A mutation in <i>GABRB3</i> associated with Dravet syndrome

Le, Sy Vinh; Le, Phan Hoang Truc; Le, Thi Khanh Van; Huynh, Thi Thuy Kieu; Hang, Đo Thi Thu

doi:10.1002/ajmg.a.38282

Cited by 28 publications

(29 citation statements)

References 28 publications

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“…Dravet syndrome and GEFS+ phenotypes may result from mutations in other genes that alter GABAergic transmission, such as GABRA1 , GABRB2 , GABRB3 , and GABRG2 , which encode corresponding subunits of the GABA A receptor …”

Section: Gene Dysfunction In Age‐dependent Epilepsy Phenotypesmentioning

confidence: 99%

“…3 Dravet syndrome and GEFS+ phenotypes may result from mutations in other genes that alter GABAergic transmission, such as GABRA1, GABRB2, GABRB3, and GABRG2, which encode corresponding subunits of the GABA A receptor. [27][28][29][30] Structural maintenance of chromosomes 1 (SMC1A) encephalopathy is clinically very similar to the phenotype generated by protocadherin 19 (PCDH19) mutations since febrile seizures tend to cluster. 31 PCDH19 encephalopathy affects females (epilepsy in females with intellectual disability) for which, at onset, the phenotype may be difficult to distinguish from Dravet syndrome owing to mutation in SCN1A.…”

Section: Dravet Syndrome and Related Conditionsmentioning

confidence: 99%

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Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Gataullina

Bienvenu

Nabbout

et al. 2019

Develop Med Child Neuro

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The aim of this study was to disentangle mechanisms of epileptogenesis in monogenic epilepsies in children. We reviewed paediatric monogenic epilepsies excluding brain malformation or an inborn error of metabolism, but including the gene function whether there is loss‐of‐function or gain‐of‐function, age at gene expression when available, and associated epilepsy syndrome. Genes for which at least five patients with similar epilepsy phenotype had been reported were selected. Three mechanisms are shared by most monogenic epilepsies: (1) excess of N‐methyl‐d‐aspartate (NMDA) transmission activation (NMDA‐pathies); (2) abnormal gamma‐aminobutyric acid (GABA) transmission with reduced inhibition (phasic GABA‐pathies); and (3) tonic activation of extrasynaptic GABAA receptors by extracellular GABA (tonic GABA‐pathies). NMDA‐pathies comprise early epileptic encephalopathy with suppression‐burst, neonatal/infantile benign seizures, West and Lennox–Gastaut syndromes, and encephalopathy with continuous spike waves in slow sleep, thus brief seizures with major interictal spiking. Phasic GABA‐pathies comprise mostly generalized epilepsy with febrile seizures plus and Dravet syndrome, thus long‐lasting seizures with mild interictal spiking. Tonic GABA‐pathies cause epilepsy with myoclonic–atonic seizures and Angelman syndrome, thus major high‐amplitude slow‐wave activity. This pathophysiological approach to monogenic epilepsies provides diagnostic clues and helps to guide treatment strategy. What this paper adds In paediatric monogenic epilepsies, electroclinical patterns point to three main mechanisms: NMDA‐pathies, and phasic and tonic GABA‐pathies. Antiepileptic treatment choice could be guided by each of these mechanisms.

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Section: Gene Dysfunction In Age‐dependent Epilepsy Phenotypesmentioning

confidence: 99%

Section: Dravet Syndrome and Related Conditionsmentioning

confidence: 99%

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Gataullina

Bienvenu

Nabbout

et al. 2019

Develop Med Child Neuro

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“…Specifically, Genomedics has the F-score greater than 93.3% while the pipeline of BWA and GATK is the second best method (i.e, F-score = 92.7%). Genomedics has been used to analyze whole exomes and genomes in various human genome projects [8,30,31].…”

Section: The Statistical Approachmentioning

confidence: 99%

A computational framework to analyze human genomes

Le¹

2019

JCC

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The advent of genomic technologies has led to the current genomic era. Large-scale human genome projects have resulted in a huge amount of genomic data. Analyzing human genomes is a challenging task including a number of key steps from short read alignment, variant calling, and variant annotating. In this paper, the state-of-the-art computational methods and databases for each step will be analyzed to suggest a practical and efficient guideline for whole human genome analyses. This paper also discusses frameworks to combine variants from various genome analysis pipelines to obtain reliable variants. Finally, we will address advantages as well as discordances of widely-used variant annotation methods to evaluate the clinical significance of variants. The review will empower bioinformaticians to efficiently perform human genome analyses, and more importantly, help genetic consultants understand and properly interpret mutations for clinical purposes.

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“…[2][3][4][5] Recently, the phenotypic spectrum of epilepsies in patients with GABRB3 mutations has been described in a cohort of 22 patients, 4 in addition to several case reports of de novo mutations in GABRB3 in patients with various epilepsy subtypes. [6][7][8] The epileptic phenotypes ranged from febrile seizures, genetic epilepsies with febrile seizures plus (GEFSþ), and epilepsy with myoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies (EE). None of these patients was reported to show dysmorphic features.…”

Section: Introductionmentioning

confidence: 99%

“…None of these patients was reported to show dysmorphic features. 4,[6][7][8] In mice, however, knockout of Gabrb3 causes epileptic encephalopathy and cleft lip and palate. 9,10 In addition, mutations in a different GABA A -receptor subunit (GABRA3) were associated with orofacial dysmorphism in addition to epileptic phenotypes of varying severity in one out of seven families.…”

Section: Introductionmentioning

confidence: 99%

Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy

et al. 2019

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Mutations in GABAA-receptor subunit genes are associated with a heterogeneous spectrum of epilepsies. Patients with epilepsy caused by mutations in a specific GABAA-receptor (GABRA3) occasionally present with orofacial dysmorphism (e.g., cleft palates). While cleft palates have been described in Gabrb3 knockout mice and in humans with GABRB3 variants without epilepsy, the specific combination of epilepsy and cleft palate in humans with GABRB3 mutations has not yet been reported.We describe a patient with epileptic encephalopathy (EE) who presented with therapy-refractory neonatal-onset myoclonic seizures and severe developmental delay. Electroencephalogram showed burst suppression pattern at neonatal age and hypsarrhythmia at infantile age. Initial magnetic resonance imaging was unremarkable. As he additionally presented with a cleft palate, we were curious whether cleft palate and EE had the same genetic origin. Whole exome sequencing of the index patient revealed a novel pathogenic heterozygous de novo mutation in GABRB3 (c.899T > C; p.I300T). In consistency with Gabrb3 knockout mice data, this is the first report of cleft palate in a patient with GABRB3 associated EE.We suggest to add cleft palate to the phenotypic GABRB3 spectrum and to screen for mutations in GABAA-receptors in patients with EE and orofacial dysmorphism.

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A mutation in GABRB3 associated with Dravet syndrome

Cited by 28 publications

References 28 publications

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

Gene mutations in paediatric epilepsies cause NMDA‐pathy, and phasic and tonic GABA‐pathy

A computational framework to analyze human genomes

Cleft Palate as Distinguishing Feature in a Patient with GABRB3 Epileptic Encephalopathy

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