Exploring Neuronal Vulnerability to Head Trauma Using a Whole Exome Approach.
Omar Ibrahim1, Heidi G Sutherland1, Neven Maksemous1
1Genomics Research Centre, Institute of Health and Biomedical Innovation, School of Biomedical Science, Queensland University of Technology (QUT), Kelvin Grove, Queensland, Australia.
Journal of Neurotrauma
|April 3, 2020
Summary
Genetic variants in ion channel and neurotransmitter genes may increase the risk of severe neurological symptoms after minor head trauma. This study identified rare mutations in genes linked to migraine and seizures in individuals with concussion-related symptoms.
Area of Science:
- Neurogenetics
- Molecular Neurology
- Traumatic Brain Injury Research
Background:
- Brain injuries trigger oxidative stress and disrupt neuronal homeostasis.
- Mutations in the CACNA1A gene are linked to familial hemiplegic migraine (FHM) and concussion symptoms after head trauma.
- The genetic basis for severe responses to minor head injuries requires further investigation.
Purpose of the Study:
- To explore the role of variants in ion channel genes beyond CACNA1A in individuals experiencing neurological and concussion-related symptoms after minor head trauma.
- To identify potential genetic predispositions to severe responses following trivial head injuries.
Main Methods:
- Whole exome sequencing (WES) was performed on 16 individuals with neurological and concussion symptoms post-minor head trauma, who tested negative for known FHM gene mutations.
- WES data was filtered for rare variants (MAF <0.01) in neural and brain-expressed genes using in silico prediction tools (SIFT, PolyPhen, PredictSNP, Mutation Taster, Mutation Assessor).
- Analysis focused on rare (MAF <0.001) or novel heterozygous variants in ion channel, neurotransmitter, and ubiquitin-related genes.
Main Results:
- Rare or novel heterozygous variants in 7 ion channel genes (CACNA1I, CACNA1C, ATP10A, ATP7B, KCNAB1, KCNJ10, and SLC26A4) were found in 37.5% (6/16) of cases.
- Rare variants in neurotransmitter genes (GABRG1, GRIK1) were identified in 2 cases, and in ubiquitin-related genes (SQSTM1, TRIM2, HECTD1) in 4 cases.
- A significant proportion of potentially pathogenic variants were identified in genes previously associated with migraine and seizure disorders.
Conclusions:
- The study supports a role for heterozygous deleterious mutations in genes associated with neurological dysfunction in increasing the risk of poor response to trivial head trauma.
- Findings align with previous research implicating variants in CACNA1A and ATP1A2 in severe head trauma responses.
- Genetic variations in ion channel and related genes may contribute to susceptibility to severe neurological outcomes after minor head injuries.
