Abstract
Objective: We aimed to improve the classification of SCN1A missense variants in patients with Dravet syndrome (DS) by combining and modifying the current variants classification criteria to minimize inconclusive test results.Methods: We established a score classification workflow based on evidence of pathogenicity to adapt the classification of DS-related SCN1A missense variants. In addition, we compiled the variants reported in the literature and our cohort and assessed the proposed pathogenic classification criteria. We combined information regarding previously established pathogenic amino acid changes, mode of inheritance, population-specific allele frequencies, localization within protein domains, and deleterious effect prediction analysis.Results: Our meta-analysis showed that 46% (506/1,101) of DS-associated SCN1A variants are missense. We applied the score classification workflow and 56.5% (286/506) of the variants had their classification changed from VUS: 17.8% (90/506) into “pathogenic” and 38.7% (196/506) as “likely pathogenic.”Conclusion: Our results indicate that using multimodal analysis seems to be the best approach to interpret the pathogenic impact of SCN1A missense changes for the molecular diagnosis of patients with DS. By applying the proposed workflow, most DS related SCN1A variants had their classification improved.
Highlights
Recent scientific and technical breakthroughs have allowed for the increasing use of genetic testing in clinical practice, providing more precise diagnoses and having significant prognostic and treatment implications [1, 2]
Patients were regularly followed in an outpatient epilepsy clinic and fulfilled the clinical criteria for Dravet syndrome (DS) according to the International League Against Epilepsy (ILAE) guidelines [8, 9]
multiplex ligation-dependent probe amplification (MLPA) analysis did not reveal any copy number variants in SCN1A in the other patients with DS apart from the 18-base-pair deletion found in the monozygotic twins
Summary
Recent scientific and technical breakthroughs have allowed for the increasing use of genetic testing in clinical practice, providing more precise diagnoses and having significant prognostic and treatment implications [1, 2]. Interpreting the clinical significance of genetic variants found in molecular tests can still be challenging, for variants of uncertain significance. Multimodal Analysis of SCN1A Variants (VUS) [3]. A straightforward answer for clinicians regarding these variants is often not possible, posing an important difficulty in risk assessment and proper genetic counseling [1]. Patients with Dravet syndrome (DS) possess the majority of SCN1A variants identified to date, with variants detected in 70–80% of these patients [4, 5]. DS is an epileptic encephalopathy characterized by early onset febrile tonic clonic seizures followed by myoclonic jerks, atypical absences, and complex focal seizures and is highly resistant to treatment with antiepileptic drugs [6, 7]
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