Recessive PKD1 Mutations Are Associated With Febrile Seizures and Epilepsy With Antecedent Febrile Seizures and the Genotype-Phenotype Correlation

Abstract

ObjectiveThe PKD1 encodes polycystin-1, a large transmembrane protein that plays important roles in cell proliferation, apoptosis, and cation transport. Previous studies have identified PKD1 mutations in autosomal dominant polycystic kidney disease (ADPKD). However, the expression of PKD1 in the brain is much higher than that in the kidney. This study aimed to explore the association between PKD1 and epilepsy.MethodsTrios-based whole-exome sequencing was performed in a cohort of 314 patients with febrile seizures or epilepsy with antecedent febrile seizures. The damaging effects of variants was predicted by protein modeling and multiple in silico tools. The genotype-phenotype association of PKD1 mutations was systematically reviewed and analyzed.ResultsEight pairs of compound heterozygous missense variants in PKD1 were identified in eight unrelated patients. All patients suffered from febrile seizures or epilepsy with antecedent febrile seizures with favorable prognosis. All of the 16 heterozygous variants presented no or low allele frequencies in the gnomAD database, and presented statistically higher frequency in the case-cohort than that in controls. These missense variants were predicted to be damaging and/or affect hydrogen bonding or free energy stability of amino acids. Five patients showed generalized tonic-clonic seizures (GTCS), who all had one of the paired missense mutations located in the PKD repeat domain, suggesting that mutations in the PKD domains were possibly associated with GTCS. Further analysis demonstrated that monoallelic mutations with haploinsufficiency of PKD1 potentially caused kidney disease, compound heterozygotes with superimposed effects of two missense mutations were associated with epilepsy, whereas the homozygotes with complete loss of PKD1 would be embryonically lethal.ConclusionPKD1 gene was potentially a novel causative gene of epilepsy. The genotype-phenotype relationship of PKD1 mutations suggested a quantitative correlation between genetic impairment and phenotypic variation, which will facilitate the genetic diagnosis and management in patients with PKD1 mutations.

ZFHX3variants cause childhood partial epilepsy and infantile spasms with favorable outcomes

“…Detailed sequencing methods were described in our previous studies. [7][8][9] A case-by-case analytical approach was adopted to identify candidate causative variants in each trio. 10,11 Primarily, the rare variants were prioritized with a minor allele frequency (MAF) < 0.005 in the gnomAD database (gnomad.broadinstitute.org).…”

Complex PKD1 Genetics in Early-Onset Cystic Kidney Disease

“…8 Curiously, compound heterozygous missense PKD1 variants that are predicted to be pathogenic have also been reported in eight unrelated patients with febrile seizures and epilepsy, although none had enlarged kidneys or kidney cysts, again demonstrating the challenges of variant interpretation, pathogenicity prediction, and incomplete penetrance. 9 In sum, while the pathogenicity of hypomorphic variants remains difficult to pin down for individual patients, the current case series emphasizes that homozygous or compound heterozygous missense PKD1 variants should be considered in patients with in utero or pediatric-onset severe cystic kidney disease, a phenocopy that can mimic autosomal recessive polycystic kidney disease.…”

“… 8 Curiously, compound heterozygous missense PKD1 variants that are predicted to be pathogenic have also been reported in eight unrelated patients with febrile seizures and epilepsy, although none had enlarged kidneys or kidney cysts, again demonstrating the challenges of variant interpretation, pathogenicity prediction, and incomplete penetrance. 9 …”