Risk-conferringHLAvariants in an epilepsy cohort: benefits of multifaceted use of whole genome sequencing in clinical practice

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Background Whole genome sequencing is increasingly used in healthcare, particularly for diagnostics. However, its clinically multifaceted potential for individually customised diagnostic and therapeutic care remains largely unexploited. We used existing whole genome sequencing data to screen for pharmacogenomic risk factors related to antiseizure medication-induced cutaneous adverse drug reactions (cADRs), such as human leucocyte antigenHLA-B*15:02,HLA-A*31:01variants. Methods Genotyping results, generated from the Genomics England UK 100 000 Genomes Project primarily for identification of disease-causing variants, were used to additionally screen for relevantHLAvariants and other pharmacogenomic variants. Medical records were retrospectively reviewed for clinical and cADR phenotypes forHLAvariant carriers. Descriptive statistics and the χ2test were used to analyse phenotype/genotype data forHLAcarriers and compare frequencies of additional pharmacogenomic variants betweenHLAcarriers with and without cADRs, respectively. Results 1043 people with epilepsy were included. FourHLA-B*15:02and 86HLA-A*31:01carriers were identified. One out of the four identifiedHLA-B*15:02carriers had suffered antiseizure medication-induced cADRs; the point prevalence of cADRs was 16.9% forHLA-A*31:01carriers of European origin (n=46) and 14.4% forHLA-A*31:01carriers irrespective of ancestry (n=83). Conclusions Comprehensive utilisation of genetic data spreads beyond the search for causal variants alone and can be extended to additional clinical benefits such as identifying pharmacogenomic biomarkers, which can guide pharmacotherapy for genetically-susceptible individuals.

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