Long QT Genes in SIDS
Abstract & Commentary
By John P. DiMarco, MD, PhD, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville. Dr. DiMarco is a consultant for Novartis, and does research for Medtronic and Guidant.
Synopsis: Sudden arrhythmic death associated with genetically determined long QT syndrome is a significant cause of SIDS.
Source: Arnestad M, et al. Prevalence of long-QT Syndrome Gene Variants in Sudden Infant Death Syndrome. Circulation. 2007;115:361-367.
The cause or causes of the Sudden Infant Death Syndrome (SIDS) have remained mysterious. In this article, Arnestad et al report the frequency of long QT syndrome (LQTS) gene variants and mutations in infants dying with SIDS. The authors evaluated 252 cases of unexpected infant death that occurred in the Southwestern region of Norway over a 6-year period. The cases were categorized as either pure SIDS, borderline or probable SIDS (ie, minor coexisting disease) or clearly due to infection or violence. The pure and probable SIDS patients, the patients with infectious or violent deaths and another group of 137 adults who died from noncardiac causes in the same acute geographic region were screened genetically for mutations/variants in the genes known to be associated with LQTS. The study was reviewed by a Norwegian ethics committee and this group mandated complete anonymity of the samples. This restriction prevented further contact with families of the victims in whom gene variants were identified.
Genomic DNA was extracted from blood or frozen tissue samples. Genetic techniques were used to amplify the coding sequences of 7 of the genes that have been identified as causes of long QT syndrome. Genetic variants identified were classified as either mutations, rare variants, and common (not clinically relevant) genetic variants. Mutations defined as genetic variants were not identified in ethnically matched controls nor in previously recorded control populations. Rare genetic variants were those that are absent in Norwegian controls, but reported in less than 0.7% of other white control populations or in nonwhite populations. Common genetic variants are those identified in greater than 0.7% of Norwegian or other white control populations.
There were 201 cases classified as either pure or borderline SIDS with a median age at the time of death of 3.5 months. Mutations and rare variants in the LQTS genes were identified in 26 of 201 cases (12.9%). The genes most frequently involved were SCN5A (13 cases, 50%), followed by KCNQ1 (5 cases, 19%), KCNH2 (5 cases, 19%), CAV3 (3 cases, 11%), and KCNE2 (1 case, 4%). One subject was identified who carried variants in both SCN5A and CAV3. Eleven different mutations and 9 rare variants were identified. The sodium channel variants identified were associated with an increased persistent sodium current or accelerated inactivation when assayed in vitro. In contrast, potassium channel variants identified in the SIDS cases may have been incidental findings since 4 of the 9 mutations identified in 6 cases had no evidence for channel dysfunction when assayed in vitro. In addition to the mutations and rare genetic variants identified, 13 common variants were detected. These were considered not to be related to SIDS. As a result, the overall data suggest that 19 of the 201 SIDS victims (9.5%) were carriers of functional defect likely to be the cause of sudden arrhythmic death.
The authors conclude that sudden arrhythmic death associated with genetically determined long QT syndrome is a significant cause of SIDS. They argue that an early ECG taken the third and fourth week of life, at a time when the QT interval is stable, would identify most of these infants and could lead to the initiation of effective preventive therapy.
Commentary
Sudden infant death syndrome has remained a frustrating clinical problem. Current opinion now holds that the syndrome has multiple causes, but defining a cause in an individual case often proves difficult. Prospective identification of infants at high risk would be a major advance. This paper provides further support for the concept that a significant fraction of SIDS cases are caused by ion channel mutations that result in unstable cardiac repolarization. It is striking in this paper that most of the mutations involve sodium channel defects, one of the less frequent causes of long QT syndrome in older children and adults. However, patients with sodium channel defect related LQTS often have their clinical events during sleep and this is certainly consistent with the pattern seen in SIDS.
The authors' recommendation that infants receive a screening ECG between 3 and 4 weeks of age would require a change in current pediatric practice. In any screening program, there is always a fear of causing harm by false-positive findings. However, as genetic testing for long QT syndrome has become more sophisticated, the value of screening becomes greater since a reliable follow-up test for those infants with QTC intervals over 470 msec is now available. Costs of such a program will have to be carefully evaluated, if such a testing program is to become standard.
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