Evaluation of the effect of c.2946+1G&gt;T mutation on splicing in the SCN1A gene

Mahmoud, Afif Ben; Mansour, Riadh Ben; Driss, Fatma; Baklouti-Gargouri, Siwar; Siala, Olfa; Mkaouar-Rebai, Emna; Fakhfakh, Faiza

doi:10.1016/j.compbiolchem.2015.01.003

Cited by 4 publications

(2 citation statements)

References 24 publications

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“…In Tunisia, the analysis of DEE remains con ned to a few cases based on candidate gene approach or clinical exome sequencing instead of targeted sequencing [21][22][23][24][25][26][27][28][29][30]. Yet, in terms of DEE for which more than 100 candidate genes were reported with a phenotypic heterogeneity, investing in targeted sequencing may be an optimal method for choice as this approach facilitates the analysis of generated sequencing data, reduces sequencing cost, increases sequencing depth, and does not include any ethical concerns in terms of the return results.…”

Section: Discussionmentioning

confidence: 99%

Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with Developmental and Epileptic Encephalopathy

Said

Jallouli

Aissa

et al. 2023

Preprint

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Background Developmental and Epileptic Encephalopathies stand for a heterogenous group of epileptic syndromes, where the epileptic activity itself and/or the etiology contribute to cognitive and behavioral impairment. In recent decades, genetic etiology has increasingly been recognized as the cause of Developmental and Epileptic Encephalopathies and numerous genes have been identified, thanks to advances in genetic technologies. These discoveries have enabled precision treatments for several syndromes. Therefore, the identification of the causal variant in a gene is an intrinsic starting point to specify a precision therapy for the patient and an adequate management. Results We developed a custom panel for Next Generation Sequencing of the coding sequences of 116 genes in individuals with Developmental and Epileptic Encephalopathy from the Tunisian population. Segregation analyses as well as in silico studies have been conducted to assess the identified variants’ pathogenicity. We report 12 pathogenic variants in SCN1A, CHD2, CDKL5, SZT2, KCNT1, GNAO1, PCDH19, MECP2, GRIN2A, and SYNGAP1 in patients with Developmental and Epileptic Encephalopathy. Five of these variants are novel: “c.149delA, p.(Asn50MetfsTer26)” in CDKL5; “c.3616C>T, p.(Arg1206Ter)” in SZT2; “c.111_113del, p.(Leu39del)” in GNAO1; “c.1435G>C , p.(Asp479His)” in PCDH19; as well as “c.2143delC, p. (Arg716GlyfsTer10)”in SYNGAP1. Additionally, for five of our patients, the genetic result facilitated the choice of the appropriate treatment. Conclusion This is the first report of a custom gene panel to identify genetic variants implicated in Developmental and Epileptic Encephalopathy in the Tunisian population as well as the North African region (Tunisia, Egypt, Libya, Algeria, Morocco) with a diagnostic rate of 30%. This high-throughput sequencing panel has considerably improved the rate of positive diagnosis of Developmental and Epileptic Encephalopathy in the Tunisian population, which was less than 15% using Sanger sequencing. The benefit of genetic testing in these patients was approved by both physicians and parents.

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Section: Discussionmentioning

confidence: 99%

Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with Developmental and Epileptic Encephalopathy

Said

Jallouli

Aissa

et al. 2023

Preprint

Self Cite

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“…The most likely outcomes of alterations at acceptor (3′) or donor (5′) splice sites are exon skipping or cryptic splice site activation causing insertions, deletions, or intron retention [ 29 , 30 , 31 ]. Studies have demonstrated that an altered donor site could lead to skipping of the exon upstream the genetic change [ 32 , 33 , 34 ] as well as utilising the cryptic splice site upstream or downstream the canonical splicing site [ 35 , 36 , 37 ]. Moreover, a recent study by X. Lv et al revealed and further confirmed that a single variant in the canonical splicing site could induce production of several transcripts of different lengths and exonic/intronic structures.…”

Section: Discussionmentioning

confidence: 99%

Donor Splice Site Variant in SLC9A6 Causes Christianson Syndrome in a Lithuanian Family: A Case Report

et al. 2022

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Background and Objectives: The pathogenic variants of SLC9A6 are a known cause of a rare, X-linked neurological disorder called Christianson syndrome (CS). The main characteristics of CS are developmental delay, intellectual disability, and neurological findings. This study investigated the genetic basis and explored the molecular changes that led to CS in two male siblings presenting with intellectual disability, epilepsy, behavioural problems, gastrointestinal dysfunction, poor height, and weight gain. Materials and Methods: Next-generation sequencing of a tetrad was applied to identify the DNA changes and Sanger sequencing of proband’s cDNA was used to evaluate the impact of a splice site variant on mRNA structure. Bioinformatical tools were used to investigate SLC9A6 protein structure changes. Results: Sequencing and bioinformatical analysis revealed a novel donor splice site variant (NC_000023.11(NM_001042537.1):c.899 + 1G > A) that leads to a frameshift and a premature stop codon. Protein structure modelling showed that the truncated protein is unlikely to form any functionally relevant SLC9A6 dimers. Conclusions: Molecular and bioinformatical analysis revealed the impact of a novel donor splice site variant in the SLC9A6 gene that leads to truncated and functionally disrupted protein causing the phenotype of CS in the affected individuals.

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Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with developmental and epileptic encephalopathy

Ben Said,

Jallouli,

Ben Aissa

et al. 2024

Epilepsia Open

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ObjectiveTo develop a high throughput sequencing panel for the diagnosis of developmental and epileptic encephalopathy in Tunisia and to clarify the frequency of disease‐causing genes in this region.MethodsWe developed a custom panel for next generation sequencing of the coding sequences of 116 genes in individuals with developmental and epileptic encephalopathy from the Tunisian population. Segregation analyses as well as in silico studies have been conducted to assess the identified variants’ pathogenicity.ResultsWe report 12 pathogenic variants in SCN1A, CHD2, CDKL5, SZT2, KCNT1, GNAO1, PCDH19, MECP2, GRIN2A, and SYNGAP1 in patients with developmental and epileptic encephalopathy. Five of these variants are novel: “c.149delA, p.(Asn50MetfsTer26)” in CDKL5; “c.3616C>T, p.(Arg1206Ter)” in SZT2; “c.111_113del, p.(Leu39del)” in GNAO1; “c.1435G>C , p.(Asp479His)” in PCDH19; as well as “c.2143delC, p. (Arg716GlyfsTer10)”in SYNGAP1. Additionally, for four of our patients, the genetic result facilitated the choice of the appropriate treatment.SignificanceThis is the first report of a custom gene panel to identify genetic variants implicated in developmental and epileptic encephalopathy in the Tunisian population as well as the North African region (Tunisia, Egypt, Libya, Algeria, Morocco) with a diagnostic rate of 30%. This high‐throughput sequencing panel has considerably improved the rate of positive diagnosis of developmental and epileptic encephalopathy in the Tunisian population, which was less than 15% using Sanger sequencing. The benefit of genetic testing in these patients was approved by both physicians and parents.

show abstract

Evaluation of the effect of c.2946+1G>T mutation on splicing in the SCN1A gene

Cited by 4 publications

References 24 publications

Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with Developmental and Epileptic Encephalopathy

Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with Developmental and Epileptic Encephalopathy

Donor Splice Site Variant in SLC9A6 Causes Christianson Syndrome in a Lithuanian Family: A Case Report

Customized targeted massively parallel sequencing enables the identification of novel pathogenic variants in Tunisian patients with developmental and epileptic encephalopathy

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