Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls.

PURPOSE: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. METHODS: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. RESULTS: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10-18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10-13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. CONCLUSION: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing

Pulsed Laser-Induced Micro-Pits: As Bone Stabilizers

6th International WLT Conference on Lasers in Manufacturing (LiM) -- MAY 23-26, 2011 -- Munich, GERMANYWOS: 000298853300033Mechanical interlocking concept is a crucial criteria for osseointegration which is based on micro-porous surface structures. Several surface treatment methods have been used to modify the surface morphology of titanium implants in order to increase the effective interfacial area. The aim of the present preliminary study is two folds: to develop 3D finite element models for micro-pits on implant surfaces as bone stabilizers in order to evaluate the mechanical response of interfacial area and compare the estimated interfacial shear strength and the maximum effective shear strain with other biomechanical theories. Second is to produce novel regular micro-pit patterns using a 20 Watt ytterbium fiber laser and characterize these novel micro-stabilizers.German Sci Laser Soc (WLT

Coexistence of atrioventricular accessory pathways and drug-induced type 1 Brugada pattern

WOS: 000444469600005PubMed ID: 29953624BackgroundAtrial arrhythmias, particularly atrioventricular nodal reentrant tachycardia, can coexist with drug-induced type 1 Brugada electrocardiogram (ECG) pattern (DI-Type1-BrP). The present study was designed to determine the prevalence of DI-Type1-BrP in patients with atrioventricular accessory pathways (AV-APs) and to investigate the clinical, electrocardiographic, electrophysiologic, and genetic characteristics of these patients. MethodsOne-hundred twenty-four consecutive cases of AV-APs and 84 controls underwent an ajmaline challenge test to unmask DI-Type1-BrP. Genetic screening and analysis was performed in 55 of the cases (19 with and 36 without DI-Type1-BrP). ResultsPatientswith AV-APs were significantly more likely than controls to have a Type1-BrP unmasked (16.1vs 4.8%, P=0.012). At baseline, patients with DI-Type1-BrP had higher prevalence of chest pain, QR/rSr' pattern in V-1 and QRS notching/slurring in V-2 and aVL during preexcitation, rSr' pattern in V-1-V-2, and QRS notching/slurring in aVL during orthodromic atrioventricular reentrant tachycardia (AVRT) compared to patients without DI-Type1-BrP. Abnormal QRS configuration (QRS notching/slurring and/or fragmentation) in V-2 during preexcitation was present in all patients with DI-Type1 BrP. The prevalence of spontaneous preexcited atrial fibrillation (AF) and history of AF were similar (15%vs 18.3%, P=0.726) in patients with and without DI-Type1-BrP, respectively. The prevalence of mutations in Brugada-susceptibility genes was higher (36.8%vs 8.3%, P=0.02) in patients with DI-Type1-BrP compared to patients without DI-Type1-BrP. ConclusionsDI-Type1-BrP is relatively common in patients with AV-APs. We identify 12-lead ECG characteristics during preexcitation and orthodromic AVRT that point to an underlying type1-BrP, portending an increased probability for development of malignant arrhythmias.NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [HL47678]; Wistar and Martha Morris fund; National Taiwan University Hospital, National Taiwan University [NTUH106-S3469, NTUH106-S3458, NTUH 105-012, NTUH 106-018, NTUH 105-S2995]; Ministry of Science and TechnologyMinistry of Education, Culture, Sports, Science and Technology, Japan (MEXT) [MOST 104 - 2314 - B - 002 - 193 - MY3, MOST 106-2314-B-002 -047 -MY3, MOST 106-2314-B-002 -134 -MY2, MOST 106-2314-B-002-206]; Taiwan Health FoundationWe acknowledge support from the NIH (Grant # HL47678) and from the Wistar and Martha Morris fund. Financial support for this research was also provided partially through grants NTUH106-S3469, NTUH106-S3458, NTUH 105-012, NTUH 106-018, and NTUH 105-S2995 from National Taiwan University Hospital, National Taiwan University, and MOST 104 - 2314 - B - 002 - 193 - MY3, MOST 106-2314-B-002 -047 -MY3, MOST 106-2314-B-002 -134 -MY2 and MOST 106-2314-B-002-206 from the Ministry of Science and Technology and Taiwan Health Foundation

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes—rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 × 10−18) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 × 10−13). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case–control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing