AUTHOR=Gonsales Marina C. , Montenegro Maria Augusta , Preto Paula , Guerreiro Marilisa M. , Coan Ana Carolina , Quast Monica Paiva , Carvalho Benilton S. , Lopes-Cendes Iscia 

TITLE=Multimodal Analysis of SCN1A Missense Variants Improves Interpretation of Clinically Relevant Variants in Dravet Syndrome

JOURNAL=Frontiers in Neurology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2019.00289

DOI=10.3389/fneur.2019.00289

ISSN=1664-2295

ABSTRACT=<p><bold>Objective:</bold> We aimed to improve the classification of <italic>SCN1A</italic> missense variants in patients with Dravet syndrome (DS) by combining and modifying the current variants classification criteria to minimize inconclusive test results.</p><p><bold>Methods:</bold> We established a score classification workflow based on evidence of pathogenicity to adapt the classification of DS-related <italic>SCN1A</italic> 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.</p><p><bold>Results:</bold> Our meta-analysis showed that 46% (506/1,101) of DS-associated <italic>SCN1A</italic> 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.”</p><p><bold>Conclusion:</bold> Our results indicate that using multimodal analysis seems to be the best approach to interpret the pathogenic impact of <italic>SCN1A</italic> missense changes for the molecular diagnosis of patients with DS. By applying the proposed workflow, most DS related <italic>SCN1A</italic> variants had their classification improved.</p>