Clinical exome sequencing identifies two novel mutations of the SCN1A and SCN2A genes in Moroccan patients with epilepsy: a case series

Sahli, Maryem; Zrhidri, Abdelali; Elaloui, Siham Chafai; Smaili, Wiam; Lyahyai, Jaber; Oudghiri, Fatima Zohra; Sefiani, Abdelaziz

doi:10.1186/s13256-019-2203-8

Cited by 7 publications

(8 citation statements)

References 15 publications

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“…Some authors suggest that the conventional way of initially sequencing the strongest candidate gene should be reconsidered in cases of suggestive clinical manifestations [ 36 ]. A variety of papers used targeted gene panels, and NGS has been recommended as an essential second step for SCN1A -negative patients following Sanger sequencing, as technical errors may occur with the classical technique [ 61 , 62 , 63 ]. The cost-efficiency of this approach needs to be proven.…”

Section: Discussionmentioning

confidence: 99%

“…The cost-efficiency of this approach needs to be proven. Nevertheless, in the case of the SCN1A gene and not only, NGS has also played a critical role in identifying relevant novel mutations [ 49 , 63 , 64 , 65 , 66 ].…”

Section: Discussionmentioning

confidence: 99%

“…Generally, the analysis uses a “gene panel” approach that filters data on prior knowledge. Including more genes can be attractive in that it can potentially uncover novel gene–disease associations [ 63 , 70 ].…”

Section: Discussionmentioning

confidence: 99%

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Phenotypic and Genotypic Spectrum of Early-Onset Developmental and Epileptic Encephalopathies—Data from a Romanian Cohort

Riza

Streaţă

Roza

et al. 2022

Genes

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Early-onset developmental epileptic encephalopathy (DEE) refers to an age-specific, diverse group of epilepsy syndromes with electroclinical anomalies that are associated with severe cognitive, behavioral, and developmental impairments. Genetic DEEs have heterogeneous etiologies. This study includes 36 Romanian patients referred to the Regional Centre for Medical Genetics Dolj for genetic testing between 2017 and 2020. The patients had been admitted to and clinically evaluated at Doctor Victor Gomoiu Children’s Hospital and Prof. Dr. Alexandru Obregia Psychiatry Hospital in Bucharest. Panel testing was performed using the Illumina® TruSight™ One “clinical exome” (4811 genes), and the analysis focused on the known genes reported in DEEs and clinical concordance. The overall diagnostic rate was 25% (9/36 cases). Seven cases were diagnosed with Dravet syndrome (likely pathogenic/pathogenic variants in SCN1A) and two with Genetic Epilepsy with Febrile Seizures Plus (SCN1B). For the diagnosed patients, seizure onset was <1 year, and the seizure type was generalized tonic-clonic. Four additional plausible variants of unknown significance in SCN2A, SCN9A, and SLC2A1 correlated with the reported phenotype. Overall, we are reporting seven novel variants. Comprehensive clinical phenotyping is crucial for variant interpretation. Genetic assessment of patients with severe early-onset DEE can be a powerful diagnostic tool for clinicians, with implications for the management and counseling of the patients and their families.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Phenotypic and Genotypic Spectrum of Early-Onset Developmental and Epileptic Encephalopathies—Data from a Romanian Cohort

Riza

Streaţă

Roza

et al. 2022

Genes

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“…For the past 5 years, the algorithm used for the diagnosis of NDDs at our Genetics Department, at Fundación Jiménez Díaz University Hospital (FJD), has followed the existing guidelines: array CGH (aCGH) and/or Fragile-X testing as the first-tier tests in patients with GDD/ID, ASD and other forms of NDD, followed by screening of ID genes by clinical exome sequencing in cases not solved by the first approach. Clinical exome sequencing refers to gene panels that typically target 4500–5000 known disease-associated genes and has demonstrated to provide a cost-effective sequencing analysis and easier interpretation of the results, avoiding or minimizing the unexpected or incidental findings, than when applying the whole exome or genome 17 – 19 .…”

Section: Introductionmentioning

confidence: 99%

Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders

et al. 2021

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Most consensus recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). This study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and other NDDs. These categories were further subclassified based on the most frequent accompanying signs and symptoms into isolated forms, forms with epilepsy; forms with micro/macrocephaly and syndromic forms. Two hundred and forty-five patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no additional cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results suggest that NGS could be used as a first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.

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“…Over 90 different potential disease-causing variants have been reported in SCN2A . The majority of these variants are heterozygous missense variants, most of which are associated with a severe epilepsy phenotype (e.g., L1660W, 34 A263V causing Ohtahara's syndrome and neonatal epilepsy plus late-onset ataxia, 38 46 R853G [West's syndrome], 36 Y428C, 77 and T1623N [Ohtahara's syndrome]), and are reported only in a single patient or family. Mutations occurring in parts of the channel that are important for sensing the voltage (i.e., alteration located in the voltage sensor) or the ion flux through the channel (i.e., the pore region) have been clearly associated to functional change of the channel and epilepsy.…”

Section: Genotype–phenotype Correlationmentioning

confidence: 99%

SCN2A and Its Related Epileptic Phenotypes

Sullo

Pasquetti

Patanè

et al. 2021

Journal of Pediatric Neurology

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Epilepsies due to SCN2A mutations can present with a broad range of phenotypes that are still not fully understood. Clinical characteristics of SNC2A-related epilepsy may vary from neonatal benign epilepsy to early-onset epileptic encephalopathy, including Ohtahara syndrome and West syndrome, and epileptic encephalopathies occurring at later ages (usually within the first 10 years of life). Some patient may present with intellectual disability and/or autism or movement disorders and without epilepsy. The heterogeneity of the phenotypes associated to such genetic mutations does not always allow the clinician to address his suspect on this gene. For this reason, diagnosis is usually made after a multiple gene panel examination through next generation sequencing (NGS) or after whole exome sequencing (WES) or whole genome sequencing (WGS). Subsequently, confirmation by Sanger sequencing can be obtained. Mutations in SCN2A are inherited as an autosomal dominant trait. Most individuals diagnosed with SCN2A–benign familial neonatal-infantile seizures (BFNIS) have an affected parent; however, hypothetically, a child may present SCN2A-BNFNIS as the result of a de novo pathogenic variant. Almost all individuals with SCN2A and severe epileptic encephalopathies have a de novo pathogenic variant. SNC2A-related epilepsies have not shown a clear genotype–phenotype correlation; in some cases, a same variant may lead to different presentations even within the same family and this could be due to other genetic factors or to environmental causes. There is no “standardized” treatment for SCN2A-related epilepsy, as it varies in relation to the clinical presentation and the phenotype of the patient, according to its own gene mutation. Treatment is based mainly on antiepileptic drugs, which include classic wide-spectrum drugs, such as valproic acid, levetiracetam, and lamotrigine. However, specific agents, which act directly modulating the sodium channels activity (phenytoin, carbamazepine, oxcarbamazepine, lamotrigine, and zonisamide), have shown positive result, as other sodium channel blockers (lidocaine and mexiletine) or even other drugs with different targets (phenobarbital).

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Clinical exome sequencing identifies two novel mutations of the SCN1A and SCN2A genes in Moroccan patients with epilepsy: a case series

Cited by 7 publications

References 15 publications

Phenotypic and Genotypic Spectrum of Early-Onset Developmental and Epileptic Encephalopathies—Data from a Romanian Cohort

Phenotypic and Genotypic Spectrum of Early-Onset Developmental and Epileptic Encephalopathies—Data from a Romanian Cohort

Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders

SCN2A and Its Related Epileptic Phenotypes

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