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

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.

Toxoplasmose congênita / Congenital toxoplasmosis

Toxoplasmose é causada por infecção pelo parasita protozoário Toxoplasma gondii. Foram revisados aspectos da fisiopatologia da toxoplasmose congênita. As manifestações da toxoplasmose congênita no feto ou neonato são imprevisíveis, variando desde o óbito intra-uterino, retardo mental, convulsões, cegueira, hidrocefalia e coriorretinite até lesões menos severas, em que as manifestações da toxoplasmose congênita podem não ser aparentes até a segunda ou terceira décadas de vida. Testes sorológicos são utilizados para o diagnóstico da infecção aguda na gestante e na criança. A terapêutica mais utilizada e, provavelmente, mais efetiva é a combinação de pirimetamina, sulfadiazina e ácido folínico.(AU)

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. Some aspects of the physiopathology of the congenital toxoplasmosis were revised. Manifestations of congenital toxoplasmosis in the fetus and the newborn are unpredictable. They range from intra-uterine death, mental retardation, seizures, blindness, hydrocephalia and chorioretinitis to less severe lesions in which manifestations of congenital toxoplasmosis may not become apparent until the second or third decades of life. Serological tests are used to diagnose acute infection in pregnant women or in children. The most commonly used therapeutic regimen, and probably the most effective, is the combination of pyrimethamine with sulfadiazine and folinic acid.(AU)

Toxoplasmose congênita / Congenital toxoplasmosis

Toxoplasmose é causada por infecção pelo parasita protozoário Toxoplasma gondii. Foram revisados aspectos da fisiopatologia da toxoplasmose congênita. As manifestações da toxoplasmose congênita no feto ou neonato são imprevisíveis, variando desde o óbito intra-uterino, retardo mental, convulsões, cegueira, hidrocefalia e coriorretinite até lesões menos severas, em que as manifestações da toxoplasmose congênita podem não ser aparentes até a segunda ou terceira décadas de vida. Testes sorológicos são utilizados para o diagnóstico da infecção aguda na gestante e na criança. A terapêutica mais utilizada e, provavelmente, mais efetiva é a combinação de pirimetamina, sulfadiazina e ácido folínico.

Toxoplasmosis is caused by the protozoan parasite Toxoplasma gondii. Some aspects of the physiopathology of the congenital toxoplasmosis were revised. Manifestations of congenital toxoplasmosis in the fetus and the newborn are unpredictable. They range from intra-uterine death, mental retardation, seizures, blindness, hydrocephalia and chorioretinitis to less severe lesions in which manifestations of congenital toxoplasmosis may not become apparent until the second or third decades of life. Serological tests are used to diagnose acute infection in pregnant women or in children. The most commonly used therapeutic regimen, and probably the most effective, is the combination of pyrimethamine with sulfadiazine and folinic acid.