Exploring Neuronal Vulnerability to Head Trauma Using a Whole Exome Approach

Abstract

Brain injuries are associated with oxidative stress and a need to restore neuronal homeostasis. Mutations in ion channel genes, in particular CACNA1A, have been implicated in familial hemiplegic migraine (FHM) and in the development of concussion-related symptoms in response to trivial head trauma. The aim of this study was to explore the potential role of variants in other ion channel genes in the development of such responses. We conducted whole exome sequencing (WES) on16 individuals who developed a range of neurological and concussion-related symptoms following minor or trivial head injuries. All individuals were initially tested and shown to be negative for mutations in known FHM genes. Variants identified from the WES results were filtered to identify rare variants (minor allele frequency [MAF] <0.01) in genes related to neural processes as well as genes highly expressed in the brain using a combination of in silico prediction tools (SIFT, PolyPhen, PredictSNP, Mutation Taster, and Mutation Assessor). Rare (MAF <0.001) or novel heterozygous variants in 7 ion channel genes were identified in 37.5% (6/16) of the cases (CACNA1I, CACNA1C, ATP10A, ATP7B, KCNAB1, KCNJ10, and SLC26A4), rare variants in neurotransmitter genes were found in 2 cases (GABRG1 and GRIK1), and rare variants in 3 ubiquitin-related genes identified in 4 cases (SQSTM1, TRIM2, and HECTD1). In this study, the largest proportion of potentially pathogenic variants in individuals with severe responses to minor head trauma were identified in genes previously implicated in migraine and seizure-related autosomal recessive neurological disorders. Together with results implicating variants in the hemiplegic migraine genes, CACNA1A and ATP1A2, in severe head trauma response, our results support a role for heterozygous deleterious mutations in genes implicated in neurological dysfunction and potentially increasing the risk of poor response to trivial head trauma.

The Dawn and Advancement of the Knowledge of the Genetics of Migraine

“…Ibrahim et al completed whole exome sequencing on 16 individuals with no mutations in the FHM gene [128]. They associated ATP10A (p.Ala881Val) and ATP7B (p. Leu795Phe) variants with migraine.…”

Genetics of migraine: where are we now?

“…Noteworthy, mutations in two genes involved in glutamate signalling, CACNA1B and ATXN1 , were found in several migraine families [ 136 ]. Using whole-exome sequencing in small populations, new SNPs have been associated with responsiveness to verapamil as a preventive therapy [ 137 ], and neurological outcome, including migraine, after head trauma [ 138 ]. Finally, “private” large-size-effect variants may be identified by chance, such as in the very rare families carrying mutations of KCNK18 or CSNK1D .…”

Migraine genetics: Status and road forward

“…Until now, WES was typically applied to cohorts of patients with HM, testing several hundred cases in an attempt to either find causal mutations in known HM genes or novel HM genes patients that are negative for mutations in CACNA1A, ATP1A2, and SCN1A. Until now results have not led to additional (undisputed) HM genes (9)(10)(11)51,52). This may indicate that HM in mutation-negative patients may be oligogenic or polygenic, in line with the excess presence of common variants in such patients (12).…”

“…First, SNP genotyping followed by NGS was used for linkage, haplotype, and variant analyses within a single large Finnish migraine-epilepsy family and found an association between the epilepsy phenotype and the NCOR2 gene that colocalises with one of the migraine risk loci (53). Second, in a WES of 16 individuals, who developed numerous neurological- and concussion-related symptoms following minor head injuries of which seven had developed migraines following the injury, revealed possible mutations in various ion channel, neurotransmitter, and ubiquitin-related genes, but causality of any of them needs to be established (51). Third, in an attempt to investigate whether certain genetic variants determine treatment response to verapamil prophylaxis, WES was applied to a set of 21 definitive responders and 14 definitive non-responders (discovery cohort) and promising data were further analysed in 185 verapamil-treated patients (replication cohort) to yield 39 ‘possible variants’ (54).…”