Unclassified
sudden infant death (USID) is the sudden and unexpected death of an infant that remains unexplained after thorough case investigation including performance of a complete autopsy and review of the circumstances of death and the clinical history. When the infant is below 1 year of age and with onset of the fatal episode apparently occurring during sleep, this is referred to as
sudden infant death syndrome (
SIDS). USID and
SIDS remain poorly understood despite the identification of several environmental and some genetic risk factors. In this study, we investigated genetic risk factors involved in the autonomous nervous system in 195 Dutch USID/
SIDS cases and 846 Dutch, age-matched healthy controls. Twenty-five
DNA variants from 11 genes previously implicated in the
serotonin household or in the
congenital central hypoventilation syndrome, of which some have been associated with
SIDS before, were tested. Of all
DNA variants considered, only the length variation of the
polyalanine repeat in exon 3 of the PHOX2B gene was found to be statistically significantly associated with USID/
SIDS in the Dutch population after multiple test correction. Interestingly, our data suggest that contraction of the PHOX2B exon 3
polyalanine repeat that we found in six of 160
SIDS and USID cases and in six of 814 controls serves as a probable genetic risk factor for USID/
SIDS at least in the Dutch population. Future studies are needed to confirm this finding and to understand the functional effect of the
polyalanine repeat length variation, in particular contraction, in exon 3 of the PHOX2B gene.