An Interdomain KCNH2 Mutation Produces an Intermediate Long QT Syndrome.

Hereditary long QT syndrome is caused by deleterious mutation in one of several genetic loci, including locus LQT2 that contains the KCNH2 gene (or hERG, human ether-a-go-go related gene), causing faulty cardiac repolarization. Here, we describe and characterize a novel mutation, p.Asp219Val in the hERG channel, identified in an 11-year-old male with syncope and prolonged QT interval. Genetic sequencing showed a nonsynonymous variation in KCNH2 (c.656A>T: amino acid p.Asp219Val). p.Asp219Val resides in a region of the channel predicted to be unstructured and flexible, located between the PAS (Per-Arnt-Sim) domain and its interaction sites in the transmembrane domain. The p.Asp219Val hERG channel produced K(+) current that activated with modest changes in voltage dependence. Mutant channels were also slower to inactivate, recovered from inactivation more readily and demonstrated a significantly accelerated deactivation rate compared with the slow deactivation of wild-type channels. The intermediate nature of the biophysical perturbation is consistent with the degree of severity in the clinical phenotype. The findings of this study demonstrate a previously unknown role of the proximal N-terminus in deactivation and support the hypothesis that the proximal N-terminal domain is essential in maintaining slow hERG deactivation.

Delineating the Hemostaseome as an aid to individualize the analysis of the hereditary basis of thrombotic and bleeding disorders.

Next-generation sequencing and genome-wide association studies represent powerful tools to identify genetic variants that confer disease risk within populations. On their own, however, they cannot provide insight into how these variants contribute to individual risk for diseases that exhibit complex inheritance, or alternatively confer health in a given individual. Even in the case of well-characterized variants that confer a significant disease risk, more healthy individuals carry the variant, with no apparent ill effect, than those who manifest disease. Access to low-cost genome sequence data promises to provide an unprecedentedly detailed view of the nature of the hereditary component of complex diseases, but requires the large-scale comparison of sequence data from individuals with and without disease to deliver a clinical calibration. The provision of informatics support remains problematic as there are currently no means to interpret the data generated. Here, we initiate this process, a prerequisite for such a study, by narrowing the focus from an entire genome to that of a single biological system. To this end, we examine the 'Hemostaseome,' and more specifically focus on DNA sequence changes pertaining to those human genes known to impact upon hemostasis and thrombosis that can be analyzed coordinately, and on an individual basis, to interrogate how specific combinations of variants act to confer disease predisposition. As a first step, we delineate known members of the Hemostaseome and explore the nature of the genetic variants that may cause disease in individuals whose hemostatic balance has become shifted toward either a prothrombotic or anticoagulant phenotype.

Enhancing Medical Student-Interpreter Collaboration in an Urban Free Clinic.

BACKGROUND AND OBJECTIVES: Cultural barriers and patient-provider language discordance exert deleterious effects on patient care. One solution has been the integration of medical interpreters into the care of patients with limited English proficiency. While medical schools and residency programs have started developing training programs on how to work with medical interpreters, no similar endeavor has been reported by student-run free clinics. METHODS: Over 1 year, 76 third-year medical students (MS3s) were enrolled in control and intervention groups, and evaluated by in-person interpreters during interpreted real-patient encounters. MS3s in the intervention group received a lesson- and reminder-based training program on how to work with in-person interpreters. RESULTS: MS3s who received the intervention were more likely to ask the patient one question at a time (odds ratio [OR] 3.54, P=.0079), listen to the interpreter without unnecessary interruption (OR 3.30, P=.022), and speak in short, simple sentences with pauses for interpretation (OR 3.08, P=.017). CONCLUSIONS: Our lesson- and reminder-based training program on provider-interpreter collaboration can improve the performance of MS3s within a select skill set with minimal cost and time investment.