Long QT molecular autopsy in sudden infant death syndrome

Abstract

ObjectiveTo describe experience of long QT (LQT) molecular autopsy in sudden infant death syndrome (SIDS).DesignDescriptive audit from two distinct periods: (1) A prospective, population-based series between 2006 and 2008 (‘unselected’). (2) Before and after 2006–2008, with testing guided by a cardiac genetic service (‘selected’). LQT genes 1, 2, 3, 5, 6 and 7 were sequenced. Next of kin were offered cardiac evaluation.SettingNew Zealand.Patients102 SIDS cases.InterventionsNil.Main outcome measuresDetection of genetic variants.ResultsMaori 49 (47%), and Pacific island 24 (23%), infants were over-represented. Risk factors were common; bed sharing was reported in 49%. Rare genetic variants were commoner within the selected than unselected populations (5 of 31 infants (16%) vs 3 of 71 infants (4%) p < 0.05). In the selected population two infants had variants of definite or probable pathogenicity (KCNQ1, E146K; KCNH2, R1047L), two had novel variants of possible pathogenicity in SCN5A (I795F, F1522Y) and one had R1193Q in SCN5A, of doubtful pathogenicity. R1193Q was also the only variant in the three cases from the unselected population and occurred as a second variant with R1047L. Engaging families proved challenging. Only 3 of 8 (38%) variant-positive cases and 18 of 94 (19%) of variant-negative families participated in cardiac/genetic screening.ConclusionsLQT molecular autopsy has a very low diagnostic yield among unselected SIDS cases where risk factors are common. Diagnostic yield can be higher with case selection. Engagement of the family prior to genetic testing is essential to counsel for the possible uncertainty of the results and to permit family genotype-phenotype cosegregation studies.

Cardiac genetic investigation of sudden cardiac death: advances and remaining limitations

“…In New Zealand, the well-recognized risk factors of co-sleeping (bed sharing), accidental asphyxiation, and other environmental risk factors are particularly common among Maori and Pacific peoples, in whom SIDS predominates. 5 However, such features were also common in a large US series with a likely diagnostic rate of 13%. 7 A good cardiac genetic service is multidisciplinary, usually led by cardiology or pediatric cardiology, with access to electrophysiological expertise, clinical and molecular genetics, genetic counseling, and psychological support.…”

“…3 They and others also identified that between 2% and 12% of Sudden Infant Death Syndrome (SIDS) cases were caused by mutations in the LQTS genes. [4][5][6][7] In New Zealand, an LQTS molecular autopsy was first tested in a retrospective cohort of individuals #35 years old, with DNA from the long-deceased victims being extracted from the archived neonatal screening (Guthrie) card. 8 Twenty-two percent of them were positive.…”

“…The protein is involved in the sarcoplasmic release of calcium, triggering cellular contraction; ^the overall total is taken from combined papers; data from these studies. [3][4][5][6][7][8][9] Abbreviations: SiDS, Sudden infant Death Syndrome; SUDY, sudden unexplained death in the young; CPvT, catecholaminergic polymorphic ventricular tachycardia; eCG, electrocardiography. …”

Sudden Infant Death

“…In the most widely accepted definition, there is a graded classification based predominantly on the thoroughness of the autopsy investigation in excluding potential causes, and the possibility of positional asphyxia. 10,11 Type 1 occurs between the ages of 21 days and 9 months in otherwise healthy, normal infants, and there must have been a safe sleep environment, and a thorough autopsy. Type 1a includes cases where there has been extensive scene and laboratory investigations; if one of these investigations is absent, it becomes type 1b.…”

“…Most SUDY because of LQTS occur during sleep or rest, and rare variants/mutations in SCN5A are by far the commonest, being found in 50% to 75%, compared with 8% to 10% in the LQTS registries. 11,[24][25][26] Genetic investigation of SIDS cases has had a variable yield of putative mutationsfrom <5% in prospective studies in the United States, New Zealand, and Germany 11,27,28 to a recent study from New York where 15% had rare variants or mutations, predominantly in SCN5A. 25 The first large study, from Norway 24 detected 26 rare variants among 201 cases and suggested 19 of these 26 (therefore, a total of 9.5%) were pathogenic mutations.…”