Abstract
Background:
Genetic generalized epilepsies (GGE) including childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and GGE with tonic–clonic seizures alone (GGE-TCS), are common types of epilepsy mostly determined by a polygenic mode of inheritance. Recent studies showed that susceptibility genes for GGE are numerous, and their variants rare, challenging their identification. In this study, we aimed to assess GGE genetic etiology in a Sudanese population.
Methods:
We performed whole-exome sequencing (WES) on DNA of 40 patients from 20 Sudanese families with GGE searching for candidate susceptibility variants, which were prioritized by CADD software and functional features of the corresponding gene. We assessed their segregation in 138 individuals and performed genotype–phenotype correlations.
Results:
In a family including three sibs with GGE-TCS, we identified a rare missense variant in
ADGRV1
encoding an adhesion G protein-coupled receptor V1, which was already involved in the autosomal recessive Usher type C syndrome. In addition, five other
ADGRV1
rare missense variants were identified in four additional families and absent from 119 Sudanese controls. In one of these families, an
ADGRV1
variant was found at a homozygous state, in a female more severely affected than her heterozygous brother, suggesting a gene dosage effect. In the five families, GGE phenotype was statistically associated with
ADGRV1
variants (0R = 0.9 10
3
).
Conclusion:
This study highly supports, for the first time, the involvement of
ADGRV1
missense variants in familial GGE and that
ADGRV1
is a susceptibility gene for CAE/JAE and GGE-TCS phenotypes.