RESUMEN
Purpose: The TRAK1 gene is mapped to chromosome 3p22.1 and encodes trafficking protein kinesin binding 1. The aim of this study was to investigate the genotype-phenotype of TRAK1-associated epilepsy. Methods: Trio-based whole-exome sequencing was performed on a cohort of 98 patients with epilepsy of unknown etiologies. Protein modeling and the VarCards database were used to predict the damaging effects of the variants. Detailed neurological phenotypes of all patients with epilepsy having TRAK1 variants were analyzed to assess the genotype-phenotype correlations. Results: A novel TRAK1 compound heterozygous variant comprising variant c.835C > T, p.Arg279Cys and variant c.2560A > C, p.Lys854Gln was identified in one pediatric patient. Protein modeling and VarCards database analyses revealed that the variants were damaging. The patient received a diagnosis of early infantile epileptic spasms with a developmental disorder; he became seizure-free through valproate and adrenocorticotropic hormone treatment. Further results for six variants in 12 patients with epilepsy indicated that biallelic TRAK1 variants (including homozygous or compound heterozygous variants) were associated with epilepsy with developmental disorders. Among these patients, eight (67%) had epileptic spasms and seven (58%) were intractable to anti-seizure medicines. Moreover, eight patients experienced refractory status epilepticus, of which seven (88%) died in early life. To our knowledge, this is the first reported case of epilepsy caused by TRAK1 compound heterozygous variants. Conclusion: Biallelic TRAK1 variants can cause epilepsy and developmental disorders. In these patients, seizures progress to status epilepticus, suggesting a high risk for poor outcomes and the requirement of early treatment.
RESUMEN
BACKGROUND: The etiology of unexplained epilepsy in most patients remains unclear. Variants of FRMPD4 are suggested to be associated with neurodevelopmental disorders. Therefore, we screened for disease-causing FRMPD4 variants in patients with epilepsy. METHODS: Trios-based whole-exome sequencing was conducted on a cohort of 85 patients with unexplained epilepsy, their parents, and extended family members. Additional cases with FRMPD4 variants were identified from the China Epilepsy Gene Matching Platform V.1.0. The frequency of variants was analyzed, and their subregional effects were predicted using in silico tools. The genotype-phenotype correlation of the newly defined causative genes and protein stability were analyzed using I-Mutant V.3.0 and Grantham scores. RESULTS: Two novel missense variants of FRMPD4 were identified in two families. Using the gene matching platform, we identified three additional novel missense variants. These variants presented at low or no allele frequencies in the gnomAD database. All the variants were located outside the three FRMPD4 main domains (WW, PDZ, and FERM). In silico analyses revealed that the variants were damaging and were predicted to be the least stable. All patients eventually became seizure-free. Eight of the 21 patients with FRMPD4 variants had epilepsy, of which five (63%) had missense variants located outside the domains, two had deletions involving exon 2, and one had a frameshift variant located outside the domains. Patients with epilepsy caused by missense variants were often free of intellectual disabilities (4/5), whereas patients with epilepsy caused by truncated variants had intellectual disabilities and structural brain abnormalities (3/3). CONCLUSIONS: The FRMPD4 gene is potentially associated with epilepsy. The genotype-phenotype correlation of FRMPD4 variants indicated that differences in variant types and locations of FRMPD4 may explain their phenotypic variation.