SCN1A duplications and deletions detected in Dravet syndrome: Implications for molecular diagnosis
Carla Marini,Ingrid E. Scheffer,Ingrid E. Scheffer,Rima Nabbout,Davide Mei,Kathy Cox,Leanne M. Dibbens,Leanne M. Dibbens,Jacinta M McMahon,Xenia Iona,Rochio Sanchez Carpintero,Maurizio Elia,Maria Roberta Cilio,Nicola Specchio,Lucio Giordano,Pasquale Striano,Elena Gennaro,J. Helen Cross,Sara Kivity,Miriam Y. Neufeld,Zaid Afawi,Eva Andermann,Daniel L. Keene,Olivier Dulac,Federico Zara,Samuel F. Berkovic,Renzo Guerrini,John C. Mulley,John C. Mulley +28 more
TLDR
The type, frequency, and size of microchromosomal copy number variations affecting the neuronal sodium channel α 1 subunit gene (SCN1A) in Dravet syndrome, other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus are determined.Abstract:
P>Objective:We aimed to determine the type, frequency, and size of microchromosomal copy number variations (CNVs) affecting the neuronal sodium channel alpha 1 subunit gene (SCN1A) in Dravet syndrome (DS), other epileptic encephalopathies, and generalized epilepsy with febrile seizures plus (GEFS+).Methods:Multiplex ligation-dependent probe amplification (MLPA) was applied to detect SCN1A CNVs among 289 cases (126 DS, 97 GEFS+, and 66 with other phenotypes). CNVs extending beyond SCN1A were further characterized by comparative genome hybridization (array CGH).Results:Novel SCN1A CNVs were found in 12.5% of DS patients where sequence-based mutations had been excluded. We identified the first partial SCN1A duplications in two siblings with typical DS and in a patient with early-onset symptomatic generalized epilepsy. In addition, a patient with DS had a partial SCN1A amplification of 5-6 copies. The remaining CNVs abnormalities were four partial and nine whole SCN1A deletions involving contiguous genes. Two CNVs (a partial SCN1A deletion and a duplication) were inherited from a parent, in whom there was mosaicism. Array CGH showed intragenic deletions of 90 kb and larger, with the largest of 9.3 Mb deleting 49 contiguous genes and extending beyond SCN1A.Discussion:Duplication and amplification involving SCN1A are now added to molecular mechanisms of DS patients. Our findings showed that 12.5% of DS patients who are mutation negative have MLPA-detected SCN1A CNVs with an overall frequency of about 2-3%. MLPA is the established second-line testing strategy to reliably detect all CNVs of SCN1A from the megabase range down to one exon. Large CNVs extending outside SCN1A and involving contiguous genes can be precisely characterized by array CGH.read more
Citations
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Etiological heterogeneity in autism spectrum disorders: More than 100 genetic and genomic disorders and still counting
TL;DR: An exhaustive review of the clinical genetics and research genetics literature in an attempt to collate all genes and recurrent genomic imbalances that have been implicated in the etiology of ASD shows that autism is not a single clinical entity but a behavioral manifestation of tens or perhaps hundreds of genetic and genomic disorders.
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NaV1.1 channels and epilepsy
TL;DR: A unified loss‐of‐function hypothesis for the spectrum of epilepsy syndromes caused by genetic changes in NaV1.1 channels is proposed, in which mild impairment predisposes to febrile seizures, intermediate impairment leads to GEFS+ epilepsy, and severe or complete loss of function leads to the intractable seizures and comorbidities of SMEI.
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Sodium channel SCN1A and epilepsy: mutations and mechanisms.
Andrew Escayg,Alan L. Goldin +1 more
TL;DR: Results from mouse models suggest that the primary effect of both GEFS+ and DS mutations is to decrease the activity of GABAergic inhibitory neurons, and may be a general consequence of SCN1A mutations.
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Neurological perspectives on voltage-gated sodium channels
Niels Eijkelkamp,John E. Linley,Mark D. Baker,Michael S. Minett,Roman Cregg,Robert Werdehausen,Robert Werdehausen,Francois Rugiero,John N. Wood +8 more
TL;DR: This review will outline the functions and roles of specific sodium channels in electrical signalling and disease, focusing on neurological aspects, and discuss recent advances in the development of selective sodium channel inhibitors.
Journal ArticleDOI
The genetics of Dravet syndrome
Carla Marini,Ingrid E. Scheffer,Ingrid E. Scheffer,Rima Nabbout,Arvid Suls,Peter De Jonghe,Federico Zara,Renzo Guerrini +7 more
TL;DR: Dravet syndrome has a genetic etiology: between 70% and 80% of patients carry sodium channel α1 subunit gene (SCN1A) abnormalities, and truncating mutations account for about 40% and have a significant correlation with an earlier age of seizures onset.
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An SCN9A channelopathy causes congenital inability to experience pain
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De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy.
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TL;DR: Missense mutations in the gene that codes for a neuronal voltage-gated sodium-channel alpha-subunit (SCN1A) were identified in families with generalized epilepsy with febrile seizures plus (GEFS+) and seven unrelated patients with SMEI were screened for mutations.
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Mutations in SCN9A, encoding a sodium channel alpha subunit, in patients with primary erythermalgia
Yong Yang,Y Wang,Shugang Li,Z Xu,H Li,L Ma,J Fan,D Bu,Bingya Liu,Z Fan,G Wu,J Jin,B Ding,X Zhu,Y Shen +14 more
TL;DR: The data suggest that mutations in SCN9A cause primary erythermalgia, encoding a voltage-gated sodium channel alpha subunit predominantly expressed in sensory and sympathetic neurones, may play an important role in nociception and vasomotor regulation.
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