Association of FAT1 with focal epilepsy and correlation between seizure relapse and gene expression stage

• Published in: Seizure (London, England) England), 2024-03, Vol.116, p.37-44
• Main Authors: Zou, Dong-Fang, Li, Xiao-Yan, Lu, Xin-Guo, Wang, Huai-Li, Song, Wang, Zhang, Meng-Wen, Liu, Xiao-Rong, Li, Bing-Mei, Liao, Jian-Xiang, Zhong, Jian-Min, Meng, Heng, Li, Bin
• Format: Article
• Language: English
• Subjects: Anticonvulsants - therapeutic use; Cadherins - genetics; Epilepsies, Partial - drug therapy; Epilepsy - drug therapy; FAT1 gene; Febrile seizures; Gene Expression; Gene expression stage; Genotype-phenotype correlation; Humans; Partial (focal) epilepsy; Recurrence; Seizure relapse; Seizures, Febrile - drug therapy; Seizures, Febrile - genetics
• ISSN: 1059-1311; 1532-2688
• DOI: 10.1016/j.seizure.2023.03.003

•Biallelic FAT1 variants were identified in patients with focal epilepsy and/or FS.•All the cases showed good responses to antiseizure medication.•Seizure relapsed when medication was withdrawn after being long-time seizure-free.•Epilepsy-associated variants were all missense.•Gene expression stage should be considered in withdrawing antiseizure medication. The FAT1 gene encodes FAT atypical cadherin 1, which is essential for foetal development, including brain development. This study aimed to investigate the relationship between FAT1 variants and epilepsy. Trio-based whole-exome sequencing was performed on a cohort of 313 patients with epilepsy. Additional cases with FAT1 variants were collected from the China Epilepsy Gene V.1.0 Matching Platform. Four pairs of compound heterozygous missense FAT1 variants were identified in four unrelated patients with partial (focal) epilepsy and/or febrile seizures, but without intellectual disability/developmental abnormalities. These variants presented no/very low frequencies in the gnomAD database, and the aggregate frequencies in this cohort were significantly higher than those in controls. Two additional compound heterozygous missense variants were identified in two unrelated cases using the gene-matching platform. All patients experienced infrequent (yearly/monthly) complex partial seizures or secondary generalised tonic-clonic seizures. They responded well toantiseizure medication, but seizures relapsed in three cases when antiseizure medication were decreased or withdrawn after being seizure-free for three to six years, which correlated with the expression stage of FAT1. Genotype-phenotype analysis showed that epilepsy-associated FAT1 variants were missense, whereas non-epilepsy-associated variants were mainly truncated. The relationship between FAT1 and epilepsy was evaluated to be “Strong” by the Clinical Validity Framework of ClinGen. FAT1 is a potential causative gene of partial epilepsy and febrile seizures. Gene expression stage was suggested to be one of the considerations in determining the duration ofantiseizure medication. Genotype-phenotype correlation helps to explain the mechanisms underlying phenotypic variation.