Cardiac ion channel mutations in the sudden infant death syndrome

Abstract

Sudden infant death syndrome (SIDS) is characterized by the sudden death of an infant that occurs during sleep and remains unexplained despite thorough examination. In addition to clinical associations such as prone sleeping and exposure to cigarette smoke, several genetic factors have been identified with regard to SIDS, including autonomic disorders, immunologic polymorphisms and metabolic disorders. In the past decade, postmortem genetic analysis ('molecular autopsy') of SIDS cases has revealed a number of cardiac ion channel mutations that are associated with arrhythmia syndromes, including the long QT syndrome, Brugada syndrome and short QT syndrome. Mutations have been found in genes encoding (subunits of) cardiac potassium, sodium and calcium channels, as well as in genes involved in the trafficking or regulation of these channels. Here, we review the literature on cardiac ion channel mutations in relation to SIDS. Combining data from population-based cohort studies, we conclude that at least one out of five SIDS victims carries a mutation in a cardiac ion channel-related gene and that the majority of these mutations are of a known malignant phenotype. Genetic analysis is therefore recommended in cases of sudden infant death. More research is required to further elucidate the pathophysiology of SIDS and to determine whether genetic or electrocardiographic screening of apparently healthy infants should be pursued.

Array comparative genomic hybridization as a clinical diagnostic tool in syndromic and nonsyndromic congenital heart disease

“…Specifically, two patients showed CNVs involving the genes KCNQ1 and CACNB2 (patients 34 and 38), which are associated with long QT and Brugada syndrome, respectively (7,8), whereas in the remaining seven patients (patients 4, 9, 18, 23, 28, 36, and 37) ( Table 1) the identified CNVs were associated with channelopathies (9). Genetic counseling proves problematic in cases where the CNVs include ion channel genes because it is not certain that they will lead to a late-onset severe cardiac disease.…”

Postmortem genetic screening for the identification, verification, and reporting of genetic variants contributing to the sudden death of the young

“…In many case reports and clinical evaluations in which genetic variants or inherited cardiac disease have been associated with a sudden death, some victims are speculated to have de novo pathological variants with SD as the sentinel event (Klaver et al 2011;Tester et al 2012;Giudici et al 2014). However, a variety of reports indicate that many of the known genetic variants underlying SCD due to either cardiomyopathy or channelopathy are autosomal dominant and have a 50% chance of inheritance (Shim et al 2005;Shephard and Semsarian 2009).…”

Loss-of-Function Sodium Channel Mutations in Infancy

“…6 In the causation of sudden infant death syndrome (SIDS), mutations of the sodium channel-related genes seem the most malignant, accounting for 10% of SIDS cases. 19 Interestingly, death as an adverse event following immunization, even though it is uncommon, ranged from 1.4% to 2.3% of all adverse events following immunization reported between 1991 and 2001, and most of these deaths were classified as SIDS. 20 The recent presentation of a 4-month-old girl with aborted cardiac arrest and recurrent ventricular arrhythmias associated with vaccination and/or fever in this infant and in her brother, 6 the occurrence of SIDS in a 3-month-old boy on the day after vaccination (unpublished data), and the study by Kanter et al 5 reporting rapid VT in a 5-month-old boy on the day of vaccination, all cases united by an underlying loss-offunction SCN5A mutation, lead us to believe that there might be more to sudden deaths following immunization than just SIDS.…”