Integrating precision medicine in the study and clinical treatment of a severely mentally ill person

Background. In recent years, there has been an explosion in the number of technical and medical diagnostic platforms being developed. This has greatly improved our ability to more accurately, and more comprehensively, explore and characterize human biological systems on the individual level. Large quantities of biomedical data are now being generated and archived in many separate research and clinical activities, but there exists a paucity of studies that integrate the areas of clinical neuropsychiatry, personal genomics and brain-machine interfaces. Methods. A single person with severe mental illness was implanted with the Medtronic Reclaim® Deep Brain Stimulation (DBS) Therapy device for Obsessive Compulsive Disorder (OCD), targeting his nucleus accumbens/anterior limb of the internal capsule. Programming of the device and psychiatric assessments occurred in an outpatient setting for over two years. His genome was sequenced and variants were detected in the Illumina Whole Genome Sequencing Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Results. We report here the detailed phenotypic characterization, clinical-grade whole genome sequencing (WGS), and two-year outcome of a man with severe OCD treated with DBS. Since implantation, this man has reported steady improvement, highlighted by a steady decline in his Yale-Brown Obsessive Compulsive Scale (YBOCS) score from ∼38 to a score of ∼25. A rechargeable Activa RC neurostimulator battery has been of major benefit in terms of facilitating a degree of stability and control over the stimulation. His psychiatric symptoms reliably worsen within hours of the battery becoming depleted, thus providing confirmatory evidence for the efficacy of DBS for OCD in this person. WGS revealed that he is a heterozygote for the p.Val66Met variant in BDNF, encoding a member of the nerve growth factor family, and which has been found to predispose carriers to various psychiatric illnesses. He carries the p.Glu429Ala allele in methylenetetrahydrofolate reductase (MTHFR) and the p.Asp7Asn allele in ChAT, encoding choline O-acetyltransferase, with both alleles having been shown to confer an elevated susceptibility to psychoses. We have found thousands of other variants in his genome, including pharmacogenetic and copy number variants. This information has been archived and offered to this person alongside the clinical sequencing data, so that he and others can re-analyze his genome for years to come. Conclusions. To our knowledge, this is the first study in the clinical neurosciences that integrates detailed neuropsychiatric phenotyping, deep brain stimulation for OCD and clinical-grade WGS with management of genetic results in the medical treatment of one person with severe mental illness. We offer this as an example of precision medicine in neuropsychiatry including brain-implantable devices and genomics-guided preventive health care.

--t s e T Genome level sequencing was performed and calls made across greater than 90% of the genome. Clinical interpretation was performed using the American College of Medical Genetics recommendations for interpretation on 140 conditions causally associated with 344 genes. The complete list of all interpreted variants for this patient can be found at the end of this report. A list of the 140 conditions and 344 genes can be found on the attached document.

RESULTS
A total of variants were detected in the subset of genes for this patient. Each variant was evaluated for 1247 clinical signi cance and placed into one of ve possible categories for classi cation, based on the American College of Medical Genetics and Genomics interpretation guidelines as outlined below and described at the end of this report.

MOLECULAR DIAGNOSTICS REPORT
variants in genes that could be clinically significant or confer carrier status. At this time, the evidence is too weak or contradictory to assess whether the variant is pathogenic or benign. The interpretations of these variants are likely to change as more individuals are sequenced and the community understanding of the effect of the variant improves. A complete list of these variants, the genes in which they were found, and annotation characteristics can be found in the table at the end of this report.

Benign/Likely Benign Variants
Finally, variants categorized as benign and variants categorized as likely benign polymorphisms 613 349 were also found in these 344 genes. A complete list of these variants, the genes in which they were found, and annotation characteristics can be found in the table at the end of this report.
Evaluation Criteria As additional evidence may change our understanding of the roles of these variants in their associated conditions, regular review of the implications of these variants should be considered as appropriate. Additional variants that were not included in this interpretation could potentially result in the conditions discussed. A full list of the citations used to categorize the variants into these groups can be provided upon request. Criteria for classification: Pathogenic: Reported in at least 3 unrelated cases, with control data. Functional or expression evidence suggests deleterious effect on gene function. Likely pathogenic: Reported in < 3 cases, or in a single family cohort, with or without control data. Limited or no functional evidence available, but overall biological expectations suggestive of deleterious effect. Unknown significance: Little or nothing has been reported on this variant or its effects. Likely benign: The variant has been seen in cases, but also in controls. Variant may be present in a high percentage of the population, and may be present in a non-conserved region. Benign: Established in the literature as a variant that is not associated with Mendelian (single-gene inherited) disease, or known to have an allele frequency that is far too high to be compatible with the prevalence of disease, mode of inheritance and penetrance patterns known for that condition.

BACKGROUND:
Clinical interpretation was performed using the American College of Medical Genetics recommendations for interpretation on 140 conditions causally associated with 344 genes. Genome level sequencing was performed and calls made across greater than 90% of the genome. No other variants beyond those contained within the listed genes and conditions were evaluated for possible clinical significance. Therefore, other variants of possible clinical significance may exist within this genome. It is recommended that additional evaluations be performed as appropriate. All calls within these genes were evaluated for evidence of clinical importance including: allele frequency in population studies (dbSNP, 1000 Genomes, etc.), evidence in the scientific literature for likely causation of the condition, and consideration of the likely biological implications of the variant based on its expected characteristics. This assessment represents our current best understanding of the clinical implications of the variants reported. As information within the field increases, this understanding may change and the implications reported here may change. Occasional reassessment of this information is recommended as is appropriate or medically relevant to optimize the medical care of this individual.

METHODOLOGY:
Sequence was generated from DNA that was extracted from peripheral whole blood. The regions of the genome not reported here include regions where the human reference genome has not been completely