A de novo paradigm for mental retardation

Vissers, Lisenka E.L.M.; Ligt, Joep de; Gilissen, Christian; Janssen, Irene M.; Steehouwer, Marloes; Vries, Petra de; Lier, Bart van; Arts, Peer; Wieskamp, Nienke; Rosario, Marisol del; Bon, Bregje W.M. van; Hoischen, Alexander; Vries, Bert B.A. de; Brunner, Han G.; Veltman, Joris A.

doi:10.1038/ng.712

Cited by 735 publications

(644 citation statements)

References 30 publications

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“…Supplementary Table I summarizes the available clinical data on the 26 individuals who have been reported to date with presumed causative mutations in SYNGAP1 or deletions or translocations involving this gene [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Cook, 2011; Klitten et al, 2011; Zollino et al, 2011; Clement et al, 2012; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Dyment et al, 2014; O'Roak et al, 2014; Redin et al, 2014]. De novo mutations in this gene are undoubtedly a significant cause of intellectual disability, accounting for 0.62% of all the patients in the DDD Study [Wright et al, 2014] and major contributors to other cohorts that have been studied (Supplementary Table II).…”

Section: Discussionmentioning

confidence: 99%

“…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%

“…Carvill et al performed massively parallel sequencing in 500 individuals with epileptic encephalopathy and identified four patients with de novo SYNGAP1 mutations [Carvill et al, 2013]. Further patients have been described as part of large next generation sequencing studies of individuals with ID [Vissers et al, 2010; de Ligt et al, 2012; Rauch et al, 2012; Redin et al, 2014]. …”

Section: Introductionmentioning

confidence: 99%

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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

111

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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

111

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“…4 It has been suggested that intellectual disability is under negative selection, and that recent deleterious mutations have an important role in the underlying aetiology. 5,6 The wealth of molecular genetic data currently available allows estimates of inbreeding on a genome-wide level and to examine the effects of long-term ancestral levels of inbreeding. 7 Such an association with inbreeding, as measured by runs of homozygous polymorphisms (ROH), has previously been identified with several behavioural traits, such as schizophrenia, Parkinson's disease and personality measures, [8][9][10] as well as non-behavioural traits such as height.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

et al. 2013

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The consequence of reduced cognitive ability from inbreeding has long been investigated, mainly restricted to cousin-cousin marriages. Molecular genetic techniques now allow us to test the relationship between increased ancestral inbreeding and cognitive ability in a population of traditionally unrelated individuals. In a representative UK sample of 2329 individuals, we used genome-wide SNP data to estimate the percentage of the genome covered by runs of homozygous SNPs (ROH). This was tested for association with general cognitive ability, as well as measures of verbal and non-verbal ability. Further, association was tested between these traits and specific ROH. Burden of ROH was not associated with cognitive ability after correction for multiple testing, although burden of ROH was nominally associated with increased non-verbal cognitive ability (P ¼ 0.03). Moreover, although no individual ROH was significantly associated with cognitive ability, there was a significant bias towards increased cognitive ability in carriers of ROH (P ¼ 0.002). A potential explanation for these results is increased positive assortative mating in spouses with higher cognitive ability, although we found no evidence in support of this hypothesis in a separate sample. Reduced minor allele frequency across the genome was associated with higher cognitive ability, which could contribute to an apparent increase in ROH. This may reflect minor alleles being more likely to be deleterious.

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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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A de novo paradigm for mental retardation

Cited by 735 publications

References 30 publications

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

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

Genome-wide estimates of inbreeding in unrelated individuals and their association with cognitive ability

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

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