Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Lemke, Johannes R.; Lal, Dennis; Reinthaler, Eva M.; Steiner, Isabelle; Nothnagel, Michael; Alber, Michael; Geider, Kirsten; Laube, Bodo; Schwake, Michael; Finsterwalder, Katrin; Franke, André; Schilhabel, Markus B.; Jähn, Johanna A.; Muhle, Hiltrud; Boor, Rainer; Paesschen, Wim Van; Caraballo, Roberto; Fejerman, Natalio; Weckhuysen, Sarah; Jonghe, Peter De; Larsen, Jan; Møller, Rikke S.; Hjalgrim, Helle; Addis, Laura; Tang, Shan; Hughes, Elaine; Pal, Deb K.; Veri, Kadi; Vaher, Ulvi; Talvik, Tiina; Dimova, Petia; Guerrero, Rosa; Serratosa, Joan; Linnankivi, Tarja; Lehesjoki, Anna‐Elina; Ruf, Susanne; Wolff, Markus; Buerki, Sarah E.; Wohlrab, Gabriele; Kroell, Judith; Datta, Alexandre N.; Fiedler, Barbara; Kurlemann, Gerhard; Kluger, Gerhard; Hahn, Andreas; Haberlandt, D Edda; Kutzer, Christina; Sperner, J.; Becker, Felicitas; Weber, Yvonne G.; Feucht, Martha; Steinböck, Hannelore; Neophythou, Birgit; Ronen, Gabriel M.; Gruber-Sedlmayr, U; Geldner, Julia; Harvey, Robert J.; Hoffmann, Per; Herms, Stefan; Altmüller, Janine; Toliat, Mohammad Reza; Thiele, Holger; Nürnberg, Peter; Wilhelm, Christian; Stephani, Ulrich; Helbig, Ingo; Lerche, Holger; Zimprich, Fritz; Neubauer, Bernd A.; Biskup, Saskia; Spiczak, Sarah von

doi:10.1038/ng.2728

Cited by 391 publications

(353 citation statements)

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“…9,10 Homozygous or biallelic variants have not been reported so far for genes encoding other subunits of NMDA receptors, such as GRIN2A and GRIN2B, whose heterozygous variants cause various ranges of neurodevelopmental disorders with epilepsy. [11][12][13][14] The present family together with previous reports suggests that heterozygous variants located in the aminoterminal domain may have a hypomorphic effect, whereas heterozygous variants located in the transmembrane region may rather lead to a gain-of-function.…”

Section: Discussionmentioning

confidence: 79%

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

et al. 2017

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We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1. Massive parallel sequencing was performed using a gene panel including 450 genes related to intellectual disability and autism spectrum disorders. We found a homozygous missense variation of GRIN1 (c.679G4C; p.(Asp227His)) in the two affected sibs, which was inherited from both unaffected heterozygous parents. Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders. The p.(Asp227His) variant is located in the same aminoterminal protein domain as the recently published p.(Arg217Trp), which was found at the homozygous state in two patients with a similar phenotype of severe intellectual disability and autistic features but without epilepsy. In silico predictions were consistent with a deleterious effect. The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance. European Journal of Human Genetics (2017) 25, 376-380; doi:10.1038/ejhg.2016.163; published online 4 January 2017 INTRODUCTION GRIN1 (MIM *138249) encodes the GluN1 subunit of N-methyl-Daspartate receptors, members of the glutamate receptor channel superfamily, which are heteromeric protein complexes with multiple subunits arranged to form a ligand-gated ion channel. These subunits have a key role in the plasticity of synapses, which underlies memory and learning. 1 De novo heterozygous variants of GRIN1 were first identified by targeted Sanger sequencing in two patients with intellectual disability (ID) with or without epilepsy (MIM #614254). 2 Recent advances in nextgeneration sequencing have shown that GRIN1 de novo heterozygous variants represent a recurrent cause of epileptic encephalopathy with early onset. 3,4 A recent paper provided a better delineation of the GRIN1 phenotypic spectrum that includes severe ID with absent speech, muscular hypotonia, hyperkinetic movements, oculogyric crises, hand stereotypies, cortical blindness, and epilepsy. 5 This article also reported for the first time two homozygous GRIN1 variants in families with severe neurodevelopmental phenotypes.In the present paper we report a second family including two affected sibs with a homozygous missense variant, thus expanding the phenotype-genotype correlations related to GRIN1 variants.

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Section: Discussionmentioning

confidence: 79%

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

et al. 2017

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“…A series of mutations of this gene have been described in subjects/families with a phenotype overlapping that of our patient including learning disabilities. 33,34 Patient 13-B had a missense mutation of SCN2A inherited from her mother. Mutations of this gene are associated with noteworthy clinical variability ranging from familial benign seizures to generalized epilepsy with febrile seizures or epileptic encephalopathy.…”

Section: Discussionmentioning

confidence: 99%

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

et al. 2014

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We analyzed by next-generation sequencing (NGS) 67 epilepsy genes in 19 patients with different types of either isolated or syndromic epileptic disorders and in 15 controls to investigate whether a quick and cheap molecular diagnosis could be provided. The average number of nonsynonymous and splice site mutations per subject was similar in the two cohorts indicating that, even with relatively small targeted platforms, finding the disease gene is not an univocal process. Our diagnostic yield was 47% with nine cases in which we identified a very likely causative mutation. In most of them no interpretation would have been possible in absence of detailed phenotype and familial information. Seven out of 19 patients had a phenotype suggesting the involvement of a specific gene. Disease-causing mutations were found in six of these cases. Among the remaining patients, we could find a probably causative mutation only in three. None of the genes affected in the latter cases had been suspected a priori. Our protocol requires 8-10 weeks including the investigation of the parents with a cost per patient comparable to sequencing of 1-2 medium-to-large-sized genes by conventional techniques. The platform we used, although providing much less information than whole-exome or whole-genome sequencing, has the advantage that can also be run on 'benchtop' sequencers combining rapid turnaround times with higher manageability.

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“…Language skills may recover after the remission of seizures that occurs in adolescence, or may be permanently impaired. Although the genetic architecture of EAS disorders is still not fully understood, studies have shown that heterozygous disruptions of GRIN2A account for around 10-20 % of cases, including both inherited and de novo occurrences of the disorder Lemke et al 2013;Carvill et al 2013;DeVries and Patel 2013). GRIN2A encodes a subunit of the NMDA receptor, a ligand-and voltage-gated cation channel which is central to synaptic plasticity (Fan et al 2014).…”

Section: Epilepsy-aphasia Spectrum Disordersmentioning

confidence: 99%

Insights into the Genetic Foundations of Human Communication

2015

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The human capacity to acquire sophisticated language is unmatched in the animal kingdom. Despite the discontinuity in communicative abilities between humans and other primates, language is built on ancient genetic foundations, which are being illuminated by comparative genomics. The genetic architecture of the language faculty is also being uncovered by research into neurodevelopmental disorders that disrupt the normally effortless process of language acquisition. In this article, we discuss the strategies that researchers are using to reveal genetic factors contributing to communicative abilities, and review progress in identifying the relevant genes and genetic variants. The first gene directly implicated in a speech and language disorder was FOXP2. Using this gene as a case study, we illustrate how evidence from genetics, molecular cell biology, animal models and human neuroimaging has converged to build a picture of the role of FOXP2 in neurodevelopment, providing a framework for future endeavors to bridge the gaps between genes, brains and behavior.

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Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes

Cited by 391 publications

References 31 publications

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

Improving molecular diagnosis in epilepsy by a dedicated high-throughput sequencing platform

Insights into the Genetic Foundations of Human Communication

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