Functional impact of global rare copy number variation in autism spectrum disorders

Pinto, Dalila; Pagnamenta, Alistair T.; Klei, Lambertus; Anney, Richard; Merico, Daniele; Regan, Regina; Conroy, Judith; Magalhães, Tiago R.; Correia, Catarina; Abrahams, Brett S.; Almeida, Joana; Bacchelli, Elena; Bader, Gary D.; Bailey, Anthony; Baird, Gillian; Battaglia, Agatino; Berney, T. P.; Bolshakova, Nadia; Bölte, Sven; Bolton, Patrick; Bourgeron, Thomas; Brennan, S.; Brian, Jessica; Bryson, Susan E.; Carson, Andrew R.; Casallo, Guillermo; Casey, Jillian P.; Chung, Brian Hon‐Yin; Cochrane, Lynne; Corsello, Christina; Crawford, Emily L.; Crossett, Andrew; Cytrynbaum, Cheryl; Dawson, Geraldine; Jonge, Maretha de; Delorme, Richard; Drmic, Irene; Duketis, Eftichia; Duque, Frederico; Estes, Annette; Farrar, Penny; Fernandez, Bridget A.; Folstein, Susan E.; Fombonne, Éric; Freitag, Christine M.; Gilbert, John R.; Gillberg, Christopher; Glessner, Joseph T.; Goldberg, Jeremy; Green, Andrew; Green, Jonathan; Guter, Stephen J.; Hákonarson, Hákon; Heron, Elizabeth A.; Hill, Matthew; Holt, R. J.; Howe, Jennifer; Hughes, Gillian; Hus, Vanessa; Igliozzi, Roberta; Kim, Cecilia; Klauck, Sabine M.; Kolevzon, Alexander; Korvatska, Olena; Kustanovich, Vlad; Lajonchere, Clara; Lamb, Janine; Laskawiec, Magdalena; Leboyer, Marion; Couteur, Ann Le; Leventhal, Bennett L.; Lionel, Anath C.; Liu, Xiao Qing; Lord, Catherine; Lotspeich, Linda; Lund, Sabata C.; Maestrini, Elena; Mahoney, William J.; Mantoulan, Carine; Marshall, Christian R.; McConachie, Helen; McDougle, Christopher J.; McGrath, Jane; McMahon, William M.; Merikangas, Alison; Migita, Ohsuke; Minshew, Nancy J.; Mirza, Ghazala; Munson, Jeff; Nelson, Stanley F.; Noakes, Carolyn; Noor, Abdul; Nygren, Gudrun; Oliveira, Guiomar; Papanikolaou, Κaterina; Parr, Jeremy; Parrini, Barbara; Paton, Tara; Pickles, Andrew; Pilorge, Marion; Piven, Joseph; Ponting, Chris P.; Posey, David J.; Poustka, Annemarie; Poustka, Fritz; Prasad, Aparna; Ragoussis, Jiannis; Renshaw, Katy; Rickaby, Jessica; Roberts, Wendy; Roeder, Kathryn; Rogé, Bernadette; Rutter, Michael; Bierut, Laura J.; Rice, John P.; Salt, Jeff; Sansom, Katherine; Sato, Daisuke; Segurado, Ricardo; Sequeira, Ana Filipa; Senman, Lili; Shah, Naisha; Sheffield, Val C.; Soorya, Latha; Sousa, Inês; Stein, Olaf; Sykes, Nuala; Stoppioni, Vera; Strawbridge, Christina P.; Tancredi, Raffaella; Tansey, Katherine E.; Thiruvahindrapduram, Bhooma; Thompson, Ann; Thomson, Susanne; Tryfon, Ana; Tsiantis, John; Engeland, Hermán van; Vincent, John B.; Volkmar, Fred R.; Wallace, Simon; Wang, Kai; Wang, Zhouzhi; Wassink, Thomas H.; Webber, Caleb; Weksberg, Rosanna; Wing, Kirsty; Wittemeyer, Kerstin; Wood, Shawn; Wu, Jing; Yaspan, Brian L.; Zurawiecki, Danielle; Zwaigenbaum, Lonnie; Buxbaum, Joseph D.; Cantor, Rita M.; Cook, Edwin H.; Coon, Hilary; Cuccaro, Michael L.; Devlin, Bernie; Ennis, Sean; Gallagher, Louise; Geschwind, Daniel H.; Gill, Michael; Haines, Jonathan L.; Hallmayer, Joachim; Miller, Judith S.; Monaco, Anthony P.; Nürnberger, John I.; Paterson, Andrew D.; Pericak‐Vance, Margaret A.; Schellenberg, Gerard D.; Szatmári, Péter; Vicente, Astrid M.; Vieland, Veronica J.; Wijsman, Ellen M.; Scherer, Stephen W.; Sutcliffe, James S.; Betancur, Catalina

doi:10.1038/nature09146

Cited by 1,812 publications

(1,858 citation statements)

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“…Besides structural rearrangements, other abnormalities of chromosomal numbers or aneuploidies are detected in ASD including trisomy 21, Turner syndrome (45, X), and Klinefelter syndrome (47, XXY; Devlin & Scherer, 2012). Thanks to the comparative genomic hybridization (CGH) technique or SNPs array, CNVs were also found in multiple chromosomal regions at 1q21.1, 16p11.2, 17q12, and 22q11.2 (Jacquemont et al., 2006; Marshall et al., 2008; Matsunami et al., 2013; O'Roak et al., 2012; Pinto et al., 2010; Sebat et al., 2007). Further studies supported the association with ASD of two recurrent de novo CNVs at 16p11.2 (duplication and deletion) and 7q11.23 (duplication; Levy et al., 2011; Sanders Stephan et al., 2011).…”

Section: Reviewmentioning

confidence: 99%

“…The chromosomal deletion found at 7q11.23 has been linked to William's syndrome, which includes intellectual disabilities, facial dysmorphic features, congenital heart defect, and transient hypercalcemia. The intellectual disabilities suggest that this chromosomal region may also contain genes associated with social behaviors (Pinto et al., 2010). CNVs were found enriched in groups of genes implicated in cell signaling pathways that regulate neuronal development and cell proliferation along with a group of genes associated with the GTPase/Ras signaling pathway and neuronal plasticity (Pinto et al., 2010).…”

Section: Reviewmentioning

confidence: 99%

“…The intellectual disabilities suggest that this chromosomal region may also contain genes associated with social behaviors (Pinto et al., 2010). CNVs were found enriched in groups of genes implicated in cell signaling pathways that regulate neuronal development and cell proliferation along with a group of genes associated with the GTPase/Ras signaling pathway and neuronal plasticity (Pinto et al., 2010). CNVs studies demonstrated also that there is alteration in the fragile X mental retardation protein (FMRP) in patients with ASD.…”

Section: Reviewmentioning

confidence: 99%

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Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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BackgroundAutism spectrum disorder (ASD) comprises a group of neurodevelopmental psychiatric disorders characterized by deficits in social interactions, interpersonal communication, repetitive and stereotyped behaviors and may be associated with intellectual disabilities. The description of ASD as a synaptopathology highlights the importance of the synapse and the implication of ion channels in the etiology of these disorders.MethodsA narrative and critical review of the relevant papers from 1982 to 2017 known by the authors was conducted.ResultsGenome‐wide linkages, association studies, and genetic analyses of patients with ASD have led to the identification of several candidate genes and mutations linked to ASD. Many of the candidate genes encode for proteins involved in neuronal development and regulation of synaptic function including ion channels and actors implicated in synapse formation. The involvement of ion channels in ASD is of great interest as they represent attractive therapeutic targets. In agreement with this view, recent findings have shown that drugs modulating ion channel function are effective for the treatment of certain types of patients with ASD.ConclusionThis review describes the genetic aspects of ASD with a focus on genes encoding ion channels and highlights the therapeutic implications of ion channels in the treatment of ASD.

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Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

Section: Reviewmentioning

confidence: 99%

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Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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“…Dozens of single genes and chromosomal copy number variants (CNVs)3 increase the relative risk of autism spectrum disorder (ASD) nearly 5–50 times over the current background risk. Yet no single gene or CNV causes ASD in 100% of children who carry the mutation,4 and no single DNA mutation accounts for more than 1–2% of all ASD 5.…”

Section: Introductionmentioning

confidence: 99%

Low‐dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

Naviaux

Curtis

et al. 2017

Ann Clin Transl Neurol

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ObjectiveNo drug is yet approved to treat the core symptoms of autism spectrum disorder (ASD). Low‐dose suramin was effective in the maternal immune activation and Fragile X mouse models of ASD. The Suramin Autism Treatment‐1 (SAT‐1) trial was a double‐blind, placebo‐controlled, translational pilot study to examine the safety and activity of low‐dose suramin in children with ASD.MethodsTen male subjects with ASD, ages 5–14 years, were matched by age, IQ, and autism severity into five pairs, then randomized to receive a single, intravenous infusion of suramin (20 mg/kg) or saline. The primary outcomes were ADOS‐2 comparison scores and Expressive One‐Word Picture Vocabulary Test (EOWPVT). Secondary outcomes were the aberrant behavior checklist, autism treatment evaluation checklist, repetitive behavior questionnaire, and clinical global impression questionnaire.ResultsBlood levels of suramin were 12 ± 1.5 μmol/L (mean ± SD) at 2 days and 1.5 ± 0.5 μmol/L after 6 weeks. The terminal half‐life was 14.7 ± 0.7 days. A self‐limited, asymptomatic rash was seen, but there were no serious adverse events. ADOS‐2 comparison scores improved by −1.6 ± 0.55 points (n = 5; 95% CI = −2.3 to −0.9; Cohen's d = 2.9; P = 0.0028) in the suramin group and did not change in the placebo group. EOWPVT scores did not change. Secondary outcomes also showed improvements in language, social interaction, and decreased restricted or repetitive behaviors.InterpretationThe safety and activity of low‐dose suramin showed promise as a novel approach to treatment of ASD in this small study.

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“…Heterozygous, de novo loss‐of‐function mutations in SYNGAP1 have been described in 26 individuals to date [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Zollino et al, 2011; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Redin et al, 2014]. SYNGAP1 encodes Ras/Rap GTPase‐activating protein SynGAP, which is a major component of the post‐synaptic density that regulates synaptic plasticity and ERK/MAPK signaling probably via N‐methyl‐d‐aspartate (NMDA) receptor activation [Komiyama et al, 2002; Muhia et al, 2010].…”

Section: Introductionmentioning

confidence: 99%

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

Parker

Fryer

Shears

et al. 2015

American J of Med Genetics Pt A

115

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De novo mutations (DNM) in SYNGAP1, encoding Ras/Rap GTPase‐activating protein SynGAP, have been reported in individuals with nonsyndromic intellectual disability (ID). We identified 10 previously unreported individuals with SYNGAP1 DNM; seven via the Deciphering Developmental Disorders (DDD) Study, one through clinical analysis for copy number variation and the remaining two (monozygotic twins) via a research multi‐gene panel analysis. Seven of the nine heterozygous mutations are likely to result in loss‐of‐function (3 nonsense; 3 frameshift; 1 whole gene deletion). The remaining two mutations, one of which affected the monozygotic twins, were missense variants. Each individual carrying a DNM in SYNGAP1 had moderate‐to‐severe ID and 7/10 had epilepsy; typically myoclonic seizures, absences or drop attacks. 8/10 had hypotonia, 5/10 had significant constipation, 7/10 had wide‐based/unsteady gait, 3/10 had strabismus, and 2/10 had significant hip dysplasia. A proportion of the affected individuals had a similar, myopathic facial appearance, with broad nasal bridge, relatively long nose and full lower lip vermilion. A distinctive behavioral phenotype was also observed with aggressive/challenging behavior and significant sleep problems being common. 7/10 individuals had MR imaging of the brain each of which was reported as normal. The clinical features of the individuals reported here show significant overlap with those associated with 6p21.3 microdeletions, confirming that haploinsufficiency for SYNGAP1 is responsible for both disorders. © 2015 The Authors. American Journal of Medical Genetics Part A Published by Wiley Periodicals, Inc.

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Functional impact of global rare copy number variation in autism spectrum disorders

Cited by 1,812 publications

References 31 publications

Autism throughout genetics: Perusal of the implication of ion channels

Autism throughout genetics: Perusal of the implication of ion channels

Low‐dose suramin in autism spectrum disorder: a small, phase I/II, randomized clinical trial

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

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