Tramadol is a unique analgesic medication, available in variety of formulations, with both monoaminergic reuptake inhibitory and opioid receptor agonist activity increasingly prescribed worldwide as an alternative for high-affinity opioid medication in the treatment of acute and chronic pain. It is a prodrug that is metabolized by cytochrome P450 (CYP) enzymes CYP2D6 and CYP3A4 to its more potent opioid analgesic metabolites, particularly the O-demethylation product M1. The opioid analgesic potency of a given dose of tramadol is influenced by an individual's CYP genetics, with poor metabolizers experiencing little conversion to the active M1 opioid metabolite and individuals with a high metabolic profile, or ultra-metabolizers, experiencing the greatest opioid analgesic effects. The importance of the CYP metabolism has led to the adoption of computer clinical decision support with pharmacogenomics tools guiding tramadol treatment in major medical centers. Tramadol's simultaneous opioid agonist action and serotonin (5-HT) and norepinephrine reuptake inhibitory effects result in a unique side effect profile and important drug interactions that must be considered. Abrupt cessation of tramadol increases the risk for both opioid and serotonin-norepinephrine reuptake inhibitor withdrawal syndromes. This review provides updated important information on the pharmacology, pharmacokinetics, CYP genetic polymorphisms, drug interactions, toxicity, withdrawal, and illicit use of tramadol.

PurposeWe evaluated clinical and genetic features enriched in patients with multiple Mendelian conditions to determine which patients are more likely to have multiple potentially relevant genetic findings (MPRF).MethodsResults of the first 7698 patients who underwent exome sequencing at Ambry Genetics were reviewed. Clinical and genetic features were examined and degree of phenotypic overlap between the genetic diagnoses was evaluated.ResultsAmong patients referred for exome sequencing, 2% had MPRF. MPRF were more common in patients from consanguineous families and patients with greater clinical complexity. The difference in average number of organ systems affected is small: 4.3 (multiple findings) vs. 3.9 (single finding) and may not be distinguished in clinic.ConclusionPatients with multiple genetic diagnoses had a slightly higher number of organ systems affected than patients with single genetic diagnoses, largely because the comorbid conditions affected overlapping organ systems. Exome testing may be beneficial for all cases with multiple organ systems affected. The identification of multiple relevant genetic findings in 2% of exome patients highlights the utility of a comprehensive molecular workup and updated interpretation of existing genomic data; a single definitive molecular diagnosis from analysis of a limited number of genes may not be the end of a diagnostic odyssey.

Patients with dystonia are particularly appropriate for diagnostic exome sequencing (DES), due to the complex, diverse features and genetic heterogeneity. Personal and family history data were collected from test requisition forms and medical records from 189 patients with reported dystonia and available family members received for clinical DES. Of them, 20.2% patients had a positive genetic finding associated with dystonia. Detection rates for cases with isolated and combined dystonia were 22.4% and 25.0%, respectively. 71.4% of the cohort had co-occurring non-movementrelated findings and a detection rate of 24.4%. Patients with childhood-onset dystonia trended toward higher detection rates (31.8%) compared to infancy (23.6%), adolescence (12.5%), and early-adulthood onset (16%). Uncharacterized gene findings were found in 6.7% (8/119) of cases that underwent analysis for genes without an established disease relationship. Patients with intellectual disability/developmental delay, seizures/epilepsy and/or multifocal dystonia were more likely to have positive findings (P = .0093, .0397, .0006). Four (2.1%) patients had findings in two genes, and seven (3.7%) had reclassification after the original report due to new literature, new clinical information or reanalysis request. Pediatric patients were more likely to have positive findings (P = .0180). Our observations show utility of family-based DES in patients with dystonia and illustrate the complexity of testing. K E Y W O R D S dystonia, exome, genetic testing

Purpose Clinical history data reported on test requisition forms (TRFs) for hereditary cancer multigene panel testing (MGPT) are routinely used by genetic testing laboratories. More recently, publications have incorporated TRF-based clinical data into studies exploring yield of testing by phenotype and estimating cancer risks for mutation carriers. We aimed to assess the quality of TRF data for patients undergoing MGPT. Patients and Methods Ten percent of patients who underwent hereditary cancer MGPT between January and June 2015 at a clinical laboratory were randomly selected. TRF-reported cancer diagnoses were evaluated for completeness and accuracy for probands and relatives using clinical documents such as pedigrees and chart notes as the comparison standard in cases where these documents were submitted after the time of test order. Results TRF-reported cancer sites and ages at diagnosis were complete for > 90.0% of proband cancer diagnoses overall, and the completion rate was even higher (> 96.0%) for breast, ovarian, colorectal, and uterine cancers. When reported, these data were accurate on TRFs for > 99.5% of proband cancer sites and > 97.5% of proband ages at diagnosis. Cancer site and age at diagnosis data were also complete on the TRF for the majority of cancers among first- and second-degree relatives. Completeness decreased as relation to the proband became more distant, whereas accuracy remained high across all degrees of relation. Conclusion Data collected as part of cancer genetic risk assessment is completely and accurately reported on TRFs for the majority of probands and their close relatives and is comparable to information directly obtained from clinic notes, particularly for breast and other cancers commonly associated with hereditary cancer syndromes.

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