The functional spectrum of low-frequency coding variation

Background Rare coding variants constitute an important class of human genetic variation, but are underrepresented in current databases that are based on small population samples. Recent studies show that variants altering amino acid sequence and protein function are enriched at low variant allele frequency, 2 to 5%, but because of insufficient sample size it is not clear if the same trend holds for rare variants below 1% allele frequency. Results The 1000 Genomes Exon Pilot Project has collected deep-coverage exon-capture data in roughly 1,000 human genes, for nearly 700 samples. Although medical whole-exome projects are currently afoot, this is still the deepest reported sampling of a large number of human genes with next-generation technologies. According to the goals of the 1000 Genomes Project, we created effective informatics pipelines to process and analyze the data, and discovered 12,758 exonic SNPs, 70% of them novel, and 74% below 1% allele frequency in the seven population samples we examined. Our analysis confirms that coding variants below 1% allele frequency show increased population-specificity and are enriched for functional variants. Conclusions This study represents a large step toward detecting and interpreting low frequency coding variation, clearly lays out technical steps for effective analysis of DNA capture data, and articulates functional and population properties of this important class of genetic variatio

withdrawn 2017 hrs ehra ecas aphrs solaece expert consensus statement on catheter and surgical ablation of atrial fibrillation

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Molecular Diagnosis of Pompe Disease in the Genomic Era: Correlation with Acid Alpha-Glucosidase Activity in Dried Blood Spots

Measurement of alpha-glucosidase activity on dried blood spots has been the main method to screen for Pompe disease, but a paradigm shift has been observed in recent years with the incorporation of gene panels and exome sequencing in molecular diagnostic laboratories. An 89-gene panel has been available to Canadian physicians since 2017 and was analyzed in 2030 patients with a suspected muscle disease. Acid alpha-glucosidase activity was measured in parallel in dried blood spots from 1430 patients. Pompe disease was diagnosed in 14 patients, representing 0.69% of our cohort. In 7 other patients, low enzyme activities overlapping those of Pompe disease cases were attributable to the presence of pseudodeficiency alleles. Only two other patients had enzymatic activity in the Pompe disease range, and a single heterozygous pathogenic variant was identified. It is possible that a second variant could have been missed; we suggest that RNA analysis should be considered in such cases. With gene panel testing increasingly being performed as a first-tier analysis of patients with suspected muscle disorders, our study supports the relevance of performing reflex enzymatic activity assay in selected patients, such as those with a single GAA variant identified and those in whom the observed genotype is of uncertain clinical significance

Emergency Management of Pediatric Anaphylaxis due to an Unknown Cause: A 5-year follow-up study in Canada

Rationale There is limited data regarding treatment and management of anaphylaxis due to unknown causes (AUC). This study aims to assess the socio-demographics, clinical characteristics and management of pediatric AUC cases across Canada. Methods Data on 204 pediatric AUC cases were prospectively collected between 2011 and 2017 in emergency rooms at 5 centres across Canada (Montreal Children’s Hospital, Sacré-Coeur Hospital, Sainte-Justine Hospital, Janeway Children’s Hospital and BC Children’s Hospital) as part of the Cross-Canada Anaphylaxis Registry (C-CARE). Severe cases were defined as ones that manifested as cyanosis, hypoxia (saturation \u3c92%), respiratory arrest, hypotension, dysrhythmia, confusion or loss of consciousness. A primary analysis was done using multivariate logistic regression to identify factors associated with epinephrine treatment. Results Among 204 cases of AUC, 54.5% were males, and the median age was 9.1 years (IQR: 5.1, 14.4). 18.2% (95%CI 13.3%, 24.4%) had asthma, and 43.3% (95%CI 36.5%, 50.5%) had a known food allergy. 37.7% (95%CI 30.8%, 45.0%) of cases were severe. Epinephrine was not administered in 27.1% (95%CI 21.2%, 33.8%) of cases. Epinephrine auto-injector was prescribed to 79.6% (95%CI 73.2%, 84.8%) of cases and 75.4% (95%CI 68.9%, 81.1%) were referred to an allergist. Anaphylactic reactions occurring at home were more likely to be managed without epinephrine (adjusted OR for age, sex, and presence of asthma: 2.4 (95%CI 1.1, 4.7). Conclusions Our findings highlight the need to increase awareness of appropriate management of AUC with epinephrine followed by consultation with an allergist. It is possible that cases of AUC occurring outside the home have greater accessibility to epinephrine

Priority III

The Priority III Priority Setting Partnership identified priorities for future research around how we plan, do and share the results of rapid reviews in the context of healthcare using a modified JLA approac