Less than 15% of more than 400 SIDS cases had a "potentially informative" variant in a GHD-susceptibility gene, predominantly in the 4- to 12-month age group. Only 4.3% of cases possessed immediately clinically actionable variants. Consistent with previous studies, ultra-rare, nonsynonymous variants within the major cardiac channelopathy-associated genes were overrepresented in SIDS cases in infants of European ethnicity. These findings have major implications for the investigation of SIDS cases and families.

Backgroung: Brugada Syndrome (BrS) is an arrhythmogenic disease associated with sudden

SummaryBackgroundSudden infant death syndrome (SIDS) is the leading cause of post-neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over-represented in infants who died from SIDS.MethodsWe did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0·00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system.FindingsFour (1·4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0·0057).InterpretationRare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths.FundingUK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

Objective: To determine if a monogenic basis explains sudden infant death syndrome (SIDS) using an exome-wide focus. Study design: A cohort of 427 unrelated cases of SIDS (257 males; average age = 2.7 ± 1.9 months) underwent whole exome sequencing (WES). Exome-wide rare variant analyses were carried out with 278 European ancestry SIDS cases (173 males; average age = 2.7 ± 1.98 months) and 973 ethnic-matched controls based on six genetic models. Ingenuity Pathway Analysis was also performed. The cohort was collected in collaboration with coroners, medical examiners, and pathologists by St George's University of London, UK and Mayo Clinic, Rochester, Minnesota, USA. WES was performed at the Genomic Laboratory, Kings College London, UK or Mayo Clinic’s Medical Genome Facility, Rochester, Minnesota. Results: Although no exome-wide significant (P < 2.5×10−6) difference in burden of ultra-rare variants was detected for any gene, 405 genes had a higher prevalence (p<0.05) of ultra-rare non-synonymous variants among cases with seventeen genes at p<0.005. Some of these potentially overrepresented genes may represent biologically plausible novel candidate genes for a monogenic basis for a portion of patients with SIDS. The top canonical pathway identified was glucocorticoid biosynthesis (p=0.01). Conclusions: The lack of exome-wide significant genetic associations indicates an extreme heterogeneity of etiologies underlying SIDS. Our approach to understanding the genetic mechanisms of SIDS has far reaching implications for the SIDS research community as a whole and may catalyze new evidence-based SIDS research across multiple disciplines. Perturbations in glucocorticoid biosynthesis may represent a novel SIDS-associated biological pathway for future SIDS investigative research.

Background-Sudden arrhythmic death syndrome defines a sudden unexpected and unexplained death despite comprehensive pathological and toxicological investigation. Previous studies have focused on evaluation of adult relatives. There is, however, a lack of data in children, leading to highly variable management. We sought to determine the clinical utility of cardiac evaluation in pediatric relatives of sudden arrhythmic death syndrome probands. Methods and Results-Retrospective review was undertaken of pediatric patients with a family history of sudden arrhythmic death syndrome assessed from 2010 to 2013 in 2 centers. Clinical history, cardiac, and genetic investigations were assessed, including diagnoses made after evaluation of adult relatives. A total of 112 pediatric relatives from 61 families were evaluated (median age at presentation, 8 years; range, 0.5-16 years). A probable diagnosis was made in 18 (29.5%) families: Brugada syndrome, 13/18 (72%); long QT syndrome, 3/18 (17%); and catecholaminergic polymorphic ventricular tachycardia, 2/18 (11%). Genetic testing identified mutations in 20% of Brugada syndrome (2/10) and 50% of long QT syndrome (1/2) and catecholaminergic polymorphic ventricular tachycardia families (1/2) who were tested. Pediatric evaluation diagnosed 6/112 relatives (5.4%), increasing to 7% (6/85) if only first-degree relatives were assessed. The only useful diagnostic tests were the 12-lead and exercise electrocardiograms and ajmaline provocation test. The median duration of follow-up was 2.1 years (range, 0.2-8.2 years) with no cardiac events. Conclusions-The yield of evaluating pediatric relatives is significant and higher when focused on first-degree relatives and on conditions usually expressed in childhood. We propose a management pathway for these children. (Circ Arrhythm Electrophysiol. 2014;7:800-806.)

In this large paediatric cohort of SCN5A mutation-positive subjects, cardiac conduction disorders were the most prevalent phenotype; CEs occurred in about one-third of genotype-positive children, and several independent risk factors were identified, including age ≤1 year at diagnosis, compound mutation, and mutation with both gain- and loss-of-function.

Sudden unexplained death in childhood is a traumatic event for both the immediate family and medical professionals. This is termed sudden unexplained or arrhythmic death syndrome (SUDS/SADS) for children over 1 year of age while sudden unexplained death in infancy or sudden infant death syndrome (SUDI/SIDS) refers to unexplained deaths in the first year of life. There is increasing evidence for the role of undiagnosed inherited cardiac conditions, particularly channelopathies, as the cause of these deaths. This has far-reaching implications for the family regarding the potential risk to other family members and future pregnancies, providing a challenge not only in the counselling but also in the structured assessment and management of immediate relatives. This review will discuss the cardiac risk involved in sudden unexplained deaths of infants and children, the role of molecular autopsy, family cardiological screening, current management strategies, and future directions in this area.

A monogenic basis for SIDS amongst the previously implicated noncardiac genes and their encoded biological pathways is negligible.