Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

O’Roak, Brian J.; Deriziotis, Pelagia; Lee, Choli; Vives, Laura; Schwartz, Jerrod J.; Girirajan, Santhosh; Karakoç, Emre; MacKenzie, Alexandra P.; Ng, Sarah; Baker, Carl; Rieder, Mark J.; Nickerson, Deborah A.; Bernier, Raphael; Fisher, Simon E.; Shendure, Jay; Eichler, Evan E.

doi:10.1038/ng.835

Cited by 1,081 publications

(985 citation statements)

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“…Using NGS, O'Rack et al. identified de novo variations in FOXP1 , GRIN2B , SCN1A , LAMC3, and rare inherited CNTNAP2 variations (De Rubeis et al., 2014; O'Roak et al., 2011). Three genes were found in ASD probands with two de novo variations in each of these genes: BRCA2 , FAT1, and KCNMA1 (Neale et al., 2012).…”

Section: Reviewmentioning

confidence: 99%

“…Others genes encoding synaptic proteins linked to ASD were also identified by NGS: They include the glutamate receptors (GRIK2, GRIA3), the cell adhesion molecule CNTNAP2, and the scaffolding protein SHANK3. SHANK3 is involved in (i) synapse formation and maturation, (ii) the link between neurotransmitter receptors and ion channels, and (iii) the interaction with scaffolding proteins and gene regulatory proteins (e.g., protein of chromatin remodeling CHD8; Anney et al., 2010; Cotney et al., 2015; De Rubeis et al., 2014; O'Roak et al., 2011). NRXN1 , NLGN3/4X, and SHANK3 genes, which encode proteins involved in neuronal cell adhesion and in the regulation of synaptic transmission, are considered strong candidate loci for ASD (Weiss & Arking, 2009).…”

Section: Reviewmentioning

confidence: 99%

“…NRXN1 , NLGN3/4X, and SHANK3 genes, which encode proteins involved in neuronal cell adhesion and in the regulation of synaptic transmission, are considered strong candidate loci for ASD (Weiss & Arking, 2009). Variations in those loci have also been detected in several patients with ASD (Anney et al., 2010; O'Roak et al., 2011; Table 1). …”

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%

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Autism throughout genetics: Perusal of the implication of ion channels

et al. 2018

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“…Since then, other patients have been identified with chromosomal rearrangements affecting multiple genes including CNTNAP2, which are likely to confound the effects resulting from CNTNAP2 mutation [3][4][5][6][7][8][9] (Table 1). However, patients carrying point mutations or microdeletions that affect only the CNTNAP2 locus have now been reported, which provides insight into the deficit caused specifically by reduction or loss of CNTNAP2; [10][11][12][13][14][15][16] (Table 1).…”

Section: Cntnap2 and Cognitive Disorders Mutations Of Cntnap2mentioning

confidence: 99%

Shining a light on CNTNAP2: complex functions to complex disorders

2013

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The genetic basis of complex neurological disorders involving language are poorly understood, partly due to the multiple additive genetic risk factors that are thought to be responsible. Furthermore, these conditions are often syndromic in that they have a range of endophenotypes that may be associated with the disorder and that may be present in different combinations in patients. However, the emergence of individual genes implicated across multiple disorders has suggested that they might share similar underlying genetic mechanisms. The CNTNAP2 gene is an excellent example of this, as it has recently been implicated in a broad range of phenotypes including autism spectrum disorder (ASD), schizophrenia, intellectual disability, dyslexia and language impairment. This review considers the evidence implicating CNTNAP2 in these conditions, the genetic risk factors and mutations that have been identified in patient and population studies and how these relate to patient phenotypes. The role of CNTNAP2 is examined in the context of larger neurogenetic networks during development and disorder, given what is known regarding the regulation and function of this gene. Understanding the role of CNTNAP2 in diverse neurological disorders will further our understanding of how combinations of individual genetic risk factors can contribute to complex conditions.

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“…Research investigations using Genome Wide Association Study (GWAS) (Network and Pathway Analysis Subgroup of the Psychiatric Genomics Consortium, 2015; Wood, 2013), exome‐based sequencing (Girard et al, 2011; Iossifov et al, 2012; O'Roak et al, 2011; Vissers et al, 2010; Xu et al, 2012), and whole genome sequencing (Kong et al, 2012) techniques have revealed several candidate genes that are associated with common neuropsychiatric disorders such as Autism Spectrum Disorder (ASD), intellectual disability, and schizophrenia. However, in the case of rare disorders, understanding the genetic origins and progressions of disorders—one of the key objectives of Precision Medicine research (Collins & Varmus, 2015; Kohane, 2015; Kohane, Churchill, & Murphy, 2012)—is hindered by small patient population size, the consequent paucity of patient data, and the lack of robust phenotyping protocols (Baynam et al, 2015; Delude, 2015; Robinson, Mungall, & Haendel, 2015).…”

Section: Introductionmentioning

confidence: 99%

Phelan‐McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports

Kothari

Wack

Hassen‐Khodja

et al. 2017

American J of Med Genetics Pt B

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The heterogeneity of patient phenotype data are an impediment to the research into the origins and progression of neuropsychiatric disorders. This difficulty is compounded in the case of rare disorders such as Phelan‐McDermid Syndrome (PMS) by the paucity of patient clinical data. PMS is a rare syndromic genetic cause of autism and intellectual deficiency. In this paper, we describe the Phelan‐McDermid Syndrome Data Network (PMS_DN), a platform that facilitates research into phenotype–genotype correlation and progression of PMS by: a) integrating knowledge of patient phenotypes extracted from Patient Reported Outcomes (PRO) data and clinical notes—two heterogeneous, underutilized sources of knowledge about patient phenotypes—with curated genetic information from the same patient cohort and b) making this integrated knowledge, along with a suite of statistical tools, available free of charge to authorized investigators on a Web portal https://pmsdn.hms.harvard.edu. PMS_DN is a Patient Centric Outcomes Research Initiative (PCORI) where patients and their families are involved in all aspects of the management of patient data in driving research into PMS. To foster collaborative research, PMS_DN also makes patient aggregates from this knowledge available to authorized investigators using distributed research networks such as the PCORnet PopMedNet. PMS_DN is hosted on a scalable cloud based environment and complies with all patient data privacy regulations. As of October 31, 2016, PMS_DN integrates high‐quality knowledge extracted from the clinical notes of 112 patients and curated genetic reports of 176 patients with preprocessed PRO data from 415 patients.

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Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations

Cited by 1,081 publications

References 51 publications

Autism throughout genetics: Perusal of the implication of ion channels

Autism throughout genetics: Perusal of the implication of ion channels

Shining a light on CNTNAP2: complex functions to complex disorders

Phelan‐McDermid syndrome data network: Integrating patient reported outcomes with clinical notes and curated genetic reports

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