We performed the first whole exome sequencing study in Saudi Arabia epilepsy subjects. Using 144 individuals we compared putative pathogenic variants as well as variants of unknown significance with population based whole exome sequencing and whole genome sequencing databases.
The highest number of observed mutations across the 144 subjects were observed in NIPA2, a highly selective magnesium transporter. This in-frame insertion variant (NP001171818.1 p. (Asn334Glu335insAsp)) was observed in 7 subjects from 144 overall (5%). This variant has been previously reported within a population of subjects with childhood absence epilepsy (CAE) [36, 37, 38].
A missense variant in CHRNA4 was observed in 4 subjects. CHRNA4 is a nicotinic acetylcholine receptor, belonging to a superfamily of ligand-gated ion channels which play an established role in signal transmission at synapses. Mutations in CHRNA4 have been reported with nocturnal frontal lobe epilepsy type 1. A missense variant in SH2B3 was observed in 4 subjects. This gene is involved in a range of signaling activities by growth factor and cytokine receptors as part of the SH2B adaptor family of proteins. Mutations in this gene have been associated with susceptibility to celiac disease type 13 and susceptibility to insulin-dependent diabetes mellitus. It has low expression in the brain however as evident in the Genotype-Tissue Expression (GTEx) database. Missense mutations in STIL were observed in 3 subjects. STIL is a cytoplasmic protein which plays a role in the regulation of the mitotic checkpoint machinery. It too has low expression levels in all GTEx brain tissues.
There are a number of prioritized signals observed in this Saudi epilepsy study that may be novel or have very limited reports of association. Deficiency of WARS2 was observed in a patient with severe infantile-onset leukoencephalopathy, profound intellectual disability, spastic quadriplegia, epilepsy and microcephaly [39]. Rare mutations in DPYD have been implicated in children with unspecific neurological symptoms [40]. Epileptic encephalopathy caused by recessive loss-of-function (LoF) mutations have been reported in DENND5A [41]. A previous report of infantile cerebral and cerebellar atrophy showed association with a mutation in MED17 [42]. A LoF mutation in HCN4 has been reported to be associated with Familial benign myoclonic epilepsy in infancy [43]. Mutations in STRADA, SYNJ1, CACNA1A and NPRL3 have also been reported with severe epilepsy related disease [44, 45, 46, 47, 48, 49, 50, 51].
A number of prioritized signals of putative pathogenicity were observed that have no reports of association with epilepsy in the literature including SEC24D, PCCA, MYO5A which may be good candidates for further functional studies. SECD24D was reported to play a role in in vesicle trafficking and mutations in this gene are associated with Cole-Carpenter syndrome, a disorder affecting bone formation [52]. PCCA codes for the alpha subunit of the mitochondrial enzyme Propionyl-CoA carboxylase, and mutations in this gene leads to enzyme deficiency and are associated with propionic acidemia [53]. MYO5A encodes myosin 5A and mutations in this genes are associated with Griscelli Syndrome, which is characterized by hypopigmentation and a primary neurological abnormality [54]. These aforementioned genes may be good candidates for further functional studies.
This study is limited in that incomplete pedigrees and depth of sub-phenotyping is present, although putative pathogenic variants many known epilepsy-related loci are evident, and a number of potential new loci may be prioritized for further investigation.