Intellectual disability without epilepsy associated with STXBP1 disruption

Hamdan, Fadi F.; Gauthier, Julie; Dobrzeniecka, Sylvia; Lortie, Anne; Mottron, Laurent; Vanasse, Michel; D’Anjou, Guy; Lacaille, Jean-Claude; Rouleau, Guy A.; Michaud, Jacques L.

doi:10.1038/ejhg.2010.183

Cited by 90 publications

(73 citation statements)

References 10 publications

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“…Table 1 summarizes our array findings and the clinical phenotype of these patients. We consider 11 CNVs to be pathogenic in our patients based on the loss or predicted loss of function of the encoded protein and the phenotypic overlap between our patients and those previously reported (STXBP1, 11,18 28 and 9p24 microdeletions). We consider two whole gene duplications to be likely pathogenic (patients 224, 8327); DCX duplication has not been reported in ID, but is sensitive to loss, 29 the PI4KA duplication in our patient has already been published.…”

Section: Resultsmentioning

confidence: 99%

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

et al. 2013

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Intellectual disability affects about 3% of individuals globally, withB50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copynumber variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis.

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Section: Resultsmentioning

confidence: 99%

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

et al. 2013

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“…In addition to intractable seizures, individuals with mutations in MUNC18-1 further exhibit profound intellectual disability, physical deficits and varying degrees of cerebral atrophy (Saitsu et al, 2008). Although disruption of MUNC18-1 is most closely associated with Ohtahara syndrome, de novo mutations in MUNC18-1 have also been identified in individuals with severe intellectual disability and non-syndromic epilepsy, individuals with non-syndromic intellectual disability, and individuals with Rett syndrome (Hamdan et al, 2011(Hamdan et al, , 2009Olson et al, 2015;Romaniello et al, 2015). Likewise, recent studies have revealed possible connections between mutations in exocyst genes and neurological disorders (Evers et al, 2014;Frühmesser et al, 2013;Wen et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Regulation of dendrite growth and maintenance by exocytosis

Peng

Lee

Rowland

et al. 2015

Journal of Cell Science

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Dendrites lengthen by several orders of magnitude during neuronal development, but how membrane is allocated in dendrites to facilitate this growth remains unclear. Here, we report that Ras opposite (Rop), the Drosophila ortholog of the key exocytosis regulator Munc18-1 (also known as STXBP1), is an essential factor mediating dendrite growth. Neurons with depleted Rop function exhibit reduced terminal dendrite outgrowth followed by primary dendrite degeneration, suggestive of differential requirements for exocytosis in the growth and maintenance of different dendritic compartments. Rop promotes dendrite growth together with the exocyst, an octameric protein complex involved in tethering vesicles to the plasma membrane, with Rop-exocyst complexes and exocytosis predominating in primary dendrites over terminal dendrites. By contrast, membrane-associated proteins readily diffuse from primary dendrites into terminals, but not in the reverse direction, suggesting that diffusion, rather than targeted exocytosis, supplies membranous material for terminal dendritic growth, revealing key differences in the distribution of materials to these expanding dendritic compartments.

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“…relation to these diseases is uncertain (Niemann et al, 2008;Hamdan et al, 2011;Tarabeux et al, 2011;Matsuno et al, 2015).The frequency of NMDA receptor mutations found in epilepsy patients with slow wave sleep syndrome and benign epilepsy with centrotemporal spikes (Carvill et al, 2013b;Lemke et al, 2013), together with the rates of incidence of these conditions (from the Centers for Disease Control, http:// www.cdc.gov/epilepsy/basics/fast_facts.html; Pavlou et al, 2012;Singhal and Sullivan, 2014), suggests that thousands of North American pediatric epilepsy patients have undiagnosed NMDA receptor mutations. In addition to seizure disorders, NMDA receptor mutations have been identified in patients with Alzheimer's disease, attention deficit hyperactivity disorder, autism spectrum disorder, developmental delay, schizophrenia, and intellectual disability ( Table 2).…”

Section: Gaba/glutamate Receptor Mutations In Neurologic Diseasesmentioning

confidence: 99%

“…For example, of more than 100 published mutations in NMDA receptor subunits, functional data are reported for only 12 (Endele et al, 2010;Hamdan et al, 2011;Carvill et al, 2013b;Lemke et al, 2013Lemke et al, , 2014Lesca et al, 2013;Adams et al, 2014;Pierson et al, 2014;Yuan et al, 2014). The lack of functional information for de novo mutations in genes with a strong genetic link to disease underscores a pressing need.…”

Section: Gaba/glutamate Receptor Mutations In Neurologic Diseasesmentioning

confidence: 99%

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

Yuan¹,

Low²,

Moody³

et al. 2015

Mol Pharmacol

186

176

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The advent of whole exome/genome sequencing and the technology-driven reduction in the cost of next-generation sequencing as well as the introduction of diagnostic-targeted sequencing chips have resulted in an unprecedented volume of data directly linking patient genomic variability to disorders of the brain. This information has the potential to transform our understanding of neurologic disorders by improving diagnoses, illuminating the molecular heterogeneity underlying diseases, and identifying new targets for therapeutic treatment. There is a strong history of mutations in GABA receptor genes being involved in neurologic diseases, particularly the epilepsies. In addition, a substantial number of variants and mutations have been found in GABA receptor genes in patients with autism, schizophrenia, and addiction, suggesting potential links between the GABA receptors and these conditions. A new and unexpected outcome from sequencing efforts has been the surprising number of mutations found in glutamate receptor subunits, with the GRIN2A gene encoding the GluN2A N-methyl-D-aspartate receptor subunit being most often affected. These mutations are associated with multiple neurologic conditions, for which seizure disorders comprise the largest group. The GluN2A subunit appears to be a locus for epilepsy, which holds important therapeutic implications. Virtually all a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor mutations, most of which occur within GRIA3, are from patients with intellectual disabilities, suggesting a link to this condition. Similarly, the most common phenotype for kainate receptor variants is intellectual disability. Herein, we summarize the current understanding of disease-associated mutations in ionotropic GABA and glutamate receptor families, and discuss implications regarding the identification of human mutations and treatment of neurologic diseases.

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Intellectual disability without epilepsy associated with STXBP1 disruption

Cited by 90 publications

References 10 publications

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

Regulation of dendrite growth and maintenance by exocytosis

Ionotropic GABA and Glutamate Receptor Mutations and Human Neurologic Diseases

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