A major issue in genetic disorders is to find out clues, which may help to interpret the phenotypic heterogeneity, in order to provide more precise diagnoses and more significant prognostic and therapeutic implications [1,2]. That’s particularly true for mutations, whose pathogenic significance is often challenging and of uncertain significance. Lopes-Cendes et al  turned their attention to Dravet syndrome (DS), a severe epileptic encephalopathy of childhood onset with intellectual disability, chronic course, and highly resistant to treatment. DS is associated to mutations in SCN1A, encoding the neuronal voltage-gated sodium channel Nav1.1, whose variants are detected in 70-80% of patients. The vast majority of SCN1A variants occur de novo (as compared to other clinical phenotypes associated with mutations in SCN1A). Authors referred to the SCN1A missense variants detected in 21 patients. They established a score classification workflow based on evidence of pathogenicity, to improve the classification of potentially deleterious DS-related SCN1A missense variants, and assessed their results matching them with SCN1A variants reported from literature. To establish pathogenic classification criteria they performed a multimodal analysis, which took into account both genetic (variant inheritance, variant frequency in population) and molecular criteria (already established pathogenicity of the variant, location within or nearby functional domains of the protein, in silico prediction). According to the authors their strategy is likely to improve the accuracy of prediction, offering therefore a relevant contribution to clinician. In our view, this methodology may be applied to other genetic diseases of the CNS, and may contribute to improve the quality of selection of patients suitable for treatment with targeted “orphan drugs”.
Multimodal analysis of missense variants in Dravet syndrome
Prediction of variant pathogenicity
Phenotypic Heterogeneity; Missense Variants; Multimodal Analysis; Dravet Syndrome
1. Ottman R et al. Genetic Testing in the epilepsies-report of the ILAE Genetic Commission. Epilepsia 2019; 51:655-70. [PMID:20100225]
2. Brunklaus A et al. The clinical utility of an SCN1A genetic diagnosis in infantile-onset epilepsy. Dev Med Child Neurol 2013; 55:154-61.
3. Lopes-Cendes I et al. Multimodal analysis of SCN1A missense variants improves interpretation of clinically relevant variants in Dravet syndrome. Front Neurol 28 March 2019 doi.org/10.3389/fneur.2019.00289