Recessive LAMA5 Variants Associated With Partial Epilepsy and Spasms in Infancy

Abstract

ObjectiveThe LAMA5 gene encodes the laminin subunit α5, the most abundant laminin α subunit in the human brain. It forms heterotrimers with the subunit β1/β2 and γ1/γ3 and regulates neurodevelopmental processes. Genes encoding subunits of the laminin heterotrimers containing subunit α5 have been reported to be associated with human diseases. Among LAMAs encoding the laminin α subunit, LAMA1-4 have also been reported to be associated with human disease. In this study, we investigated the association between LAMA5 and epilepsy.MethodsTrios-based whole-exome sequencing was performed in a cohort of 118 infants suffering from focal seizures with or without spasms. Protein modeling was used to assess the damaging effects of variations. The LAMAs expression was analyzed with data from the GTEX and VarCards databases.ResultsSix pairs of compound heterozygous missense variants in LAMA5 were identified in six unrelated patients. All affected individuals suffered from focal seizures with mild developmental delay, and three patients presented also spasms. These variants had no or low allele frequencies in controls and presented statistically higher frequency in the case cohort than in controls. The recessive burden analysis showed that recessive LAMA5 variants identified in this cohort were significantly more than the expected number in the East Asian population. Protein modeling showed that at least one variant in each pair of biallelic variants affected hydrogen bonds with surrounding amino acids. Among the biallelic variants in cases with only focal seizures, two variants of each pair were located in different structural domains or domains/links, whereas in the cases with spasms, the biallelic variants were constituted by two variants in the identical functional domains or both with hydrogen bond changes.ConclusionRecessive LAMA5 variants were potentially associated with infant epilepsy. The establishment of the association between LAMA5 and epilepsy will facilitate the genetic diagnosis and management in patients with infant epilepsy.

Identification of novel pathogenic genes of childhood epileptic encephalopathies

“…In contrast, the two cases (LG242 and LG40) with compound heterozygous variants that had both variants located at nonfunctional regions (p.Ser1214Cys & p.Phe2036Leu and p.Thr2105Ser & p.Arg2875Gln) achieved seizure-free with monotherapy of valproate/lamotrigine. Among the other four cases with one of the paired variants located in the functional domains, two cases (LG150 and LG238, who had variants p.Thr1110Ile and p.Ser2329Asn in functional domains, respectively) presented refractory seizures; one case (LG230, with p.Pro1471Thr in the laminin G-like domain) achieved seizure-free but had intellectual disability; and the other case (LG54) achieved seizure-free without intellectual disability and had compound heterozygous variants with two variants located furthest apart (p.Pro588Arg and p.Glu2849Lys, a distance of 2261 amino acids), which have been suggested to be associated with phenotype severity 32,33 .…”

CELSR1 variants are associated with partial epilepsy of childhood

“…It is noted that in each pair of the compound heterozygous variants, one variant was located in the N‐terminal and the other one in the C‐terminal. Considering that homozygous CELSR1 knockout mice display prenatal lethality, it was suspected that compound heterozygous variants with two variants located far apart from each other might cause fewer damage effects (Luo et al, 2022) and lead to survived individuals with epilepsy; and the patients with CELSR1 heterozygous variants would present further mild epileptic phenotype such as BECTS.…”

Expanding the phenotypic spectrum of KCNK4: From syndromic neurodevelopmental disorder to rolandic epilepsy

“…Genomic DNAs were extracted from blood samples using the Qiagen Flexi Gene DNA kit (Qiagen, Hilden, Germany). WES was performed using a NextSeq500 sequencing instrument (Illumina, San Diego, California, United States) following previously described standard procedures ( Wang et al, 2018 ; Luo et al, 2022 ). The sequencing data were generated by massively parallel sequencing with an average depth of >125x and >98% coverage of the capture region on the chip for obtaining high-quality reads that were mapped to the Genome Reference Consortium Human genome build 37 by Burrows-Wheeler alignment.…”