Sudden infant death syndrome (SIDS) is a diagnosis of exclusion which should be made only after a thorough autopsy without identification of a specific cause of death (Mage and Donner, 2004).
Weese-Mayer et al. (2007) provided ... Sudden infant death syndrome (SIDS) is a diagnosis of exclusion which should be made only after a thorough autopsy without identification of a specific cause of death (Mage and Donner, 2004). Weese-Mayer et al. (2007) provided a detailed review of genetic factors that have been implicated in SIDS. The authors concluded that SIDS represents more than 1 entity and has a heterogeneous etiology most likely involving several different genetically controlled metabolic pathways.
Opdal et al. (1999) identified 3 different point mutations in the mitochondrial DNA (mtDNA) of 4 of 158 SIDS cases and in none of 97 controls. One mutation occurred in the MTTL1 gene, and the other 2 occurred ... Opdal et al. (1999) identified 3 different point mutations in the mitochondrial DNA (mtDNA) of 4 of 158 SIDS cases and in none of 97 controls. One mutation occurred in the MTTL1 gene, and the other 2 occurred in the MTND1 gene. The authors pointed to descriptions of other mutations in the MTTL1 gene that had been found in association with SIDS. Schwartz et al. (2000) reported a clinically typical instance of 'near-SIDS' in an infant who was found to be heterozygous for a missense mutation in the SCN5A gene (600163.0015). Ackerman et al. (2001) performed postmortem mutation analysis of the SCN5A gene in 93 cases of SIDS or undetermined infant death and identified missense mutations (600163.0019-600163.0020) in 2 cases. Schwartz et al. (2001) identified a de novo, heterozygous mutation in the KCNQ1 gene (607542.0030) in an infant who died from SIDS. They found the same mutation in affected members of a family with long QT syndrome. Schwartz et al. (2001) concluded that these findings confirmed the hypothesis that some deaths from SIDS are caused by long QT syndrome and supported implementation of neonatal electrocardiographic screening during the second or third week of life when the risk of spuriously long QT intervals (false positives) is extremely small. Narita et al. (2001) examined the long/short promoter polymorphism of the SLC6A4 gene (182138.0001) in Japanese SIDS cases and found an excess of the L/L genotype and L allele in the SIDS group relative to controls. Weese-Mayer et al. (2003) investigated this variable tandem repeat sequence polymorphism in the promoter region in a cohort of 87 SIDS cases (43 African American and 44 Caucasian) and gender/ethnicity-matched controls. They likewise found increases in the L/L genotype and the L allele. Weese-Mayer et al. (2003) subsequently showed in the same cohort that an intron 2 polymorphism (12-repeat allele), which also differentially regulates 5-HTT expression, was associated with increased risk of SIDS in African American but not Caucasian SIDS cases. In a review article, Opdal and Rognum (2004) stated that the genetic component of SIDS comprises 2 categories: mutations that cause genetic disorders that result in death and polymorphisms that may predispose infants to death in critical situations. A well-studied example of the former is medium-chain acyl-CoA dehydrogenase deficiency (201450), a disorder of fatty acid oxidation caused by mutation in the MCAD gene (see, e.g., 607008.0001). Another well-studied example is long QT syndrome. By contrast, evidence tended to exclude hypoglycemia and thrombosis as major causes of SIDS. The authors concluded that there is unlikely to be a single causative mutation or polymorphism in all SIDS cases; however, it is likely that there are several genes that operate to predispose infants to SIDS in combination with environmental risk factors. Opdal and Rognum (2004) emphasized the difficult position of SIDS in both the medical and legal professions. Plant et al. (2006) identified homozygosity for the S1103Y variant of the SCN5A gene (600163.0024) in 3 African American autopsy-confirmed cases of SIDS. Among 1,056 African American controls, 120 were carriers of the heterozygous genotype, suggesting that infants with 2 copies of S1103Y have a 24-fold increased risk for SIDS. Variant Y1103 channels were found to operate normally under baseline conditions in vitro. Because risk factors for SIDS include apnea and respiratory acidosis, Y1103 and wildtype channels were subjected to lowered intracellular pH; only Y1103 channels developed abnormal function, with late reopenings suppressible by the drug mexiletine. Plant et al. (2006) suggested that the Y1103 variant confers susceptibility to acidosis-induced arrhythmia, a gene-environment interaction. Cronk et al. (2007) analyzed the LQT9 (611818)-associated CAV3 gene in necropsy tissue from 134 unrelated cases of SIDS and identified 3 missense mutations in 3 of 50 black infants (601253.0018; 601253.0020; 601253.0021). No mutations were detected in 1 Hispanic or 83 white infants, and CAV3 mutations occurred in 2 infants who died after age 6 months versus 1 infant who died before 6 months (2 of 12 vs 1 of 124; p = 0.02). The mutations were not found in 400 reference alleles, of which 200 were ethnically matched.