Screening of <scp><i>CACNA1A</i></scp> and <scp><i>ATP1A2</i></scp> genes in hemiplegic migraine: clinical, genetic, and functional studies

Carreño, Oriel; Corominas, Roser; Serra, Selma A.; Sintas, Cèlia; Fernàndez‐Castillo, Noèlia; Vila‐Pueyo, Marta; Toma, Claudio; Gené, Gemma G.; Pons, Roser; Llaneza, M.; Sobrido, María-Jesús; Grinberg, Daniel; Valverde, Miguel A.; Fernández-Fernández, José M.; Macaya, Alfons; Cormand, Bru

doi:10.1002/mgg3.24

Cited by 36 publications

(38 citation statements)

References 84 publications

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“…This may occur because these symptoms result from multiple genetic causes. For example though plegic episodes are classically associated with mutation in ATP1A3 , or CACNA1A, such episodes have also been described in individuals with mutation in ATP1A2, PRRT2, SLC2A1 , SLC1A3 , MR1 and SCN1A . Similarly, nocturnal spells, though most suggestive of mutation in ADCY5 , have also been described in patients with PRRT2 and SLC16A2 mutations.…”

Section: Resultsmentioning

confidence: 99%

Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes

Zima

Ceulemans

Reiner

et al. 2018

Ann Clin Transl Neurol

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Paroxysmal movement disorders encompass varied motor phenomena. Less recognized features and wide phenotypic and genotypic heterogeneity are impediments to straightforward molecular diagnosis. We describe a family with episodic ataxia type 1, initially mis‐characterized as paroxysmal dystonia to illustrate this diagnostic challenge. We summarize clinical features in affected individuals to highlight underappreciated aspects and provide comprehensive phenotypic description of the rare familial KCNA1 mutation. Delayed diagnosis in this family is emblematic of the broader challenge of diagnosing other paroxysmal motor disorders. We summarize genotypic and phenotypic overlap and provide a suggested diagnostic algorithm for approaching patients with these conditions.

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Section: Resultsmentioning

confidence: 99%

Paroxysmal motor disorders: expanding phenotypes lead to coalescing genotypes

Zima

Ceulemans

Reiner

et al. 2018

Ann Clin Transl Neurol

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“…Mutations in CACNA1A gene determine two allelic disorders with a dominant-autosomic transmission: Spinocerebellar Ataxia 6 and Episodic Ataxia 2 [25]. Furthermore, mutations have been described in patients with alternating hemiplegia and recurrent ischemic stroke [26]. Mutations in ATP1A2 are reported in case of alternating hemiplegia [27].…”

Section: Methodsmentioning

confidence: 99%

Analysis of amplicon-based NGS data from neurological disease gene panels: a new method for allele drop-out management

et al. 2016

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BackgroundAmplicon-based targeted resequencing is a commonly adopted solution for next-generation sequencing applications focused on specific genomic regions. The reliability of such approaches rests on the high specificity and deep coverage, although sequencing artifacts attributable to PCR-like amplification can be encountered. Between these artifacts, allele drop-out, which is the preferential amplification of one allele, causes an artificial increase in homozygosity when heterozygous mutations fall on a primer pairing region.Here, a procedure to manage such artifacts, based on a pipeline composed of two steps of alignment and variant calling, is proposed. This methodology has been compared to the Illumina Custom Amplicon workflow, available on Illumina MiSeq, on the analysis of data obtained with four newly designed TruSeq Custom Amplicon gene panels.ResultsFour gene panels, specific for Parkinson disease, for Intracerebral Hemorrhage Diseases (COL4A1 and COL4A2 genes) and for Familial Hemiplegic Migraine (CACNA1A and ATP1A2 genes) were designed.A total of 119 samples were re-sequenced with Illumina MiSeq sequencer and panel characterization in terms of coverage, number of variants found and allele drop-out potential impact has been carried out. Results show that 14 % of identified variants is potentially affected by allele drop-out artifacts and that both the Custom Amplicon workflow and the procedure proposed here could correctly identify them.Furthermore, a more complex configuration in presence of two mutations was simulated in silico. In this configuration, our proposed methodology outperforms Custom Amplicon workflow, being able to correctly identify two mutations in all the studied configurations.ConclusionsAllele drop-out plays a crucial role in amplicon-based targeted re-sequencing and specific procedures in data analysis of amplicon data should be adopted. Although a consensus has been established in the elimination of primer sequences from aligned data (e.g., via primer sequence trimming or soft clipping), more complex configurations need to be managed in order to increase the retrieved information from available data. Our method shows how to manage one of these complex configurations, when two mutations occur.Electronic supplementary materialThe online version of this article (doi:10.1186/s12859-016-1189-0) contains supplementary material, which is available to authorized users.

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“…Mutations in the CACNA1A gene have not only been associated with FHM, but also with episodic ataxia type 2 and spinocerebellar degeneration type 6. 8 The first paper from Grieco and colleagues presents an exhaustive screening of the CACNA1A gene in a sample of 137 patients with 5 clinical phenotypes: FHM1, sporadic hemiplegic migraine, episodic ataxia type 2, migraine with aura, and migraine without aura. Not only did this paper expand the inter-family clinical phenotypes associated with CACNA1A mutations, it also detected intra-familial phenotypic variability associated with the same deletion.…”

Section: Roth C Ferbertmentioning

confidence: 99%