Normative Heart-Rate Corrected Values for Repolarisation Length From Holter Recordings in Children and Adults.

BACKGROUND: Normative values for heart-rate corrected repolarisation length are not available in children and are scarce in adults. We wished to define repeatability and normative values of Holter recording measurements of repolarisation length in healthy individuals using a commercially available system, and compare measurements with those from 12-lead electrocardiograms (ECGs). METHODS: Twenty-four-hour (24-) Holter recordings were made on 99 Healthy volunteers: 52 children (7 months to 14 years) and 47 adults (≥15 yrs). Mean and peak values of QTc, and RTPc (R-wave to peak T-wave) were assessed. Bazett heart rate correction was employed for each measurement and only heart rates between 40 and 120 bpm were analysed. The end of the T-wave was defined from the zero-crossing point. QTc was also determined from 12-lead ECGs from the same population by manual measurement recording the longest QTc of leads 2 and V5. The tangent technique was used to define the end of the T-wave. RESULTS: Interobserver repeatability: mean QTc ±15 ms (CI 3.5%), peak QTc ±25 ms (CI 4.5%), mean RTPc ±3 ms (CI 1%), peak RTPc ±44 ms (CI 11%). Mean values were very similar for <15 years and all females and were therefore amalgamated: mean (±2 SD); mean QTc 424 ms (394-454), mean RTPc 291ms (263-319). Values were lower in males ≥15 years; (mean QTc 408 ms (370-446), p<0.01; mean RTPc 274 ms (234-314), p<0.01. The highest mean QTc value was 467 ms in an adult female. QTc from 12-lead ECG: females <15 years 409 ms (384-434) males <15 years 408 ms (383-433), females ≥15 years 426 ms (401-451), males ≥15 years 385 ms (362-408). CONCLUSIONS: Holter measurements of mean QTc and RTPc are highly repeatable. Males ≥15 years have shorter mean repolarisation length over 24 hours than males <15 years and all females. Mean QTc Holter values were on average 15-17 ms longer than QTc from 12-lead ECGs except in females >15 years.

A Prospective Study of Sudden Cardiac Death among Children and Young Adults.

BACKGROUND: Sudden cardiac death among children and young adults is a devastating event. We performed a prospective, population-based, clinical and genetic study of sudden cardiac death among children and young adults. METHODS: We prospectively collected clinical, demographic, and autopsy information on all cases of sudden cardiac death among children and young adults 1 to 35 years of age in Australia and New Zealand from 2010 through 2012. In cases that had no cause identified after a comprehensive autopsy that included toxicologic and histologic studies (unexplained sudden cardiac death), at least 59 cardiac genes were analyzed for a clinically relevant cardiac gene mutation. RESULTS: A total of 490 cases of sudden cardiac death were identified. The annual incidence was 1.3 cases per 100,000 persons 1 to 35 years of age; 72% of the cases involved boys or young men. Persons 31 to 35 years of age had the highest incidence of sudden cardiac death (3.2 cases per 100,000 persons per year), and persons 16 to 20 years of age had the highest incidence of unexplained sudden cardiac death (0.8 cases per 100,000 persons per year). The most common explained causes of sudden cardiac death were coronary artery disease (24% of cases) and inherited cardiomyopathies (16% of cases). Unexplained sudden cardiac death (40% of cases) was the predominant finding among persons in all age groups, except for those 31 to 35 years of age, for whom coronary artery disease was the most common finding. Younger age and death at night were independently associated with unexplained sudden cardiac death as compared with explained sudden cardiac death. A clinically relevant cardiac gene mutation was identified in 31 of 113 cases (27%) of unexplained sudden cardiac death in which genetic testing was performed. During follow-up, a clinical diagnosis of an inherited cardiovascular disease was identified in 13% of the families in which an unexplained sudden cardiac death occurred. CONCLUSIONS: The addition of genetic testing to autopsy investigation substantially increased the identification of a possible cause of sudden cardiac death among children and young adults. (Funded by the National Health and Medical Research Council of Australia and others.).

High Arrhythmic Burden but Low Mortality during Long-term Follow-up in Arrhythmogenic Right Ventricular Cardiomyopathy.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a high incidence of ventricular tachyarrhythmia and sudden death. The mainstay of management is the implantable cardioverter defibrillator (ICD). A small number of patient cohorts have generated a large number of reports. METHODS: Prospective registry data supplemented with clinical and ICD records of 30 patients with ARVC fulfilling the 2010 modified Task Force Criteria. This cohort has not been reported on previously. RESULTS: Median age at diagnosis: 46yrs (range 21-68); 20 (80%) male; six (19%) Maori. Duration of follow-up: 7.4yrs (range 1.7-23). Implantable cardioverter defibrillator implantation in 26; three (12%) for resuscitated sudden cardiac death; 17 (65%) for symptomatic ventricular tachyarrhythmia; three (12%) for syncope; and three (12%) for family history of sudden death attributable to ARVC. Two patients died during follow-up, one had an ICD, though died of a carcinoma. Thirteen (50%) experienced appropriate ICD therapy with median time to therapy 12 months, and four (15%) experienced inappropriate shock therapy. Male gender was an independent predictor of appropriate ICD therapy (HR 1.6, 95% CI 1.5-2.7, P=0.01). CONCLUSIONS: The long-term prognosis of patients with ARVC is favourable although high proportions receive appropriate ICD therapy. Male gender is an independent predictor of appropriate ICD therapy.

NOS1AP Polymorphisms Modify QTc Interval Duration But Not Cardiac Arrest Risk in Hypertrophic Cardiomyopathy.

INTRODUCTION: The accurate prediction of the risk of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM) remains elusive. Corrected QT interval (QTc) duration is a known risk factor in various cardiac conditions. Single nucleotide polymorphisms (SNPs) have been linked to QTc length, and to SCD. Here we investigated the role of 21 candidate SNPs in QTc duration and SCD events in patients with HCM. METHODS AND RESULTS: This HCM registry-based study included patients with an ECG, medical history, first SCD event data, and DNA available. Each individual SNP was assessed using logistic regression for associations with 2 outcomes: a prolonged QTc ( ≥440 milliseconds), and first SCD event (SCD, resuscitated cardiac arrest, and appropriate implantable cardioverter defibrillator (ICD) shock for ventricular fibrillation/ventricular tachycardia (VF/VT). In 272 HCM patients, there were 31 SCD events (8 SCD, 9 resuscitated cardiac arrest, 14 ICD shocks for VF/VT; 11%). A QTc ≥ 500 milliseconds was associated with SCD events on multivariate analysis (odds ratio [OR] = 4.0, 95% confidence interval [CI], 1.19-12.02, P = 0.016). In 228 Caucasian patients, 2 SNPs in the NOS1AP gene (rs10494366 and rs12143842) were associated with a prolonged QTc after correction for multiple testing. This remained significant after adjustment for current age, sex, and ≥1 SCD risk factor (OR 1.59 per copy of the minor allele, 95% CI 1.08-2.39, P = 0.022, and OR 1.63, 95% CI 1.09-2.49, P = 0.020, respectively). No SNPs were directly associated with SCD events. CONCLUSION: SNPs in the NOS1AP gene influence QTc interval duration but we have not demonstrated a direct association with the risk of SCD.

Genetic Testing Yield and Clinical Characteristics of Hypertrophic Cardiomyopathy in Understudied Ethnic Groups: Insights From a New Zealand National Registry.

BACKGROUND: Aotearoa/New Zealand has a multiethnic population. Patients with hypertrophic cardiomyopathy (HCM) are enrolled in the national Cardiac Inherited Diseases Registry New Zealand. Here, we report the characteristics of Cardiac Inherited Diseases Registry New Zealand HCM probands with and without pathogenic or likely pathogenic (P/LP) genetic variants for HCM, and assess genetic testing yield and variant spectrum by self-identified ethnicity. METHODS: Probands with HCM and enrolled in Cardiac Inherited Diseases Registry New Zealand who have undergone clinical genetic testing over a 17-year period were included. Clinical data, family history, and genetic test results were analyzed. RESULTS: Of 336 probands, 121 (36%) were women, 220 (66%) were European ethnicity, 41 (12%) were Maori, 26 (8%) were Pacific people, and 49 (15%) were other ethnicities. Thirteen probands (4%) presented with sudden death and 19 (6%) with cardiac arrest. A total of 134 (40%) had a P/LP variant identified; most commonly in the MYBPC3 gene (60%) followed by the MYH7 gene (24%). A P/LP variant was identified in 27% of Maori or Pacific probands versus 43% European or other ethnicity probands (P=0.022); 16% of Maori or Pacific probands had a variant of uncertain significance identified, compared with 9% of European or other ethnicity probands (P=0.092). Women more often had a P/LP variant identified than men (48% versus 35%; P=0.032), and variant-positive probands were younger at clinical diagnosis than variant of uncertain significance/variant-negative probands (39±17 versus 50±17 years; P<0.001) and more likely to have experienced cardiac arrest or sudden death events over their lifetime (P=0.002). CONCLUSIONS: Carriage of a P/LP variant in HCM probands is associated with presentation at younger age, and cardiac arrest or sudden death events. Maori or Pacific probands were less likely to have a P/LP variant identified than European or other ethnicity probands.

Evaluation of autopsy and police reports in the investigation of sudden unexplained death in the young.

To evaluate police and autopsy reports in sudden unexplained deaths in 0-40 year olds. A structured, blind review of police and autopsy reports send to a cardiac genetic service from before (February 2006-December 2007) and after (January-December 2009) new best practice guidelines were introduced in Australia and New Zealand was performed. The reviews focused on reporting on: (1) presentation and clinical history, (2) cardiac autopsy, (3) histological tests and toxicology, and (4) detailed examination of coronary arteries. 110 reports were evaluated against the guidelines. 100 % reported location, 95 % activity at time of death, and 84 % some clinical history. Less than 25 % reported on family history, presence/absence of illicit drugs or alcohol, recorded a possible arrhythmic trigger, or history of fits/faints or collapses. Over 95 % listed heart weight, valvular examinations, pulmonary and some myocardial histology. Less than 50 % commented on septal, LV (left ventricle) and RV (right ventricle) wall thickness. Less than 50 % mentioned site of histology samples, or gave specific description of LV or RV histology or conduction system. Toxicology was not mentioned in a third. Histology of coronary arteries was described in only 18 %. Post guidelines reporting increased in some areas, e.g. in 1-40 year olds: antecedent symptoms (22-61 %), number and location of histology samples (0-47 %), and histology of coronary arteries (6-50 %). Most police and autopsy reports fall short of best practice guidelines. They have improved somewhat after the new guidelines were introduced, but need to be more consistent and particularly need to include significant negative findings.

Holter Recordings at Initial Assessment for Long QT Syndrome: Relationship to Genotype Status and Cardiac Events.

Background: The relationship of Holter recordings of repolarization length to outcome in long QT syndrome (LQTS) is unknown. Methods: Holter recordings and initial 12 lead ECG QTc were related to outcome in 101 individuals with LQTS and 28 gene-negative relatives. Mean QTc (mQTc) and mean RTPc (R-wave to peak T-wave, mRTPc) using Bazett correction were measured, analyzing heart rates 40 to 120 bpm. Previously reported upper limit of normal (ULN) were: women and children (<15 years), mQTc 454, mRTPc 318 ms; men mQTc 446 ms, mRTPc 314 ms. Results: Measurements in LQTS patients were greatly prolonged; children and women mean mQTc 482 ms (range 406−558), mRTPc 351 ms (259−443); males > 15 years mQTc 469 ms (407−531), mRTPc 338 ms (288−388). Ten patients had cardiac arrest (CA), and 24 had arrhythmic syncope before or after the Holter. Holter values were more closely related to genotype status and symptoms than 12 lead QTc, e.g., sensitivity/specificity for genotype positive status, mRTPc > ULN (89%/86%); CA, mRTPc > 30 ms over ULN (48%/100%). Of 34 symptomatic (CA/syncope) patients, only 9 (26%) had 12 lead QTc > 500 ms, whereas 33/34 (94%) had an mRTPc or mQTc above ULN. In 10 with CA, all Holter measurements were > 15 ms above ULN, but only two had 12 lead QTc > 500 m. Conclusions: Holter average repolarization length, particularly mRTPc, reflects definite LQTS status and clinical risk better than the initial 12 lead QTc. Values below ULN indicate both a low risk of having LQTS and a low risk of cardiac events in the small percentage that do.

Symptoms and signs associated with syncope in young people with primary cardiac arrhythmias.

BACKGROUND: It is often reported that clinical symptoms are useful in differentiating cardiac from non-cardiac syncope. Studies in the young are rare. This study was designed to capture the symptoms and signs reported by patients with cardiac syncope before the patients or their attending clinicians knew the final diagnosis. METHODS: Retrospective case-note review of 35 consecutive unrelated gene-positive probands with a proven cardiac channelopathy. RESULTS: The presentation leading to diagnosis of cardiac channelopathy was resuscitated sudden cardiac death in 7 patients; syncope in 20; collapse with retained consciousness in 2; palpitations in 1 and an incidental finding in 5. For the 20 patients with syncope (LQTS 18, Brugada syndrome 2), median age at presentation was 13.9 years (1.8 day to 40.8 years). Of the 17 patients able to describe the onset of syncope, 11 (65%) had at least one symptom prior to collapse, though none reported nausea. Dizziness or lightheadedness was the most frequent symptom, being experienced by 8 (47%). Nine (of 20) patients (45%) had witnessed seizure-like activity and 8 (40%) had urinary incontinence. Nineteen patients were capable of describing the post-syncopal period, of whom 15 (79%) reported symptoms, the most common (12; 65%) being drowsiness or exhaustion. CONCLUSIONS: Cardiac syncope in the young frequently presents with symptoms and signs that are typically associated with other causes of transient loss of consciousness, including vasovagal syncope and seizure disorders. The presence of symptoms may not be as helpful in differentiating arrhythmic from non-arrhythmic events as is often supposed. A thorough history, appropriate investigations and a high index of suspicion remain essential in the assessment of syncope.

Genetic testing in Polynesian long QT syndrome probands reveals a lower diagnostic yield and an increased prevalence of rare variants.

BACKGROUND: New Zealand has a multiethnic population and a national cardiac inherited disease registry (Cardiac Inherited Disease Registry New Zealand [CIDRNZ]). Ancestry is reflected in the spectrum and prevalence of genetic variants in long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to study the genetic testing yield and mutation spectrum of CIDRNZ LQTS probands stratified by self-identified ethnicity. METHODS: A 15-year retrospective review of clinical CIDRNZ LQTS probands with a Schwartz score of ≥2 who had undergone genetic testing was performed. RESULTS: Of the 264 included LQTS probands, 160 (61%) reported as European, 79 (30%) NZ Maori and Pacific peoples (Polynesian), and 25 (9%) Other ethnicities, with comparable clinical characteristics across ethnic groups (cardiac events in 72%; age at presentation 28±19 years; corrected QT interval 512±55 ms). Despite comparable testing (5.3±1.4 LQTS genes), a class III-V LQTS variant was identified in 35% of Polynesian probands as compared with 63% of European and 72% of Other probands (P<.0001). Among variant-positive CIDRNZ LQTS probands (n=148), Polynesians were more likely to have non-missense variants (57% vs 39% and 25% in probands of European and Other ethnicity, respectively; P=.005) as well as long QT syndrome type 1-3 variants not reported elsewhere (71% vs European 22% and Other 28%; P<.0001). Variants found in multiple probands were more likely to be shared within the same ethnic group; P<.01). CONCLUSION: Genetic testing of Polynesian LQTS probands has a lower diagnostic yield, despite comparable testing and clinical disease severity. Rare LQTS variants are more common in Polynesian LQTS probands. These data emphasize the importance of increasing the knowledge of genetic variation in the Polynesian population.

A Population-Based Registry of Patients With Inherited Cardiac Conditions and Resuscitated Cardiac Arrest.

BACKGROUND: The relative proportion of each cardiac inherited disease (CID) causing resuscitated sudden cardiac arrest (RSCA) on a population basis is unknown. OBJECTIVES: This study describes the profile of patients with CIDs presenting with RSCA; their data were collected by the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ). METHODS: Data were collated from CIDRNZ probands presenting with RSCA (2002 to 2018). RESULTS: CID was identified in 115 (51%) of 225 RSCA cases: long QT syndrome (LQTS) (n = 48 [42%]), hypertrophic cardiomyopathy (HCM) (n = 28 [24%]), Brugada syndrome (BrS) (n = 16 [14%]), catecholaminergic polymorphic ventricular tachycardia (CPVT) (n = 9 [8%]), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 9 [8%]), and dilated cardiomyopathy (n = 5 [4%]). Seventy-one (62%) of 115 were male. Of 725 probands from the CIDRNZ with CID, the proportion presenting with RSCA was: CPVT, 9 (53%) of 17; BrS, 16 (33%) of 49; ARVC, 9 (25%) of 36; LQTS, 48 (20%) of 238; dilated cardiomyopathy, 5 (9%) of 58; and HCM, 28 (8%) of 354. Incident activity was: normal everyday activities, 44 (40%); exercising, 33 (30%); concurrent illness, 13 (12%); sleeping, 10 (9%); drugs/medication, 9 (8%); and emotion, 2 (2%). LQTS and CPVT predominated in those <24 years of age, 30 (77%) of 39; cardiomyopathies and BrS predominated in those >24 years of age, 49 (64%) of 76. For those >40 years of age, HCM was the most common (33%) CID. A genetic diagnosis in patients with CID was made in 48 (49%) of 98 tested. Diagnosis by age range was as follows: age 1 to 14 years, 78%; age 15 to 24 years, 53%; age 25 to 39 years, 54%; and age >40 years, 26%. CONCLUSIONS: The commonest CID identified after RSCA was LQTS; the most common CID cause of RSCA for those >40 years of age was HCM. CPVT was the CID most likely to present with RSCA and HCM the least. Genetic yield decreases with age. Only one-third of RSCA cases due to CID occurred while exercising.

The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy.

Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.

Misdiagnosis of long QT syndrome as epilepsy at first presentation.

STUDY OBJECTIVE: Long QT syndrome has significant mortality, which is reduced with appropriate management. It is known that long QT syndrome masquerades as other conditions, including seizure disorders. We aim to evaluate a series of patients with genetically confirmed long QT syndrome to establish the frequency of delayed recognition. We also examine causes and potential consequences of diagnostic delay. METHODS: A consecutive case series of patients with long QT syndrome was identified through the Cardiac Inherited Disease Registry in New Zealand between 2000 and 2005. Detailed retrospective review of 31 cases was undertaken. The primary outcome was the time from first presentation with sudden loss of consciousness to a diagnosis of long QT syndrome. If the diagnosis was not made at the initial presentation, it was considered delayed. For the patients with a delayed diagnosis, the median duration of delay was compared between the subgroup of patients initially misdiagnosed with epilepsy and the others. RESULTS: Genetic mutations in 31 probands were consistent with long QT type 1 in 18 (58%) patients, long QT type 2 in 10 (32%) and long QT type 3 in 3 (10%). Median age at diagnosis was 21 years (1 day to 54 years). Thirteen patients (39%) experienced diagnostic delay after presentation with syncope or seizure: median delay 2.4 years (2 months to 23 years). Electroencephalograms were obtained in 10 patients; 5 were diagnosed with epilepsy. For those labeled epileptic, diagnostic delay was significantly longer than with other misdiagnoses: estimated median difference 9.75 years (95% confidence interval 7.6 to 20.7 years). During the delay period, 4 sudden unexplained deaths reportedly occurred in young relatives. Ten of the 13 had an ECG before diagnosis, with unrecognized pulse rate-corrected QT interval prolongation in 8 cases (range 0.47 to 0.65 seconds). CONCLUSION: Delayed diagnosis of long QT syndrome is frequent. Symptoms are often attributed to alternative diagnoses, most commonly seizure disorder. Patients labeled as epileptic experience a particularly long diagnostic delay. ECGs were frequently requested, but interpretation errors were common. Given the potentially preventable mortality of long QT syndrome, emergency physicians investigating syncope and seizure should maintain a high index of suspicion.

Long QT molecular autopsy in sudden unexplained death in the young (1-40 years old): Lessons learnt from an eight year experience in New Zealand.

BACKGROUND: To review long QT syndrome molecular autopsy results in sudden unexplained death in young (SUDY) between 2006 and 2013 in New Zealand. METHODS: Audit of the LQTS molecular autopsy results, cardiac investigations and family screening data from gene-positive families. RESULTS: During the study period, 365 SUDY cases were referred for molecular autopsy. 128 cases (35%) underwent LQTS genetic testing. 31 likely pathogenic variants were identified in 27 cases (21%); SCN5A (14/31, 45%), KCNH2 (7/31, 22%), KCNQ1 (4/31, 13%), KCNE2 (3/31, 10%), KCNE1 (2/31, 7%), KCNJ2 (1/31, 3%). Thirteen variants (13/128, 10%) were ultimately classified as pathogenic. Most deaths (63%) occurred during sleep. Gene variant carriage was more likely with a positive medical history (mostly seizures, 63% vs 36%, p = 0.01), amongst females (36% vs 12%, p = 0.001) and whites more than Maori (31% vs 0, p = 0.0009). Children 1-12 years were more likely to be gene-positive (33% vs 14%, p = 0.02). Family screening identified 42 gene-positive relatives, 18 with definitive phenotypic expression of LQTS/Brugada. 76% of the variants were maternally inherited (p = 0.007). Further family investigations and research now support pathogenicity of the variant in 13/27 (48%) of gene-positive cases. CONCLUSION: In New Zealand, variants in SCN5A and KCNH2, with maternal inheritance, predominate. A rare variant in LQTS genes is more likely in whites rather than Maori, females, children 1-12 years and those with a positive personal and family history of seizures, syncope or SUDY. Family screening supported the diagnosis in a third of the cases. The changing classification of variants creates a significant challenge.

Long QT and Brugada syndrome gene mutations in New Zealand.

BACKGROUND: Genetic testing in long QT syndrome (LQTS) is moving from research into clinical practice. We have recently piloted a molecular genetics program in a New Zealand research laboratory with a view to establishing a clinical diagnostic service. OBJECTIVE: This study sought to report the spectrum of LQTS and Brugada mutations identified by a pilot LQTS gene testing program in New Zealand. METHODS: Eighty-four consecutive index cases referred for LQT gene testing, from New Zealand and Australia, were evaluated. The coding sequence and splice sites of 5 LQTS genes (KCNQ1, HERG, SCN5A, KCNE1, and KCNE2) were screened for genomic variants by transgenomics denaturing high-performance liquid chromatography (dHPLC) system and automated DNA sequencing. RESULTS: Forty-five LQTS mutations were identified in 43 patients (52% of the cohort): 25 KCNQ1 mutations (9 novel), 13 HERG mutations (7 novel), and 7 SCN5A mutations (2 novel). Forty patients had LQTS, and 3 had Brugada syndrome. Mutations were identified in 14 patients with resuscitated sudden cardiac death: 4 KCNQ1, 5 HERG, 5 SCN5A. In 17 cases there was a family history of sudden cardiac death in a first-degree relative: 8 KCNQ1, 6 HERG, 2 SCN5A, and 1 case with mutations in both KCNQ1 and HERG. CONCLUSION: The spectrum of New Zealand LQTS and Brugada mutations is similar to previous studies. The high proportion of novel mutations (40%) dictates a need to confirm pathogenicity for locally prevalent mutations. Careful screening selection criteria, cellular functional analysis of novel mutations, and development of locally relevant control sample cohorts will all be essential to establishing regional diagnostic services.

Splice Site Variants in the KCNQ1 and SCN5A Genes: Transcript Analysis as a Tool in Supporting Pathogenicity.

BACKGROUND: Approximately 75% of clinically definite long QT syndrome (LQTS) cases are caused by mutations in the KCNQ1, KCNH2 and SCN5A genes. Of these mutations, a small proportion (3.2-9.2%) are predicted to affect splicing. These mutations present a particular challenge in ascribing pathogenicity. METHODS: Here we report an analysis of the transcriptional consequences of two mutations, one in the KCNQ1 gene (c.781_782delinsTC) and one in the SCN5A gene (c.2437-5C>A), which are predicted to affect splicing. We isolated RNA from lymphocytes and used a directed PCR amplification strategy of cDNA to show mis-spliced transcripts in mutation-positive patients. RESULTS: The loss of an exon in each mis-spliced transcript had no deduced effect on the translational reading frame. The clinical phenotype corresponded closely with genotypic status in family members carrying the KCNQ1 splice variant, but not in family members with the SCN5A splice variant. These results are put in the context of a literature review, where only 20% of all splice variants reported in the KCNQ1, KCNH2 and SCN5A gene entries in the HGMDPro 2015.4 database have been evaluated using transcriptional assays. CONCLUSIONS: Prediction programmes play a strong role in most diagnostic laboratories in classifying variants located at splice sites; however, transcriptional analysis should be considered critical to confirm mis-splicing. Critically, this study shows that genuine mis- splicing may not always imply clinical significance, and genotype/phenotype cosegregation remains important even when mis-splicing is confirmed.

Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome.

BACKGROUND: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. OBJECTIVES: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives. METHODS: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls. RESULTS: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%. CONCLUSIONS: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

ß-Blocker Adherence in Familial Long QT Syndrome.

BACKGROUND: Long-term uninterrupted ß-blockade significantly reduces cardiac events in long QT syndrome (LQTS). Despite this, data on nonadherence are scarce and quantified only on the day of cardiac arrest in LQTS literature. We aimed to describe ß-blocker adherence, and predictors thereof, among patients with LQTS types 1 and 2. METHODS AND RESULTS: Electronic health records and pharmacy dispensing data were reviewed for 90 patients with LQTS 1 and 2 who reside in Auckland, New Zealand, during a 34-month period. For each patient, the medication possession ratio (MPR: proportion of follow-up days patients were dispensed ß-blocker) was calculated. Adequate adherence was characterized by an MPR ≥0.8 and ideal as MPR=1.0. Clinical and demographic features were assessed to determine whether they predicted adherence. Long-term ß-blockers were prescribed to 74 patients (82%). Side effects were described as intolerable by 6 (8%) and their ß-blockers were stopped. MPR was calculated in the remaining 68 patients >151.7 patient-years of follow-up. Median MPR was 0.79 (range, 0-1.3). Suboptimal adherence (MPR<0.8) was recorded in 35 (51%). Seven patients (10%) never took up a prescription (MPR=0). Adequate adherence was present in 33 (49%), including 9 (13%) who had ideal adherence. Age, sex, clinical presentation, family history of sudden death, ethnicity, and deprivation index did not predict adherence. CONCLUSIONS: Adherence to ß-blockers in LQTS is suboptimal in half of those with LQTS 1 and 2. Risk factors for nonadherence could not be identified in our population. Further research into ß-blocker adherence is imperative in this high-risk population.

Inpatient detection of cardiac-inherited disease: the impact of improving family history taking.

OBJECTIVES: 'Idiopathic' cardiac conditions such as dilated cardiomyopathy (DCM) and resuscitated sudden cardiac death (RSCD) may be familial. We suspected that inpatient cardiology services fail to recognise this. Our objective was to compare diagnostic value of family histories recorded by inpatient cardiology teams with a multigenerational family tree obtained by specially trained allied professionals. METHODS: 2 experienced cardiology nurses working in 2 tertiary adult cardiac units were trained in cardiac-inherited diseases and family history (FHx) taking, and established as regional coordinators for a National Cardiac Inherited Disease Registry. Over 6 months they sought 'idiopathic' cardiology inpatients with conditions with a possible familial basis, reviewed the FHx in the clinical records and pursued a minimum 3-generation family tree for syncope, young sudden death and cardiac disease (full FHx). RESULTS: 37 patients (22 males) were selected: mean age 51 years (range 15-79). Admission presentations included (idiopathic) RSCD (14), dyspnoea or heart failure (11), ventricular tachycardia (2), other (10). 3 patients had already volunteered their familial diagnosis to the admitting team. FHx was incompletely elicited in 17 (46%) and absent in 20 (54%). 29 patients (78%) provided a full FHx to the coordinator; 12 of which (41%) were strongly consistent with a diagnosis of a cardiac-inherited disease (DCM 7, hypertrophic cardiomyopathy 3, long QT 1, left ventricular non-compaction 1). Overall, a familial diagnostic rate rose from 3/37(8%) to 12/37 (32%). CONCLUSIONS: Adult cardiology inpatient teams are poor at recording FHx and need to be reminded of its powerful diagnostic value.

Detection of sudden death syndromes in New Zealand.

AIM: To investigate regional variations in the detection of sudden death syndromes across New Zealand by assessing registrations in the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ). METHODS: The CIDRNZ has been a national entity since 2009, with a hub in Auckland and locally funded regional coordinators (Midland, Central) linked with multidisciplinary cardiac genetic teams. Registration is consent-based and voluntary, and involves the collection of clinical/genetic information and permits genetic testing and research. Registry data were extracted from the CIDRNZ in October 2015 and results are expressed as registrations per 100,000 people by district health board area. RESULTS: The CIDRNZ has 1,940 registrants from 712 families, 46% of whom are definitely or probably affected by cardiac inherited disease. There are clear regional differences in registration frequencies between regions and between the North and South Islands, both for overall registrations (56/100,000 and 14/100,000, respectively; p<0.001) and for long QT syndrome registrations (15/100,000 and 6/100,000, respectively; p<0.001). Regions with local coordinators have the highest number of registrations. CONCLUSION: The detection of sudden death syndromes in New Zealand through a cardiac genetic registry is possible but much work is needed to improve regional variation in the detection/reporting of these conditions across the country.