Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

Carvill, Gemma L.; Heavin, Sinéad B.; Yendle, Simone C.; McMahon, Jacinta M.; O’Roak, Brian J.; Cook, Joseph; Khan, Adiba; Dorschner, Michael O.; Weaver, Molly; Calvert, Sophie; Malone, Stephen M.; Wallace, Geoff; Stanley, Thorsten; Bye, Ann; Bleasel, Andrew; Howell, Katherine; Kivity, Sara; Mackay, Mark T; Rodriguez‐Casero, Victoria; Webster, Richard; Korczyn, Amos D.; Afawi, Zaid; Zelnick, Nathanel; Lerman‐Sagie, Tally; Lev, Dorit; Møller, Rikke S.; Gill, Deepak; Andrade, Danielle M.; Freeman, Jeremy L.; Sadleir, Lynette G.; Shendure, Jay; Berkovic, Samuel F.; Scheffer, Ingrid E.; Mefford, Heather C

doi:10.1038/ng.2646

Cited by 606 publications

(610 citation statements)

References 41 publications

Supporting

Mentioning

572

Contrasting

Unclassified

Order By: Relevance

“…1A). Two missense mutations of Arg1872 were described in seven patients1, 3, 11, 18 and we describe a third substitution in two patients, making this the most frequently mutated residue. The CpG dinucleotides in the codons for Arg1617 and Arg1872 are mutational hotspots (Fig.…”

Section: Introductionmentioning

confidence: 69%

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Wagnon

Barker

Hounshell

et al. 2015

Ann Clin Transl Neurol

101

View full text Add to dashboard Cite

ObjectiveThe early infantile epileptic encephalopathy type 13 (EIEE13, OMIM #614558) results from de novo missense mutations of SCN8A encoding the voltage‐gated sodium channel Nav1.6. More than 20% of patients have recurrent mutations in residues Arg1617 or Arg1872. Our goal was to determine the functional effects of these mutations on channel properties.MethodsClinical exome sequencing was carried out on patients with early‐onset seizures, developmental delay, and cognitive impairment. Two mutations identified here, p.Arg1872Leu and p.Arg1872Gln, and two previously identified mutations, p.Arg1872Trp and p.Arg1617Gln, were introduced into Nav1.6 cDNA, and effects on electrophysiological properties were characterized in transfected ND7/23 cells. Interactions with FGF14, G‐protein subunit Gβγ, and sodium channel subunit β1 were assessed by coimmunoprecipitation.ResultsWe identified two patients with the novel mutation p.Arg1872Leu and one patient with the recurrent mutation p.Arg1872Gln. The three mutations of Arg1872 and the mutation of Arg1617 all impaired the sodium channel transition from open state to inactivated state, resulting in channel hyperactivity. Other observed abnormalities contributing to elevated channel activity were increased persistent current, increased peak current density, hyperpolarizing shift in voltage dependence of activation, and depolarizing shift in steady‐state inactivation. Protein interactions were not affected.InterpretationRecurrent mutations at Arg1617 and Arg1872 lead to elevated Nav1.6 channel activity by impairing channel inactivation. Channel hyperactivity is the major pathogenic mechanism for gain‐of‐function mutations of SCN8A. EIEE13 differs mechanistically from Dravet syndrome, which is caused by loss‐of‐function mutations of SCN1A. This distinction has important consequences for selection of antiepileptic drugs and the development of gene‐ and mutation‐specific treatments.

show abstract

Section: Introductionmentioning

confidence: 69%

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Wagnon

Barker

Hounshell

et al. 2015

Ann Clin Transl Neurol

101

View full text Add to dashboard Cite

show abstract

“…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%

“…This group subsequently published eight further affected individuals through re‐sequencing predominantly ID cohorts enriched for epilepsy [2011a, b; Berryer et al, 2013]. 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%

See 1 more Smart Citation

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

109

115

View full text Add to dashboard Cite

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.

show abstract

“…This means that the definitive etiology is known, although factors influencing phenotypic variability are usually not yet understood, such as modifier genes or the influence of environmental factors. Many new etiological diagnoses are emerging such as CHD2 encephalopathy, KCNQ2 encephalopathy, and STXBP1 encephalopathy, to name a few 6, 7, 8, 9. One of the best‐known examples is an individual with Dravet syndrome, who has a known mutation of the sodium channel gene SCN1A 10…”

Section: Proposal For a Framework For Epilepsy Classification And Diamentioning

confidence: 99%

Classification of the epilepsies: New concepts for discussion and debate—Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology

et al. 2016

View full text Add to dashboard Cite

SummaryThe ILAE Task Force on Classification presents a road map for the development of an updated, relevant classification of the epilepsies. Our objective is to explain the process to date and the plan moving forward as well as to invite further discussion about the newly proposed terms and concepts. Here, we present our response to feedback about the 2010 Organization of the Epilepsies and clarify the reintroduction of the word “classification” to map out a framework for epilepsy diagnosis. We introduce some new concepts and suggest four diagnostic levels: seizure type, epilepsy category, epilepsy syndrome, and epilepsy with (specific) etiology to denote specific levels of diagnosis. We expand the etiological categories to six, focusing on those with treatment implications. Finally, we discuss the changes in terminology originally suggested and modifications in response to comments from the epilepsy community. We welcome feedback and discussion from the global epilepsy community, particularly for the new suggested terms, so that we can cement a classification that both reflects current thinking and scientific understanding and provides a dynamic, evolving framework.

show abstract

Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

Cited by 606 publications

References 41 publications

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

Pathogenic mechanism of recurrent mutations of SCN8A in epileptic encephalopathy

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

Classification of the epilepsies: New concepts for discussion and debate—Special report of the ILAE Classification Task Force of the Commission for Classification and Terminology

Contact Info

Product

Resources

About