Rare variants, risk of disease, and sensitivity to psychotropics suggests personalized pharmacogenomics: time to advance the role of molecular psychiatry at the bedside

Treatment response to psychotropics is heterogeneous, often with troublesome side effects. Understanding the role of variants, changes in target protein structure and modification of drug-protein binding, and interaction networks may help understand some pharmacodynamic aspects of both recovery and side- effects. We describe 5 cases who showed different levels of sensitivity to psychotropic side effects. These cases are discussed in context of their whole exome sequencing (WES)results, which may have contributed to both the diagnosis, as well as risk of side-effects, and thus influenced bedside decisions. The five persons were 20-40 years old, and had been ill for 1.5 – 20 years. Four were clinically diagnosed with schizophrenia, and one with bipolar affective disorder. Unusual sensitivity to extra-pyramidal side-effects is observed. One developed myoclonic jerks and abortive seizures on Clozapine; another developed severe dystonia on Risperidone, yet another showed cervical dystonia, oro-lingual and upper limb dyskinesias on risperidone and / or olanzapine, and also agranulocytosis while on Clozapine. Another developed features suggestive of rabbit syndrome on Aripiprazole 10-15mg/day, within a few weeks of treatment. One person had a mood disorder, and had an episode of Generalized Tonic Clonic Seizure (GTCS), after an overdose of Mirtazapine and Venlafaxine. Their WES results revealed plausibly damaging variants in the following genes/ Online Mendelian Inheritance in Man database findings: THOC2(case 1; intellectual development disorder, OMIM#300957), TYROBP (case 2; Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy type1 (Nasu-Hakola syndrome), TENM4 and ADCY5 (Case 3; hereditary essential tremor and autosomal dominant/recessive dyskinesia with orofacial involvement, OMIM#616736); and KCNT1 (Case 4; Developmental and epileptic encephalopathy 14 (OMIM#614959) / Epilepsy nocturnal frontal lobe, OMIM#615005); PRKRA (OMIM ID: 612067), VPS13C and HACE1 (Case 5) The cases (except one) showed only some overlapping features with the reported disorders from the OMIM, raising the possibility of pleiotropic effects. The WES findings helped us in making selection on psychotropics at some point. The variants possibly altered the protein, which in turn perturbed the network of interactions, in a sub-liminal manner, but nevertheless contributed to an increased sensitivity when exposed to medication. There was a large duplication involving in exon 7-37 of the THOC2 gene on the X-chromosome (c.(467+1_468-1)_(4754+1_4755-1)dup). This is a novel variant, and is thus labeled VUS. A homozygous missense variation in exon 4 of the TYROBP gene (chr19:g.35907222T>C; Depth: 62x; codon 122; p.Tyr122Cys; ENST00000585901.6) is severely damaging; and the patient had skeletal findings to corroborate the Nasu-Hakola syndrome, in addition to the psychiatric manifestations. Mutation in the TENM4, which codes for Ten-4 protein (which has a role in oligodendrocyte differentiation) leads to hypomyelination, and is associated with essential tremors. Better understanding is warranted of the molecular mechanisms, intercellular and intracellular networks behind drug action, and the genomics behind individual drug response and sensitivity to side effects. Variants with otherwise unknown significance, may modify responses to drugs and other exogenous influences. Hence, their documentation and validation is important.