Missense variants in PLA2G6 contribute to a spectrum of clinical syndromes and provide pharmacogenomic correlates

BackgroundRisk alleles in a gene for a genetic disorder can often cause a spectrum of syndromes. The number of copies, deleteriousness and position in the sequence could influence phenotype manifestation. MethodsWhole exome sequencing in 310 individuals from 100 families with severe mental illness revealed 851 instances of variants in the PLA2G6 gene. We assessed the population frequency and deleteriousness of the nonsynonymous variants using in-silico prediction methods. Molecular docking analyses with antipsychotics was performed to investigate possible pharmacogenomic implications of the PLA2G6 mutations identified. ResultsWe found six nonsynonymous variants predicted to be deleterious by VarSome. The frequency of non-synonymous variants was found to vary across populations. The preliminary molecular docking analysis suggests that chlorpromazine and risperidone are predicted to bind at three drug-binding sites however, risperidone has a greater binding affinity to PLA2G6. The occurrence of variants close to these drug-binding sites suggests a possible mechanism for the mediation of parkinsonian side effects on drug intake in patients harboring these variants. ConclusionVariants in the PLA2G6, a gene previously known to be associated with Parkinsons disease may thus contribute to the risk of psychiatric phenotypes, as observed in these 9 individuals from 6 families with severe mental illness.