Characterization of clinically relevant copy-number variants from exomes of patients with inherited heart disease and unexplained sudden cardiac death.

PURPOSE: Copy-number variant (CNV) analysis is increasingly performed in genetic diagnostics. We leveraged recent gene curation efforts and technical standards for interpretation and reporting of CNVs to characterize clinically relevant CNVs in patients with inherited heart disease and sudden cardiac death. METHODS: Exome sequencing data were analyzed for CNVs using eXome-Hidden Markov Model tool in 48 established disease genes. CNV breakpoint junctions were characterized. CNVs were classified using the American College of Medical Genetics and Genomics technical standards. RESULTS: We identified eight CNVs in 690 unrelated probands (1.2%). Characterization of breakpoint junctions revealed nonhomologous end joining was responsible for four deletions, whereas one duplication was caused by nonallelic homologous recombination between duplicated sequences in MYH6 and MYH7. Identifying the precise breakpoint junctions determined the genomic involvement and proved useful for interpreting the clinical relevance of CNVs. Three large deletions involving TTN, MYBPC3, and KCNH2 were classified as pathogenic in three patients. Haplotype analysis of a deletion in ACTN2, found in two families, suggests the deletion was caused by an ancestral event. CONCLUSION: CNVs infrequently cause inherited heart diseases and should be investigated when standard genetic testing does not reveal a genetic diagnosis.

TMEM43 mutations associated with arrhythmogenic right ventricular cardiomyopathy in non-Newfoundland populations.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a myocardial disease characterized by fibro-fatty replacement of right ventricular free wall myocardium and life-threatening ventricular arrhythmias. A missense mutation, c.1073C>T (p.S358L) in the transmembrane protein 43 (TMEM43) gene, has been genetically identified to cause ARVC type 5 in a founder population from Newfoundland. It is unclear whether this mutation occurs in other populations outside of this founder population or if other variants of TMEM43 are associated with ARVC disease. We sought to identify non-Newfoundland individuals with TMEM43 variants among patient samples sent for genetic assessment for possible ARVC. Of 195 unrelated individuals with suspected ARVC, mutation of desmosomal proteins was seen in 28 and the p.S358L TMEM43 mutation in six. We identified a de novo p.S358L mutation in a non-Newfoundland patient and five separate rare TMEM43 (four novel) sequence variants in non-Newfoundland patients, each occurring in an evolutionarily conserved amino acid. TMEM43 mutations occur outside of the founder population of the island of Newfoundland where it was originally described. TMEM43 sequencing should be incorporated into clinical genetic testing for ARVC patients.

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.

Reducing sudden death in young people in Australia and New Zealand: the TRAGADY initiative.

Best-practice guidelines mandate a full postmortem examination in these deaths to identify genetic causes and allow potentially life-saving interventions in the victim's relatives.

Does retrograde diastolic flow in the descending aorta signify impaired systemic perfusion in preterm infants?

High-volume systemic-to-pulmonary ductal shunting occurs frequently in preterm infants and is indicated by diastolic flow reversal in the descending aorta (DAo). We studied the relationship between ductal diameter, diastolic DAo reversal, and left ventricular output (LVO); and superior vena caval (SVC) flow (upper body perfusion) and DAo flow (lower body perfusion) in preterm (<31 wk) infants. Echocardiographic assessments were performed at 5, 12, 24, and 48 h postnatal age (80 infants, median gestation 28 wk, 1060 g). Incidence of ductal patency fell from 100% at 5 h to 72% at 48 h; incidence of pure systemic-to-pulmonary shunting increased from 66% to 95% of infants with patent ducts. In infants with duct diameter greater than the median, 35-48% of infants had DAo flow reversal. In infants with duct diameter greater than median, DAo reversal was associated with 23-29% increases in LVO at 5-48 h, and 35% decreases in DAo flow volume at 24-48 h, but no differences in SVC flow. In conclusion, a large duct with left-to-right shunting is common in preterm infants. Retrograde DAo flow is a marker of high-volume shunt, evidenced by increased LVO. Preterm infants with high-volume ductal shunt may have preserved upper body perfusion but reduced lower body perfusion.

Digital implantable loop recorders in the investigation of syncope in children: benefits and limitations.

BACKGROUND: Conventional diagnostic methods for detecting arrhythmogenic causes of syncope in children are poor. Digital implantable loop recorders are of proven value in adults. OBJECTIVES: The purpose of this study was to evaluate digital implantable loop recorders in the investigation of syncope in children. METHODS: We reviewed the clinical and technical records of 18 consecutive patients (6 female and 12 male; age