SLC25A12 as a new candidate for febrile seizures: a case-control association study

Objective: We did a case-control association study to identify common genetic variants for febrile seizures. Methods: A targeted NGS assay consist of 189 genes were performed 1490 unrelated Chinese febrile seizure patients recruited between 2018.12-2019.12 in a national wide cohort. Another 2273 unrelated healthy adults were selected as controls. New candidate associations and variants with low frequency (<0.005) and high impact (OR>2.0) were selected. We reviewed the clinical presentations of the probands and their family histories and conducted segregation analysis. Results: A total of 1478 cases and 2252 controls were retained for case-control association study after quality control. Of the 640,083 variants assessed, seventeen variants on 14 genes achieved P <0.05 and 14 were replicated in mBiobank. There were 6 variants in negative direction and 8 variants in positive direction. DGKD c.3424+2T>G was the strongest associated variant with low frequency and high impact in negative direction. ADGRV1 (c.8286delG) and SLC25A12 (c.*754C>A) were variants with low frequency and high effect sizein positive direction. There were more positive family histories in SLC25A12 c.*754C>A carriers (45.45%, 5/11) than in DGKD c.3424+2T>G carriers (21.05%, 4/19) in negative NGS finding febrile seizure kids. Additional 5 NGS negative cases with rare possibly damaging variants of SLC25A12 and positive family history were found. The sanger sequencing showed high inherited direction along with family history both in c.*754C>A (80.0%, 4/5) and in the other 5 variants (80.0%, 4/5). Significance: SLC25A12 was a possibly new febrile seizure candidate gene with evidence of co-segregation in Chinese population.