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| Open AccessPredictive impact of rare genomic copy number variations in siblings of individuals with autism spectrum disorders
Siblings of those with autism spectrum disorder (ASD) have increased likelihood of ASD or related subclinical traits. Here, studying 253 ASD families, D’Abate et al. test the predictive value of genomic copy number variation involving ASD-associated loci, with confirmation in a second cohort.
- L. D’Abate
- , S. Walker
- & S. W. Scherer
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Article
| Open AccessDisruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders
Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.
- Hui Guo
- , Elisa Bettella
- & Evan E. Eichler
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Article
| Open AccessContribution of retrotransposition to developmental disorders
Retrotransposition events have been linked to some human disorders. Here, Gardner et al. systematically search for mobile genetic elements (ME) in trio whole exome-sequencing datasets and ascertain 9 de novo MEs and further estimate genome-wide germline ME burden and constraint.
- Eugene J. Gardner
- , Elena Prigmore
- & Matthew E. Hurles
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Article
| Open AccessABCC9-related Intellectual disability Myopathy Syndrome is a KATP channelopathy with loss-of-function mutations in ABCC9
ABCC9 encodes the SUR2 subunit of KATP channels and dominant genetic variants in ABCC9 have been associated with cardiac phenotypes. Here, the authors report recessive ABCC9 mutations in individuals with mild intellectual disability, myopathy and cardiac systolic dysfunction which is associated with loss of KATP channel function.
- Marie F. Smeland
- , Conor McClenaghan
- & Gijs van Haaften
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Article
| Open AccessHaploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome
Understanding of the genetic factors and molecular mechanisms underlying neurodevelopmental disorders remains incomplete. In this study, authors show that microdeletions in the gene ANKS1B lead to loss of the neuronal synapse-enriched protein AIDA-1 and to a novel neurodevelopmental syndrome
- Abigail U. Carbonell
- , Chang Hoon Cho
- & Bryen A. Jordan
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Article
| Open AccessAMPA receptor GluA2 subunit defects are a cause of neurodevelopmental disorders
Genetic variants in ionotropic glutamate receptors have been implicated in neurodevelopmental disorders. Here, the authors report heterozygous de novo mutations in the GRIA2 gene in 28 individuals with intellectual disability and neurodevelopmental abnormalities associated with reduced Ca2+ transport and AMPAR currents.”
- Vincenzo Salpietro
- , Christine L. Dixon
- & Henry Houlden
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Article
| Open AccessPaternal-age-related de novo mutations and risk for five disorders
Advanced paternal age associates with increased risk for psychiatric and developmental disorders in offspring. Here, Taylor et al. utilize parent-child trio exome sequencing data sets to estimate the contribution of paternal age-related de novo mutations to multiple disorders, including heart disease and schizophrenia.
- Jacob L. Taylor
- , Jean-Christophe P. G. Debost
- & Elise B. Robinson
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Article
| Open AccessA genome-wide scan statistic framework for whole-genome sequence data analysis
Whole-genome sequencing data reveals a large number of variants for testing their associations with phenotypic traits and diseases. Here, the authors develop WGScan, a statistical method for detecting the existence and estimating the locations of the association signal at genome-wide scale.
- Zihuai He
- , Bin Xu
- & Iuliana Ionita-Laza
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Article
| Open AccessClinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data
Systematic analysis of postzygotic mosaicism (PZM) is difficult due to challenges in detecting such events. Here, Wright et al. analyse trio exome sequencing data from blood and saliva of 4,293 probands with developmental disorders from the DDD Study and estimate that >3% of causative de novo mutations result from PZM.
- C. F. Wright
- , E. Prigmore
- & M. E. Hurles
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Article
| Open AccessBiallelic mutations in valyl-tRNA synthetase gene VARS are associated with a progressive neurodevelopmental epileptic encephalopathy
Valyl-tRNA synthetase (VARS) charges valyl-tRNA with the amino acid valine, required for translation. Here, the authors describe a progressive epileptic encephalopathy in individuals from five families carrying biallelic mutations in the VARS gene that leave the enzyme activity partially intact.
- Jennifer Friedman
- , Desiree E. Smith
- & Joseph G. Gleeson
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Article
| Open AccessBiallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish
tRNAs are linked with their cognate amino acid by aminoacyl tRNA synthetases (ARS). Here, the authors report a developmental encephalopathy associated with biallelic VARS variants (valyl-tRNA synthetase) that lead to loss of function, as determined by several in vitro assays and a vars knockout zebrafish model.
- Aleksandra Siekierska
- , Hannah Stamberger
- & Peter De Jonghe
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Article
| Open AccessCombined loss of LAP1B and LAP1C results in an early onset multisystemic nuclear envelopathy
Nuclear envelopathies are a group of diseases caused by genetic mutations in essential nuclear envelope genes. Here, the authors report a nuclear envelopathy with a homozygous nonsense variant in TOR1AIP1 which leads to changes in the nuclear morphology including large nuclear-spanning channels in patients’ fibroblasts.
- Boris Fichtman
- , Fadia Zagairy
- & Ronen Spiegel
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Article
| Open AccessContribution of rare and common variants to intellectual disability in a sub-isolate of Northern Finland
Various types of genetic variation contribute to the etiology of intellectual disability (ID). Here, the authors study a cohort of ID patients enriched for mild ID from Finland, to investigate contributions of rare and common variants associated with ID of different levels of severity.
- Mitja I. Kurki
- , Elmo Saarentaus
- & Aarno Palotie
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Article
| Open AccessSpatial fine-mapping for gene-by-environment effects identifies risk hot spots for schizophrenia
Schizophrenia (SCZ) risk is influenced by genetic and environmental factors. Here, the authors develop a statistical method for analyzing gene-by-environment effects in SCZ risk across Denmark with fine spatial resolution.
- Chun Chieh Fan
- , John J. McGrath
- & Carsten Bøcker Pedersen
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Article
| Open AccessCHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language
Chromodomain Helicase DNA-binding (CHD) proteins have been implicated in neurodevelopmental processes. Here, the authors identify missense variants in CHD3 that disturb its chromatin remodeling activities and cause a neurodevelopmental disorder with macrocephaly and speech and language impairment.
- Lot Snijders Blok
- , Justine Rousseau
- & Philippe M. Campeau
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Article
| Open AccessSlc7a5 regulates Kv1.2 channels and modifies functional outcomes of epilepsy-linked channel mutations
Kv1.2 is a voltage-gated potassium channel that influences action potential generation and propagation in the central nervous system. Here authors use electrophysiology and find that Slc7a5, a neutral amino acid transporter, has a profound impact on Kv1.2.
- Victoria A. Baronas
- , Runying Y. Yang
- & Harley T. Kurata
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Article
| Open AccessA distal centriolar protein network controls organelle maturation and asymmetry
Removal of daughter centriole-specific/enriched proteins (DCPs) and assembly of distal appendages (DA) are important for centrosome asymmetry. Here, the authors report that a centriolar distal end protein network regulates DCP removal, DA assembly, and ciliary vesicle docking.
- Lei Wang
- , Marion Failler
- & Brian D. Dynlacht
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Article
| Open AccessRapid functional genetics of the oligodendrocyte lineage using pluripotent stem cells
The isolation and propagation of oligodendroglial cells from postnatal animals can be impractical for functional genetic studies. This study highlights the potential of a new approach to rapidly generate oligodendrocytes and their progenitors from mouse embryonic and induced pluripotent stem cells, independent of mouse strain or mutational status.
- Angela M. Lager
- , Olivia G. Corradin
- & Paul J. Tesar
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Article
| Open AccessApparent bias toward long gene misregulation in MeCP2 syndromes disappears after controlling for baseline variations
Recent studies have suggested that long genes (>100 kb) are more likely to be misregulated in some neurological diseases, such as autism and Rett syndrome. Here the authors find that the apparent length-dependent trends previously observed in MeCP2 microarray and RNA-sequencing datasets disappeared after controlling for baseline variations.
- Ayush T. Raman
- , Amy E. Pohodich
- & Zhandong Liu
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| Open AccessPervasive genetic interactions modulate neurodevelopmental defects of the autism-associated 16p11.2 deletion in Drosophila melanogaster
The 16p11.2 deletion leads to a range of neurodevelopmental phenotypes, but to date, sequencing studies have not been able to pinpoint individual genes that are causative for the disease on their own. Here, using Drosophila homologs of 14 16p11.2 genes, the authors take a combinatorial approach to show that gene interactions contribute to a neurological phenotype.
- Janani Iyer
- , Mayanglambam Dhruba Singh
- & Santhosh Girirajan
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Article
| Open AccessFasoracetam in adolescents with ADHD and glutamatergic gene network variants disrupting mGluR neurotransmitter signaling
Stimulant drugs are most commonly used to treat ADHD. Here, the authors demonstrate that in adolescents with ADHD who also have genetic variation in genes impacting metabotropic glutamate signaling, the non-stimulant mGluR activator fasoracetam is well tolerated and may be beneficial in alleviating symptoms of this disease.
- Josephine Elia
- , Grace Ungal
- & Hakon Hakonarson
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Article
| Open AccessSpermine synthase deficiency causes lysosomal dysfunction and oxidative stress in models of Snyder-Robinson syndrome
Mutations in spermine synthase lead to Snyder-Robinson syndrome, a form of intellectual disability syndrome. Here the authors develop a Drosophila model of this disease, and show that lysosomal dysfunction and oxidative stress contribute to the morphological phenotype in these flies, as well as to cellular deficits in cells derived from patients.
- Chong Li
- , Jennifer M. Brazill
- & R. Grace Zhai
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Article
| Open AccessVariation in a range of mTOR-related genes associates with intracranial volume and intellectual disability
The mTOR pathway is a key regulator of normal brain development. Here, the authors identify de novo mutations in RHEB, an mTOR activator protein, in patients with intellectual disability associated with megalencephaly and find a role for RHEB in regulating neuronal soma size and migration in vitro and in vivo.
- M. R. F. Reijnders
- , M. Kousi
- & H. G. Brunner
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Article
| Open AccessAn autism spectrum disorder-related de novo mutation hotspot discovered in the GEF1 domain of Trio
Trio is a RhoGEF protein that promotes actin polymerization and is implicated in the regulation of glutamatergic synapses in autism spectrum disorder (ASD). Here the authors identify a large cluster of de novo mutations in the GEF1 domain of Trio in whole-exome sequencing data from individuals with ASD, and confirm that some of these mutations lead to glutamatergic dysregulation in vitro.
- Anastasiia Sadybekov
- , Chen Tian
- & Bruce E. Herring
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Article
| Open AccessEpilepsy and intellectual disability linked protein Shrm4 interaction with GABABRs shapes inhibitory neurotransmission
Mutations in the gene encoding Shrm4 are associated with epilepsy and intellectual disability. The authors show that Shrm4 interacts with GABABreceptors and regulates tonic inhibition in the hippocampus, and knockdown of Shrm4 in rats leads to anxiety-like behaviour and seizures.
- Jonathan Zapata
- , Edoardo Moretto
- & Maria Passafaro
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Article
| Open AccessGenome-wide identification of splicing QTLs in the human brain and their enrichment among schizophrenia-associated loci
Alternative splicing of mRNAs occurs in tissue specific manners and may be modulated by genetic variations. Here, Takata and colleagues perform splicing quantitative trait loci analysis (sQTL) of human brain and show significant enrichment of sQTLs among neurological disease-associated loci.
- Atsushi Takata
- , Naomichi Matsumoto
- & Tadafumi Kato
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Article
| Open AccessSevere NDE1-mediated microcephaly results from neural progenitor cell cycle arrests at multiple specific stages
Human mutations in the NDE1 gene have been associated with cortical malformations and severe microcephaly. Here, the authors show in embryonic rat brains that NDE1-depleted neural progenitors arrest at three specific cell cycle stages before mitosis, resulting in a severe decrease in neurogenesis.
- David J. Doobin
- , Shahrnaz Kemal
- & Richard B. Vallee
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Article
| Open AccessBrain-specific Crmp2 deletion leads to neuronal development deficits and behavioural impairments in mice
The in vivo function of CRMP2 is unclear. Zhang et al. generate and characterize brain-specific Crmp2knockout mice. These mice show impairments in hippocampal neurogenesis, neuronal maturation and synaptic transmission, and exhibit schizophrenia-related behavioral deficits.
- Hongsheng Zhang
- , Eunchai Kang
- & Zhiheng Xu
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Article
| Open AccessDynamic changes in neural circuitry during adolescence are associated with persistent attenuation of fear memories
Flexible fear-related responses may be advantageous in adolescence. Here the authors use microprisms to image prefrontal cortical spine maturation across development and report that plasticity in adolescent fear extinction responses is associated with dynamic reorganization in the amygdalahippocampal-PFC circuit.
- Siobhan S. Pattwell
- , Conor Liston
- & Francis S. Lee
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Article
| Open AccessA small number of abnormal brain connections predicts adult autism spectrum disorder
Autism spectrum disorder (ASD) is manifested by subtle but significant changes in the brain. Here, Yahata and colleagues devise a novel machine learning algorithm and develop a reliable ASD classifier based on brain functional connectivity, with which they quantitatively measure neuroimaging dimensions between ASD and other mental disorders.
- Noriaki Yahata
- , Jun Morimoto
- & Mitsuo Kawato
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Article
| Open AccessReduction of aberrant NF-κB signalling ameliorates Rett syndrome phenotypes in Mecp2-null mice
Rett syndrome is a neurodevelopmental disorder caused by mutations in Mecp2. Here the authors show that Mecp2 loss-of-function leads to upregulation of the NF-κB pathway, and that reducing NF-κB signalling ameliorates phenotypes of Mecp2-null mice, thus offering a potential therapeutic strategy.
- Noriyuki Kishi
- , Jessica L. MacDonald
- & Jeffrey D. Macklis
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Article
| Open AccessCognitive tutoring induces widespread neuroplasticity and remediates brain function in children with mathematical learning disabilities
Mathematical learning disabilities (MLD) affect up to 20% of children and are linked to poorer socioeconomic and health outcomes in adulthood. Here, Iuculano et al. show that tutoring induced functional changes in multiple brain systems underlie remediation of poor maths skills in children with MLD.
- Teresa Iuculano
- , Miriam Rosenberg-Lee
- & Vinod Menon
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Rheb activation disrupts spine synapse formation through accumulation of syntenin in tuberous sclerosis complex
Tuberous sclerosis complex (TSC) arises from mutations in an activator of the small GTPase Rheb. Here the authors show that syntenin binds to GDP-bound Rheb, and loss of this interaction in TSC leads to increased syntenin expression and downstream signalling defects leading to aberrant spine synapse morphogenesis.
- Hiroko Sugiura
- , Shin Yasuda
- & Kanato Yamagata
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Article
| Open AccessSynaptic NMDA receptor activity is coupled to the transcriptional control of the glutathione system
How the brain’s antioxidant defenses adapt to changing demand is not well understood. Here the authors demonstrate that synaptic activity is coupled to transcriptional control of the glutathione antioxidant system via NMDA receptors, enabling neurons to tune their antioxidant defenses.
- Paul S. Baxter
- , Karen F.S. Bell
- & Giles E. Hardingham
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The amino-terminal structure of human fragile X mental retardation protein obtained using precipitant-immobilized imprinted polymers
Obtaining a protein crystal structure can be hampered by molecular flexibility. Here, the authors use precipitant-immobilized molecularly imprinted polymers to produce high quality crystals, such as of the fragile X mental retardation protein N-terminal domain, allowing for a detailed structural and functional analysis.
- Yufeng Hu
- , Zhenhang Chen
- & Xueqin Ren
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Conditional deletion of Mecp2 in parvalbumin-expressing GABAergic cells results in the absence of critical period plasticity
Critical period plasticity describes a developmental process whereby neural circuits are fine-tuned for specific functions. Here, the authors show that the Rett syndrome protein MeCP2 in GABAergic parvalbumin-expressing neurons is required for critical period plasticity of the visual cortex.
- Ling-jie He
- , Nan Liu
- & Xiao-hui Zhang
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Loss of Wdfy3 in mice alters cerebral cortical neurogenesis reflecting aspects of the autism pathology
The Wdfy3gene has been associated with autism spectrum disorders in children. Here, the authors examine two separate mutant alleles of this gene in mice and identify its role in cortical neurogenesis, reproducing pathological changes characteristic of the disorder.
- Lori A. Orosco
- , Adam P. Ross
- & Konstantinos S Zarbalis
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Microcephaly disease gene Wdr62 regulates mitotic progression of embryonic neural stem cells and brain size
Mutations in WD-repeat-containing protein 62 (Wdr62) are associated with microcephaly, a congenital disorder characterized by reduced brain size. The authors show that Wdr62 deficiency in mouse embryos leads to mitotic arrest of neural progenitors and that Wdr62 genetically interacts with Aurora kinase Ato control mitotic progression of neural progenitors.
- Jian-Fu Chen
- , Ying Zhang
- & Lee Niswander
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EphrinB2 affects apical constriction in Xenopus embryos and is regulated by ADAM10 and flotillin-1
ADAM metalloproteases cleave ephrin signalling proteins and their receptors. Here, the authors show that ADAM10-mediated cleavage of ephrinB2 is inhibited by the lipid raft protein flotillin-1 and that ephrinB2 regulates apical constriction during neural tube closure in Xenopusembryos.
- Yon Ju Ji
- , Yoo-Seok Hwang
- & Ira O. Daar