Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.

AIMS: The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible. METHODS AND RESULTS: To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands. CONCLUSION: Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.

Prevalence of J-point elevation in sudden arrhythmic death syndrome families.

OBJECTIVES: The purpose of this study was to assess the prevalence of J-point elevation among the relatives of sudden arrhythmic death syndrome (SADS) probands. BACKGROUND: J-point elevation is now known to be associated with idiopathic ventricular fibrillation. We hypothesized that this early repolarization phenomenon is an inherited trait responsible for a proportion of otherwise unexplained SADS cases. METHODS: Families of SADS probands were evaluated in an inherited arrhythmia clinic. Twelve-lead electrocardiograms were analyzed for J-point elevation defined as >0.1 mV from baseline present in 2 or more of the inferior (II, III, and aVF) or lateral (1, aVL, V(4) to V(6)) leads. Electrocardiographic data were compared with those of 359 controls of a similar age, sex, and ethnic distribution. RESULTS: A total of 363 first-degree relatives from 144 families were evaluated. J-point elevation in the inferolateral leads was present in 23% of relatives and 11% of control subjects (odds ratio: 2.54, 95% confidence interval: 1.66 to 3.90; p < 0.001). CONCLUSIONS: J-point elevation is more prevalent in the relatives of SADS probands than in controls. This indicates that early repolarization is an important potentially inheritable pro-arrhythmic trait or marker of pro-arrhythmia in SADS.

Applicants regard structured interviews as a fair method of selection: an audit of candidates.

OBJECTIVE: To discover whether applicants regard structures interviews as a fair method of selection for jobs. DESIGN: Audit study of short-listed candidates for postgraduate specialty training programmes in the London Deanery. SETTING: Postgraduate applications for the London Deanery. MAIN OUTCOME MEASURES: Satisfaction or otherwise with the application and selection process for postgraduate specialty training programmes amongst short-listed candidates in the London Deanery. Questions were asked under five categories: the applicant, the advertisement, the application form, the short-listing process, and the interview. RESULTS: 89 of 118 forms were completed and analysed. Candidates thought the advertisement was clear on who to contact (97%), when short-listed candidates would be notified of their interview (66%) and when interviews would occur (93%). The design of the application form and the short-listing process both scored a median of 1 or 2 (strongly agree or agree) on all points. The interview process itself also scored well, with most candidates scoring broadly positively. CONCLUSIONS: As in the previous study, the overall response was broadly a positive one from the candidates' perspective, with the majority of candidates finding the system fair and objective.

Success of a multidisciplinary heart failure clinic for initiation and up-titration of key therapeutic agents.

BACKGROUND: Heart failure has a poor prognosis, yet drugs known to improve outcomes are either not prescribed, or prescribed at sub-therapeutic doses. The National Service Framework (NSF) for coronary heart disease recommended specialist heart failure clinics to address this problem but their efficacy has not been evaluated. OBJECTIVES: To determine the effectiveness of a protocol-driven heart failure clinic staffed by nurse and pharmacist specialists for improving symptoms and optimising treatment with key therapeutic agents, without adversely affecting renal function. RESULTS: Of the 234 patients with at least one follow-up visit, 127 (57%) were receiving none or only one key therapeutic agent when first seen, this was reduced to 25 patients (11%) at most recent follow-up. The improvement in prescription rates was accompanied by significant up-titration of dose, the proportion of patients on "medium" or "high" doses rising from 43 (18%) to 134 (57%) for beta-blockers, and from 129 (55%) to 201 (86%) for ACE-inhibitors/angiotensin receptor blockers. Clinical improvement was reflected in reductions in patients with NYHA functional classes III and IV (93 (40%) to 53 (23%)), and in patients with moderate or severe symptoms. Significant reductions in alcohol consumption and cigarette smoking were recorded. Up-titration of treatment was associated with reductions in heart rate and systolic blood pressure; increases in serum potassium and creatinine concentrations were small. CONCLUSION: In a heart failure clinic staffed by nurse and pharmacist specialists, it is possible to achieve target doses of key therapeutic agents and improve symptoms without adversely affecting electrolytes or renal function.