We have previously identified polymorphisms in the serotonin transporter gene promoter region and in intron 2 that were more common among sudden infant death syndrome (SIDS) cases compared with control subjects. To elucidate further the genetic profile that might increase an infant's vulnerability to SIDS, we focused on the recognized relationship between autonomic nervous system (ANS) dysregulation and SIDS. We therefore studied genes pertinent to early embryologic development of the ANS, including MASH1, BMP2, PHOX2a, PHOX2b, RET, ECE1, EDN1, TLX3, and EN1 in 92 probands with SIDS and 92 gender- and ethnicity-matched control subjects. Eleven protein-changing rare mutations were identified in 14 of 92 SIDS cases among the PHOX2a, RET, ECE1, TLX3, and EN1 genes. Only 1 of these mutations (TLX3) was identified in 2 of 92 control subjects. Black infants accounted for 10 of these mutations in SIDS cases and 2 control subjects. Four protein-changing common polymorphisms were identified in BMP2, RET, ECE1, and EDN1, but the allele frequency did not differ between SIDS cases and control subjects. However, among SIDS cases, the allele frequency for the BMP2 common polymorphism demonstrated ethnic differences; among control subjects, the allele frequency for the BMP2 and the ECE1 common polymorphisms also demonstrated ethnic differences. These data represent further refinement of the genetic profile that might place an infant at risk for SIDS.
Sudden infant death syndrome (SIDS) is the sudden and unexpected death of an infant under 1 y of age that remains unexplained after a thorough clinical history, death scene investigation, and postmortem examination (1). Introduction of an aggressive Back to Sleep campaign in 1992 targeting identified modifiable environmental risk factors for SIDS led to a decrease in SIDS incidence from 1.2 per 1000 live births (2) to 0.55 per 1000 live births in 2001 (3). Despite this decline, black infants maintain a higher SIDS incidence and a slower decline rate when compared with white infants (2, 3). Furthermore, infants of all ethnic groups continue to succumb to SIDS despite full compliance with known modifiable risk factors. These observations have led investigators to consider the possibility of gene-by-environment interaction (whereby an environmental condition or toxin affects gene expression) as an explanation for the remaining 2234 infants who died from SIDS in 2001 in the United States alone (3).
The serotonin transporter gene (5HTT) was the first gene linked to SIDS vulnerability. This gene was studied on the basis of reports of decreased serotonergic receptor binding in brainstems of SIDS victims in the United States (4) and Japan (5). Narita et al. (6) demonstrated an association between a promoter polymorphism in 5HTT, known to differentially regulate transporter expression, and SIDS risk by describing an excess of the more effective promoter long (L) allele in the Japanese SIDS group relative to control subjects. We confirmed this association in white and black SIDS cases relative to control subjects (7) and then reported an association between SIDS and a 5HTT intron 2 polymorphism, also known to regulate 5HTT expression (8). The association was significant in black SIDS cases versus control subjects, with the SIDS-associated genotype leading to more effective transporter production (12 allele). Furthermore the promoter and intron 2 loci were in linkage disequilibrium, and the L-12 haplotype was significantly associated with SIDS in the black subgroups. These results provide strong evidence for a relationship between SIDS risk and 5HTT gene activity and represent a first step in the study of a genetic basis for SIDS.
Because serotonin influences a broad range of physiologic systems, including the regulation of breathing, the cardiovascular system, temperature, and the sleep-wake cycle (9), serotonin is likely involved in regulation of the autonomic nervous system (ANS). Observations consistent with ANS dysfunction have been reported in SIDS, including profuse sweating (10), elevated body temperature (11, 12), tachycardia then bradycardia preceding the terminal event (13), reduced heart rate variability (14–16), drenching sweats and facial pallor (17), and decreased responses to obstructive sleep events (18). Accordingly, to elucidate further the genetic profile that might increase an infant's vulnerability to SIDS, we focused on genes pertinent to the embryologic origin of the ANS. This approach has been successful in clarifying the genetic basis of idiopathic congenital central hypoventilation syndrome (CCHS), known to have associated ANS dysregulation (19–21) and thought to be related to SIDS (22). Children with CCHS have been recently identified as heterozygous for the paired-like homeobox protein (PHOX) 2b polyalanine expansion mutation in 40–97% of cases (23–25). Just as in the early investigation of CCHS, we hypothesized that a subset of SIDS cases might have unique mutations or polymorphisms in genes identified embryologically or through knock-out models to be involved in ANS regulation.
Therefore, in the current study, we examined bone morphogenic protein-2(BMP2) (24, 26, 27), mammalian achaete-scute homolog-1 (MASH1) (28–30), PHOX2a (31–35), rearranged during transfection factor (RET) (36–42), endothelin converting enzyme-1 (ECE1) (24, 43), endothelin-1 (EDN1) (44), T cell leukemia homeobox protein (TLX3) (24, 45–47), and engrailed-1 (EN1) (48, 49) genes by sequence analysis in a cohort of infants who succumbed to SIDS. We also screened the SIDS cohort for the CCHS-associated polyalanine repeat mutation in PHOX2b. It was anticipated that infants who succumbed to SIDS might have unique mutations in the studied genes that would further clarify the genetic profile of the at-risk infant and explain the ethnic disparity in incidence.
Two distinct groups were investigated in this study: 92 SIDS cases and 92 matched control subjects. Ethnicity was assigned on the basis of self-report or report of the mother. This study was approved by the Rush University Medical Center institutional review board.
A total of 92 SIDS cases (mean age at death: 95 d ±52; 3 of 92 < 28 d; 9 of 92 > 180 d; median age: 85 d, 25th and 75th percentiles: 56 and 110 d, respectively) with a diagnosis made by the University of Maryland Medical Examiner were identified in the University of Maryland Brain and Tissue Bank (21 black girls, 25 black boys, 16 white girls, and 30 white boys). The diagnosis of SIDS was based on the accepted definition: the sudden and unexpected death of an infant under 1 y of age that remains unexplained after a thorough clinical history, death scene investigation, and postmortem examination (1).
A total of 92 unrelated control subjects were matched for ethnicity and gender to the SIDS cases with a 1:1 match ratio. After informed consent was obtained, a three-generation family history was taken for each control subject to ensure that no family member had a diagnosis of SIDS, Hirschsprung disease, CCHS, apparent life-threatening event, primary (nonacquired) disorder of ANS dysregulation, or tumor of neural crest origin.
Fixed frozen frontal cortex brain tissue from SIDS subjects was obtained from the University of Maryland Brain and Tissue Bank for Developmental Disorders (http://medschool.umaryland.edu/btbank/main.html). Blood from control subjects (3–10 mL) was obtained by venipuncture and collected in an EDTA tube. Genomic DNA was isolated from the brain and blood samples using standard methods as described previously (7).
PCR amplification and direct DNA sequencing of purified PCR products for BMP2, MASH1, PHOX2a, RET, ECE1, EDN1, TLX3, and EN1.
Oligonucleotide primer pairs that spanned each exon to be sequenced [sequences for genes published previously (24); sequences for primers for RET gene available upon request] and divided each region into segments of ∼500 nucleotides in length were designed using the automatic primer selection algorithm Primer 3.0. When Primer 3.0 was unable to identify suitable primer pairs, primary DNA sequence data were reviewed by the investigators and primers were selected manually. Standard PCR amplification was carried out as described (24). All sequence assemblies and polymorphisms were manually reviewed to ensure accuracy of variant identification.
Genotyping of PHOX2b polyalanine repeat sequence.
The PHOX2b exon 3 region coding for the polyalanine repeat was amplified with primer pair 5′-CCAGGTCCCAATCCCAAC-3′ (forward) and 5′-GAGCCCAGCCTTGTCCAG-3′ (reverse) as described previously (24) (patent pending).
Strategy for mutation analysis.
DNA from all 92 SIDS cases and from 26 control subjects was sequenced for exon and splice site mutations in BMP2, MASH1, PHOX2a, RET, ECE1, EDN1, TLX3, and EN1. Any base change expected to affect a splice site or result in modification of the protein sequence that was identified in SIDS subjects but not control subjects was further screened in all 92 control subjects. Any potential protein-changing polymorphisms that occurred in SIDS or control subjects were screened in all 92 control subjects to determine whether any of these polymorphisms was associated with SIDS. Samples from the SIDS and control groups were screened for the PHOX2b polyalanine repeat expansion associated with CCHS.
For each case-control comparison, we computed standard χ2 tests of independence between allele frequency and SIDS phenotype. Under the null hypothesis of no allele frequency differences, the test statistic follows a χ2 distribution with degrees of freedom equal to one less than the number of alleles. When data were sparse (expected counts fewer than five in any cell), we used Fisher's exact test to examine hypotheses regarding allelic association. Analyses were conducted within the matched sample data set, including 92 ethnicity- and gender-matched SIDS cases and control subjects.
Genotype analyses in SIDS cases and control subjects.
Data in Table 1 indicate protein-changing variants in 92 SIDS cases and 92 control subjects for the candidate genes. No protein-changing alterations were identified for MASH1 or EDN1. Sequence data from PHOX2a, RET, ECE1, TLX3, and EN1 revealed 11 rare protein-changing polymorphisms in 14 SIDS cases (15.2% of SIDS cases), and subsequent genotyping for these polymorphisms in control subjects identified 1 polymorphism in 2 control subjects (2.2% of control subjects). Each of these mutations occurred in a single SIDS case with the exception of the TLX3 base change, which occurred in four SIDS cases and two control subjects. Black infants accounted for 10 of the SIDS cases and the 2 control subjects with protein-changing mutations.
Four common protein-changing polymorphisms were identified in BMP2, RET, ECE1, and EDN1. The allele frequency did not differ between SIDS cases and control subjects, but the RET polymorphism approached significance for the SIDS versus control comparison (p = 0.072). Among SIDS cases, the allele frequencies for the BMP2 common polymorphism were significantly different between white and black infants (p < 0.0001). Among control subjects, the allele frequencies for the BMP2 and ECE1 polymorphisms were significantly different between white and black infants (p < 0.0001 and p = 0.025, respectively). None of the other comparisons reached significance.
Directed mutation analysis of polyalanine repeat sequence in PHOX2b.
None of the SIDS subjects demonstrated the PHOX2b mutation seen in CCHS. All SIDS subjects had the normal genotype with 20 polyalanine-coding repeats on each chromosome. Among control subjects, one black and two white infants were heterozygous for deletion variants that contained 14 and 15 repeats, respectively, as previously reported in control populations (23, 24).
These results represent the first report describing analysis of homeobox and signal transduction genes important in specifying cell fate in ANS differentiation in SIDS cases. Our finding of specific protein-changing mutations in PHOX2a, RET, ECE1, TLX3, and EN1 among 15.2% of SIDS cases versus 2.2% of control subjects suggests that specific polymorphisms in these genes may confer some SIDS risk. The observation that 71% of the SIDS cases with these mutations were black may be consistent with the observed ethnic disparity in SIDS, although black populations tend to exhibit higher levels of genetic variation. The identification of ethnic disparity among SIDS cases and among control subjects for the protein-changing common polymorphisms identified in BMP2 and ECE1 is consistent with population-dependent variation commonly observed at polymorphic sites. The higher incidence for these common polymorphisms among whites may confer protection or may have potential relevance to yet unidentified genes or in a larger data set. Our observation that none of the SIDS cases demonstrated the PHOX2b polyalanine expansion mutation previously identified in CCHS indicates less specific overlap between the two diseases than previously considered (children with CCHS have generalized ANS dysregulation and typically present in the newborn period and require artificial ventilatory support; infants who succumb to SIDS are seemingly normal yet have ANS dysregulation). However, as families of CCHS probands have a higher incidence of SIDS history in a family member (22) and as the anticipated incidence of this PHOX2b mutation is low in the general population, our sample size may not have been adequate to detect a case. Therefore, it may still be appropriate to evaluate infants with SIDS for the CCHS PHOX2b mutation to ascertain that CCHS was not the cause of death.
The mutations identified in this study may be benign polymorphisms or may be mutations specifically related to the SIDS phenotype. Insufficient information is currently available to distinguish these possibilities; however, all of the rare mutations in Table 1 were conserved in the mouse and the rat, with the exception of the RET R12H, RET A386V, EN1 T240I, and ECE1 T354A (although this was conserved in the frog and the cow). Mutations that occur in conserved amino acid residues (as determined through GenBank at www.ncbi.nlm.nih.gov/Genbank) are more likely to disrupt normal protein function and thus more likely to be related to the SIDS phenotype. Any amino acid change, even in nonconserved residues, however, may be responsible for some level of risk. The low rate of occurrence of mutations in this study suggests that there are yet unidentified genes that are responsible for the SIDS phenotype. It should also be noted that none of these rare mutations, with the exception of the TLX3 P66S, has been reported in GenBank, the National Institutes of Health genetic sequence database with an annotated collection of all publicly available currently known DNA sequences.
The greatest number of rare mutations was identified in the RET gene. This is of particular interest because of the relationship of RET to Hirschsprung disease and to CCHS and because of the RET knock-out model with a depressed ventilatory response to inhaled carbon dioxide with decreased frequency and tidal volume (42). The knock-out models for ECE1 (43) and TLX3 (45) also include impaired breathing and/or early death in the mouse phenotype, with suggestion of a central respiratory deficit. On the basis of these interesting and suggestive findings, further research is necessary to understand better the role of these and other genes in the SIDS phenotype and in explaining the ethnic disparity in SIDS.
sudden infant death syndrome
serotonin transporter gene
autonomic nervous system
congenital central hypoventilation syndrome
bone morphogenic protein-2 gene
mammalian achaete-scute homolog-1 gene
paired-like homeobox gene
rearranged during transfection factor
endothelin converting enzyme-1 gene
T-cell leukemia homeobox gene
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We thank Foster Lewin for the preparation of the DNA; Chinton Desai and Ronak Lahkia, who assisted with PCR assays; Amy Drendel, M.D., and Mary Hayes, M.S.N., for recruitment efforts; and the SIDS cases and their parents, as well as the control subjects who graciously shared their DNA.
Supported by The CJ Foundation for SIDS, the Joseph Tyler Gertler SIDS Research Fund, The Justin Carl Suth SIDS Research Fund, and the Spastic Paralysis and Allied Diseases of the Central Nervous System Research Foundation of the Illinois-Eastern Iowa District Kiwanis International.
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Weese-Mayer, D., Berry-Kravis, E., Zhou, L. et al. Sudden Infant Death Syndrome: Case-Control Frequency Differences at Genes Pertinent to Early Autonomic Nervous System Embryologic Development. Pediatr Res 56, 391–395 (2004). https://doi.org/10.1203/01.PDR.0000136285.91048.4A
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