Genetic heterogeneity in familial forms of genetic generalized epilepsy: from mono- to oligogenism

Abstract

Genetic generalized epilepsy (GGE) including childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), and GGE with tonic-clonic seizures (TCS) (GGE-TCS), is genetically influenced with a two- to four- fold increased risk in the first-degree relatives of patients. Since large families with GGE are very rare, international studies have focused on sporadic GGE patients using whole exome sequencing, suggesting that GGE are highly genetically heterogeneous and rather involve rare or ultra-rare variants. Moreover, a polygenic mode of inheritance is suspected in most cases. We performed SNP microarrays and whole exome sequencing in 20 families from Sudan, focusing on those with at least four affected members. Standard genetic filters and Endeavour algorithm for functional prioritization of genes selected likely susceptibility variants in FAT1, DCHS1 or ASTN2 genes. FAT1 and DCHS1 are adhesion transmembrane proteins interacting during brain development, while ASTN2 is involved in dendrite development. Our approach on familial forms of GGE is complementary to large-scale collaborative consortia studies of sporadic cases. Our study reinforces the hypothesis that GGE is genetically heterogeneous, even in a relatively limited geographic area, and mainly oligogenic, as supported by the low familial penetrance of GGE and by the Bayesian algorithm that we developed in a large pedigree with JME. Since populations with founder effect and endogamy are appropriate to study autosomal recessive pathologies, they would be also adapted to decipher genetic components of complex diseases, using the reported bayesian model.

Keywords: ASTN2; DCHS1; FAT1; Bayesian model; GGE; JME; Oligogenic; Polygenic.

Fig. 1

a Segregation of FAT1 variant in F19; b FAT1 interactome network according to STRING-db, showing close interactions with DCHS1 and FAT4; c Biallelic FAT1 variants involvement in human diseases: all previously published missense are located in the FAT1 extracellular domains, The T4586 from F19 is outlined in black, located in the C-terminal cytoplasmic domain containing a PTB-like motif (dark grey) with a PDZ-binding motif (-HTEV)

Fig. 2

a Segregation of DCHS1 and ASTN2, CAMSAP1, GTF3C5 and R3HDM1 variant in F7; b Probabilities of each predicted combination of indivuals bearing the five F7 variants calculated with the oligogenic Bayesian model; C, CACNA1A and ASTN2 variant in F8. Symbols in blue indicated JME and in black GTCS-GGE. The symbol “ + ” corresponded to the wild-type allele and “v” to the candidate variant. The vertical bar (a) shared the chromosome 2q haplotypes bearing the ASTN2, CAMSAP1 and GTF3C5 genes

Fig. 3

a Segregation of SLC38A11 and TTN variants in F12. Symbols indicated in green corresponded to CAE and in black to GTCS. The symbol “ + ” corresponded to the wild-type allele and “v” to the candidate variant. b Refinement of the candidate 2q region using WES data. Black circles represented variants shared by all 5 patients and white diamonds, variants not shared by at least one patient. The candidate region was delineated on the chromosome 2 scheme by a red square and on the genemap by the two grey vertical lines. Epilepsy genes were highlighted in yellow

Fig. 4

Segregation of SCN10A, PIGG and FBXO42 variants in F14. Symbols in black indicated GTCS-GGE. The symbol “ + ” corresponded to the wild-type allele and “v” to the candidate variant