Influence of common SCN1A promoter variants on the severity of SCN1A‐related phenotypes

Molecular Genetics & Genomic Medicine

Anja C. M. Sonsma¹  Iris M. deLange¹  Bobby P. C. Koeleman¹  Wout Weuring¹  Mark McCormack¹  Flip Mulder¹  Marjan J. A. vanKempen¹  Nine V. A. M. Knoers¹  Ruben van‘t Slot¹  Carolien deKovel¹  Eva H. Brilstra¹  Lisette J. J. M. vanGemert²  Boudewijn Gunning³ 

[1] Department of Genetics, Center for Molecular Medicine University Medical Center Utrecht Utrecht The Netherlands;Epilepsy Center Kempenhaeghe Heeze The Netherlands;Stichting Epilepsie Instellingen Nederland Zwolle The Netherlands;

关键词: Dravet;    GEFS+;    promoter;    SCN1A;    variable expression;   

DOI  :  10.1002/mgg3.727

来源: DOAJ

【 摘 要 】

Abstract Background Pathogenic variants in SCN1A cause variable epilepsy disorders with different disease severities. We here investigate whether common variation in the promoter region of the unaffected SCN1A allele could reduce normal expression, leading to a decreased residual function of Nav1.1, and therefore to more severe clinical outcomes in patients affected by pathogenic SCN1A variants. Methods Five different SCN1A promoter‐haplotypes were functionally assessed in SH‐SY5Y cells using Firefly and Renilla luciferase assays. The SCN1A promoter region was analyzed in a cohort of 143 participants with SCN1A pathogenic variants. Differences in clinical features and outcomes between participants with and without common variants in the SCN1A promoter‐region of their unaffected allele were investigated. Results All non‐wildtype haplotypes showed a significant reduction in luciferase expression, compared to the wildtype promoter‐region (65%–80%, p = 0.039–0.0023). No statistically significant differences in clinical outcomes were observed between patients with and without common promoter variants. However, patients with a wildtype promoter‐haplotype on their unaffected SCN1A allele showed a nonsignificant trend for milder phenotypes. Conclusion The nonsignificant observed trends in our study warrant replication studies in larger cohorts to explore the potential modifying role of these common SCN1A promoter‐haplotypes.

【 授权许可】

Unknown