Highlights
- •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- •Seizure relapsed when medication was withdrawn after being long-time seizure-free.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.
Abstract
Purpose
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.
Methods
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.
Results
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were decreased or withdrawn after being seizure-free for three to six years, which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.
Conclusions
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.
Keywords
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Article info
Publication history
Published online: March 11, 2023
Accepted:
March 1,
2023
Received in revised form:
February 28,
2023
Received:
February 7,
2023
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2023 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
