs Insertion of p.R211H-RRAD variant in control iPSCs by genome editing confirmed these results. In addition, iPSC-CMs from affected patients exhibited a decreased L-type Ca2+ current amplitude.

Conclusion: This study identified a potential new BrS-susceptibility gene, RRAD. Cardiomyocytes derived from induced pluripotent stem cells expressing RRAD variant recapitulated single-cell electrophysiological features of BrS, including altered Na+ current, as well as cytoskeleton disturbances.
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http://dx.doi.org/10.1093/eurheartj/ehz308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769825PMC
October 2019

Missense Variants in the Histone Acetyltransferase Complex Component Gene TRRAP Cause Autism and Syndromic Intellectual Disability.

Am J Hum Genet 2019 03 28;104(3):530-541. Epub 2019 Feb 28.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, 17176 Stockholm, Sweden; Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.

Acetylation of the lysine residues in histones and other DNA-binding proteins plays a major role in regulation of eukaryotic gene expression. This process is controlled by histone acetyltransferases (HATs/KATs) found in multiprotein complexes that are recruited to chromatin by the scaffolding subunit transformation/transcription domain-associated protein (TRRAP). TRRAP is evolutionarily conserved and is among the top five genes intolerant to missense variation. Through an international collaboration, 17 distinct de novo or apparently de novo variants were identified in TRRAP in 24 individuals. A strong genotype-phenotype correlation was observed with two distinct clinical spectra. The first is a complex, multi-systemic syndrome associated with various malformations of the brain, heart, kidneys, and genitourinary system and characterized by a wide range of intellectual functioning; a number of affected individuals have intellectual disability (ID) and markedly impaired basic life functions. Individuals with this phenotype had missense variants clustering around the c.3127G>A p.(Ala1043Thr) variant identified in five individuals. The second spectrum manifested with autism spectrum disorder (ASD) and/or ID and epilepsy. Facial dysmorphism was seen in both groups and included upslanted palpebral fissures, epicanthus, telecanthus, a wide nasal bridge and ridge, a broad and smooth philtrum, and a thin upper lip. RNA sequencing analysis of skin fibroblasts derived from affected individuals skin fibroblasts showed significant changes in the expression of several genes implicated in neuronal function and ion transport. Thus, we describe here the clinical spectrum associated with TRRAP pathogenic missense variants, and we suggest a genotype-phenotype correlation useful for clinical evaluation of the pathogenicity of the variants.
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http://dx.doi.org/10.1016/j.ajhg.2019.01.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6407527PMC
March 2019

Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome.

Genet Med 2019 09 6;21(9):2025-2035. Epub 2019 Feb 6.

Centre de Genetique et Centre de Reference Anomalies du Développement et Syndromes Malformatifs de l'Est, FHU-TRANSLAD, CHU Dijon, Dijon, France.

Purpose: Lanosterol synthase (LSS) gene was initially described in families with extensive congenital cataracts. Recently, a study has highlighted LSS associated with hypotrichosis simplex. We expanded the phenotypic spectrum of LSS to a recessive neuroectodermal syndrome formerly named alopecia with mental retardation (APMR) syndrome. It is a rare autosomal recessive condition characterized by hypotrichosis and intellectual disability (ID) or developmental delay (DD), frequently associated with early-onset epilepsy and other dermatological features.

Methods: Through a multicenter international collaborative study, we identified LSS pathogenic variants in APMR individuals either by exome sequencing or LSS Sanger sequencing. Splicing defects were assessed by transcript analysis and minigene assay.

Results: We reported ten APMR individuals from six unrelated families with biallelic variants in LSS. We additionally identified one affected individual with a single rare variant in LSS and an allelic imbalance suggesting a second event. Among the identified variants, two were truncating, seven were missense, and two were splicing variants. Quantification of cholesterol and its precursors did not reveal noticeable imbalance.

Conclusion: In the cholesterol biosynthesis pathway, lanosterol synthase leads to the cyclization of (S)-2,3-oxidosqualene into lanosterol. Our data suggest LSS as a major gene causing a rare recessive neuroectodermal syndrome.
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http://dx.doi.org/10.1038/s41436-019-0445-xDOI Listing
September 2019

The impact of a fine-scale population stratification on rare variant association test results.

PLoS One 2018 6;13(12):e0207677. Epub 2018 Dec 6.

INSERM, CNRS, UNIV Nantes, l'institut du thorax, Nantes, France.

Population stratification is a well-known confounding factor in both common and rare variant association analyses. Rare variants tend to be more geographically clustered than common variants, because of their more recent origin. However, it is not yet clear if population stratification at a very fine scale (neighboring administrative regions within a country) would lead to statistical bias in rare variant analyses. As the inclusion of convenience controls from external studies is indeed a common procedure, in order to increase the power to detect genetic associations, this problem is important. We studied through simulation the impact of a fine scale population structure on different rare variant association strategies, assessing type I error and power. We showed that principal component analysis (PCA) based methods of adjustment for population stratification adequately corrected type I error inflation at the largest geographical scales, but not at finest scales. We also showed in our simulations that adding controls obviously increased power, but at a considerably lower level when controls were drawn from another population.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207677PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283567PMC
May 2019

Whole exome sequencing study identifies novel rare and common Alzheimer's-Associated variants involved in immune response and transcriptional regulation.

Mol Psychiatry 2020 08 14;25(8):1859-1875. Epub 2018 Aug 14.

McDonnell Genome Institute, Washington University, St. Louis, MO, USA.

The Alzheimer's Disease Sequencing Project (ADSP) undertook whole exome sequencing in 5,740 late-onset Alzheimer disease (AD) cases and 5,096 cognitively normal controls primarily of European ancestry (EA), among whom 218 cases and 177 controls were Caribbean Hispanic (CH). An age-, sex- and APOE based risk score and family history were used to select cases most likely to harbor novel AD risk variants and controls least likely to develop AD by age 85 years. We tested ~1.5 million single nucleotide variants (SNVs) and 50,000 insertion-deletion polymorphisms (indels) for association to AD, using multiple models considering individual variants as well as gene-based tests aggregating rare, predicted functional, and loss of function variants. Sixteen single variants and 19 genes that met criteria for significant or suggestive associations after multiple-testing correction were evaluated for replication in four independent samples; three with whole exome sequencing (2,778 cases, 7,262 controls) and one with genome-wide genotyping imputed to the Haplotype Reference Consortium panel (9,343 cases, 11,527 controls). The top findings in the discovery sample were also followed-up in the ADSP whole-genome sequenced family-based dataset (197 members of 42 EA families and 501 members of 157 CH families). We identified novel and predicted functional genetic variants in genes previously associated with AD. We also detected associations in three novel genes: IGHG3 (p = 9.8 × 10), an immunoglobulin gene whose antibodies interact with β-amyloid, a long non-coding RNA AC099552.4 (p = 1.2 × 10), and a zinc-finger protein ZNF655 (gene-based p = 5.0 × 10). The latter two suggest an important role for transcriptional regulation in AD pathogenesis.
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http://dx.doi.org/10.1038/s41380-018-0112-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6375806PMC
August 2020

Identification of a new exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease.

Blood 2018 08 11;132(5):469-483. Epub 2018 Jun 11.

Faculty of Medicine Alexandroupolis, Democritus University of Thrace, Thrace, Greece.

Chuvash polycythemia is an autosomal recessive form of erythrocytosis associated with a homozygous p.Arg200Trp mutation in the von Hippel-Lindau () gene. Since this discovery, additional mutations have been identified in patients with congenital erythrocytosis, in a homozygous or compound-heterozygous state. is a major tumor suppressor gene, mutations in which were first described in patients presenting with VHL disease, which is characterized by the development of highly vascularized tumors. Here, we identify a new cryptic exon (termed E1') deep in intron 1 that is naturally expressed in many tissues. More importantly, we identify mutations in E1' in 7 families with erythrocytosis (1 homozygous case and 6 compound-heterozygous cases with a mutation in E1' in addition to a mutation in coding sequences) and in 1 large family with typical VHL disease but without any alteration in the other exons. In this study, we show that the mutations induced a dysregulation of splicing with excessive retention of E1' and were associated with a downregulation of VHL protein expression. In addition, we demonstrate a pathogenic role for synonymous mutations in exon 2 that altered splicing through E2-skipping in 5 families with erythrocytosis or VHL disease. In all the studied cases, the mutations differentially affected splicing, correlating with phenotype severity. This study demonstrates that cryptic exon retention and exon skipping are new alterations and reveals a novel complex splicing regulation of the gene. These findings open new avenues for diagnosis and research regarding the VHL-related hypoxia-signaling pathway.
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http://dx.doi.org/10.1182/blood-2018-03-838235DOI Listing
August 2018

Mental stress test: a rapid, simple, and efficient test to unmask long QT syndrome.

Europace 2018 12;20(12):2014-2020

l'institut du thorax, INSERM, CNRS, UNIV Nantes, CHU de Nantes, Boulevard Jacques Monod, Nantes, France.

Aims: QT prolongation during mental stress test (MST) has been associated with familial idiopathic ventricular fibrillation. In long QT syndrome (LQTS), up to 30% of mutation carriers have normal QT duration. Our aim was to assess the QT response during MST, and its accuracy in the diagnosis of concealed LQTS.

Methods And Results: All patients who are carrier of a KCNQ1 or KCNH2 mutations without QT prolongation were enrolled. A control group was constituted of patients with negative exercise and epinephrine tests. Electrocardiogram were recorded at rest and at the maximum heart rate during MST and reviewed by two physicians. Among the 70 patients enrolled (median age 41±2.1 years, 46% male), 36 were mutation carrier for LQTS (20 KCNQ1 and 16 KCNH2), and 34 were controls. KCNQ1 and KCNH2 mutation carriers presented a longer QT interval at baseline [405(389; 416) and 421 (394; 434) ms, respectively] compared with the controls [361(338; 375)ms; P < 0.0001]. QT duration during MST varied by 9 (4; 18) ms in KCNQ1, 3 (-6; 16) ms in KCNH2, and by -22 (-29; -17) ms in controls (P < 0.0001). These QT variations were independent of heart rate (P < 0.3751). Receiver operating characteristic curve analysis identified a cut-off value of QT variation superior to -11 ms as best predictor of LQTS. It provided 97% sensitivity and 97% specificity of QT prolongation in the diagnosis of LQTS.

Conclusion: We identified a paradoxical response of the QT interval during MST in LQTS. Easy to assess, MST may be efficient to unmask concealed LQTS in patients at risk of this pathology.
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http://dx.doi.org/10.1093/europace/euy078DOI Listing
December 2018

Parallel derivation of isogenic human primed and naive induced pluripotent stem cells.

Nat Commun 2018 01 24;9(1):360. Epub 2018 Jan 24.

Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France.

Induced pluripotent stem cells (iPSCs) have considerably impacted human developmental biology and regenerative medicine, notably because they circumvent the use of cells of embryonic origin and offer the potential to generate patient-specific pluripotent stem cells. However, conventional reprogramming protocols produce developmentally advanced, or primed, human iPSCs (hiPSCs), restricting their use to post-implantation human development modeling. Hence, there is a need for hiPSCs resembling preimplantation naive epiblast. Here, we develop a method to generate naive hiPSCs directly from somatic cells, using OKMS overexpression and specific culture conditions, further enabling parallel generation of their isogenic primed counterparts. We benchmark naive hiPSCs against human preimplantation epiblast and reveal remarkable concordance in their transcriptome, dependency on mitochondrial respiration and X-chromosome status. Collectively, our results are essential for the understanding of pluripotency regulation throughout preimplantation development and generate new opportunities for disease modeling and regenerative medicine.
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http://dx.doi.org/10.1038/s41467-017-02107-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783949PMC
January 2018

Rare Coding Variants in ANGPTL6 Are Associated with Familial Forms of Intracranial Aneurysm.

Am J Hum Genet 2018 01;102(1):133-141

INSERM, CNRS, UNIV Nantes, l'institut du thorax, 44007 Nantes, France; CHU Nantes, l'institut du thorax, 44093 Nantes, France. Electronic address:

Intracranial aneurysms (IAs) are acquired cerebrovascular abnormalities characterized by localized dilation and wall thinning in intracranial arteries, possibly leading to subarachnoid hemorrhage and severe outcome in case of rupture. Here, we identified one rare nonsense variant (c.1378A>T) in the last exon of ANGPTL6 (Angiopoietin-Like 6)-which encodes a circulating pro-angiogenic factor mainly secreted from the liver-shared by the four tested affected members of a large pedigree with multiple IA-affected case subjects. We showed a 50% reduction of ANGPTL6 serum concentration in individuals heterozygous for the c.1378A>T allele (p.Lys460Ter) compared to relatives homozygous for the normal allele, probably due to the non-secretion of the truncated protein produced by the c.1378A>T transcripts. Sequencing ANGPTL6 in a series of 94 additional index case subjects with familial IA identified three other rare coding variants in five case subjects. Overall, we detected a significant enrichment (p = 0.023) in rare coding variants within this gene among the 95 index case subjects with familial IA, compared to a reference population of 404 individuals with French ancestry. Among the 6 recruited families, 12 out of 13 (92%) individuals carrying IA also carry such variants in ANGPTL6, versus 15 out of 41 (37%) unaffected ones. We observed a higher rate of individuals with a history of high blood pressure among affected versus healthy individuals carrying ANGPTL6 variants, suggesting that ANGPTL6 could trigger cerebrovascular lesions when combined with other risk factors such as hypertension. Altogether, our results indicate that rare coding variants in ANGPTL6 are causally related to familial forms of IA.
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http://dx.doi.org/10.1016/j.ajhg.2017.12.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778084PMC
January 2018

bioalcidae, samjs and vcffilterjs: object-oriented formatters and filters for bioinformatics files.

Bioinformatics 2018 04;34(7):1224-1225

Cardiovascular Genetics, L'Institut du Thorax, INSERM, CNRS, UNIV Nantes, Nantes 44007, France.

Motivation: Reformatting and filtering bioinformatics files are common tasks for bioinformaticians. Standard Linux tools and specific programs are usually used to perform such tasks but there is still a gap between using these tools and the programming interface of some existing libraries.

Results: In this study, we developed a set of tools namely bioalcidae, samjs and vcffilterjs that reformat or filter files using a JavaScript engine or a pure java expression and taking advantage of the java API for high-throughput sequencing data (htsjdk).

Availability And Implementation: https://github.com/lindenb/jvarkit.

Contact: [email protected]
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http://dx.doi.org/10.1093/bioinformatics/btx734DOI Listing
April 2018

De Novo Mutations in Protein Kinase Genes CAMK2A and CAMK2B Cause Intellectual Disability.

Am J Hum Genet 2017 Nov;101(5):768-788

Nottingham Regional Genetics Service, City Hospital Campus, Nottingham University Hospitals NHS Trust, The Gables, Hucknall Road, Nottingham NG5 1PB, UK.

Calcium/calmodulin-dependent protein kinase II (CAMK2) is one of the first proteins shown to be essential for normal learning and synaptic plasticity in mice, but its requirement for human brain development has not yet been established. Through a multi-center collaborative study based on a whole-exome sequencing approach, we identified 19 exceedingly rare de novo CAMK2A or CAMK2B variants in 24 unrelated individuals with intellectual disability. Variants were assessed for their effect on CAMK2 function and on neuronal migration. For both CAMK2A and CAMK2B, we identified mutations that decreased or increased CAMK2 auto-phosphorylation at Thr286/Thr287. We further found that all mutations affecting auto-phosphorylation also affected neuronal migration, highlighting the importance of tightly regulated CAMK2 auto-phosphorylation in neuronal function and neurodevelopment. Our data establish the importance of CAMK2A and CAMK2B and their auto-phosphorylation in human brain function and expand the phenotypic spectrum of the disorders caused by variants in key players of the glutamatergic signaling pathway.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5673671PMC
November 2017