Unmasking immunodeficiency in sudden infant deaths: no evidence of hidden immune disorders

Introduction Sudden infant death syndrome (SIDS) remains a leading cause of post-neonatal mortality, yet its underlying mechanisms are largely unknown. Evidence suggests that immune dysfunction may play a role in a subset of cases. However, the role of inborn errors of immunity (IEI), particularly severe combined immunodeficiency (SCID), has not been systematically explored. We aimed to study their potential role in SIDS and infant deaths from infectious disease. Methods We obtained mortality data for 2012–2017 from The Norwegian Cause of Death Registry and identified eligible infants by reviewing ICD-10 codes for infection-related deaths or SIDS. The medical history and autopsy reports were reviewed and infants with predisposition to infection were excluded. Genetic testing was performed on biobanked newborn dried blood spot samples following the protocol for identifying SCID/IEI in live-born infants. Results The study population consisted of 79 infants, of which 66% ( n = 52) died of SIDS and 34% ( n = 27) due to infection. The majority of the infants in both groups had at least one genetic IEI-related variant, but no findings were clearly pathogenic. Variants of uncertain significance in autosomal dominant disease genes were identified in 18% ( n = 14). Heterozygous pathogenic variants in autosomal recessive genes were identified in 23% ( n = 18). Risk factor variants were identified in 42% ( n = 33), including two mannose-binding lectin 2 polymorphisms with alleles more frequently observed in the infection group compared to the general population. Discussion No missed cases of SCID/IEI were identified among infants who died from infections or SIDS. Yet a significant proportion of the cohort may carry genetic predispositions due to the presence of immune-related genetic variants. Even in the absence of overt immunodeficiency, these findings may reflect a latent vulnerability interacting with physiological and environmental factors.