Abstract
BackgroundHeterozygous and homozygous carriers of SCN5A-p.Ser1103Tyr, a common genetic variant with functional effects among African-Americans, have an increased risk of sudden death. We hypothesized that some heterozygous carriers may have unequal expression of wild-type and variant alleles and secondarily that predominance of the variant gene copy could further increase risk for sudden death in this population.MethodsWe quantified allele-specific expression of SCN5A-p.Ser1103Tyr by real-time reverse-transcription polymerase chain reaction (RT-PCR) in heart tissue from heterozygous African-American infants, who died from sudden infant death syndrome (SIDS) or from other causes, to test for allelic expression imbalance.ResultsWe observed significant allelic expression imbalance in 13 of 26 (50%) African-American infant hearts heterozygous for SCN5A-p.Ser1103Tyr, and a significant (p < 0.0001) bimodal distribution of log2 allelic expression ratios. However, there were no significant differences in the mean log2 allelic expression ratios in hearts of infants dying from SIDS as compared to infants dying from other causes and no significant difference in the proportion of cases with greater expression of the variant allele.ConclusionsOur data provide evidence that SCN5A allelic expression imbalance occurs in African-Americans heterozygous for p.Ser1103Tyr, but this phenomenon alone does not appear to be a marker for risk of SIDS.
Highlights
Heterozygous and homozygous carriers of SCN5A-p.Ser1103Tyr, a common genetic variant with functional effects among African-Americans, have an increased risk of sudden death
We identified 17 African-American sudden infant death syndrome (SIDS) cases and 9 African-American non-SIDS infant death controls that were heterozygous for SCN5A-p.Ser1103Tyr and that had available frozen heart tissue from which we were able to isolate intact, high quality total RNA
Analysis of all subjects revealed that 13 of 26 (50%) African-American heterozygous infant hearts exhibited log2 allelic expression ratios significantly different from zero (p < 0.002), indicating the presence of allelic expression imbalance
Summary
Heterozygous and homozygous carriers of SCN5A-p.Ser1103Tyr, a common genetic variant with functional effects among African-Americans, have an increased risk of sudden death. We hypothesized that some heterozygous carriers may have unequal expression of wild-type and variant alleles and secondarily that predominance of the variant gene copy could further increase risk for sudden death in this population. A common SCN5A genetic variant (p.Ser1103Tyr) that is found in 13% of African-Americans is associated with an increased risk for cardiac arrhythmia and sudden cardiac death in that population [7,8]. The p.Ser1103Tyr variant is over-represented in African-American SIDS victims as compared to non-SIDS infant death cases [9,10] and sodium channels with the variant allele exhibit functional defects that may increase risk for life-threatening cardiac arrhythmias [7]. Because infants dying suddenly and unexpectedly are usually brought to autopsy, they provide a unique opportunity for studying tissue-specific expression of a potentially lethal genetic variant
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