Analiza objawów klinicznych i szkodliwości wariantu c.4476+5G>T genu SCN1A w polskiej rodzinie z genetyczną epilepsją z napadzami gorączkowymi plus
[Analysis of clinical phenotypes and pathogenicity of a c.4476+5G>T variant of SCN1A gene in a Chinese pedigree affected with Genetic epilepsy with febrile seizures plus]
W skrócie
Badacze zbadali szkodliwą mutację w genie SCN1A u pięcioosobowej rodziny chińskiej, u której występuje specjalna postać epilepsji towarzysząca napadzom gorączkowymi. Zmiana genetyczna powoduje błędy w procesie czytania instrukcji do produkcji białka, co prowadzi do poważnych napadzów epilepsyjnych u trójki członków rodziny. Naukowcy potwierdzili, że ta nowa mutacja rzeczywiście powoduje chorobę i mogą ją zawsze szukać u innych pacjentów z podobnymi objawami.
Oryginalny abstract (angielski)
OBJECTIVE: To explore the pathogenicity and characteristics of a heterozygous splicing variant of SCN1A gene in a Chinese pedigree affected with Genetic epilepsy with febrile seizures plus (GEFS+). METHODS: A retrospective analysis was carried out on the clinical data and results of genetic testing of a GEFS+ pedigree consisting of 5 members who had visited the First Affiliated Hospital of Zhengzhou University on July 1, 2024. Pathogenicity of the splicing variant of the SCN1A gene was validated with a minigene splicing assay. This study was approved by the Medical Ethics Committee of the the First Affiliated Hospital of Zhengzhou University (Ethics No.: KS-2018-KY-36). RESULTS: The proband, a 24-year-old female, presented with FS in conjunct with focal seizures, and both of her younger brothers had Dravet syndrome. All of the three patients had carried a c.4476+5G>T variant of the SCN1A gene, which was unreported previously. Minigene experiment verified that the variant could cause loss of the first 7 bps of exon 24 and 138 bps from exon 23 of the SCN1A gene, resulting in alteration p.V1447_1495delfs*6 and affecting splicing. Based on the guidelines from American College of Medical Genetics and Genomics (ACMG), the variant was predicted as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.4476+5G>T variant at an intronic site of the SCN1A gene probably underlay the pathogenesis of GEFS+ in this pedigree.