TY - JOUR
T1 - Nature and nurture
T2 - understanding phenotypic variation in inborn errors of immunity
AU - Similuk, Morgan
AU - Kuijpers, Taco
N1 - Funding Information: This work was supported with funds from the NIAID Division of Intramural Research. Acknowledgments Publisher Copyright: Copyright © 2023 Similuk and Kuijpers.
PY - 2023
Y1 - 2023
N2 - The overall disease burden of pediatric infection is high, with widely varying clinical outcomes including death. Among the most vulnerable children, those with inborn errors of immunity, reduced penetrance and variable expressivity are common but poorly understood. There are several genetic mechanisms that influence phenotypic variation in inborn errors of immunity, as well as a body of knowledge on environmental influences and specific pathogen triggers. Critically, recent advances are illuminating novel nuances for fundamental concepts on disease penetrance, as well as raising new areas of inquiry. The last few decades have seen the identification of almost 500 causes of inborn errors of immunity, as well as major advancements in our ability to characterize somatic events, the microbiome, and genotypes across large populations. The progress has not been linear, and yet, these developments have accumulated into an enhanced ability to diagnose and treat inborn errors of immunity, in some cases with precision therapy. Nonetheless, many questions remain regarding the genetic and environmental contributions to phenotypic variation both within and among families. The purpose of this review is to provide an updated summary of key concepts in genetic and environmental contributions to phenotypic variation within inborn errors of immunity, conceptualized as including dynamic, reciprocal interplay among factors unfolding across the key dimension of time. The associated findings, potential gaps, and implications for research are discussed in turn for each major influencing factor. The substantial challenge ahead will be to organize and integrate information in such a way that accommodates the heterogeneity within inborn errors of immunity to arrive at a more comprehensive and accurate understanding of how the immune system operates in health and disease. And, crucially, to translate this understanding into improved patient care for the millions at risk for serious infection and other immune-related morbidity.
AB - The overall disease burden of pediatric infection is high, with widely varying clinical outcomes including death. Among the most vulnerable children, those with inborn errors of immunity, reduced penetrance and variable expressivity are common but poorly understood. There are several genetic mechanisms that influence phenotypic variation in inborn errors of immunity, as well as a body of knowledge on environmental influences and specific pathogen triggers. Critically, recent advances are illuminating novel nuances for fundamental concepts on disease penetrance, as well as raising new areas of inquiry. The last few decades have seen the identification of almost 500 causes of inborn errors of immunity, as well as major advancements in our ability to characterize somatic events, the microbiome, and genotypes across large populations. The progress has not been linear, and yet, these developments have accumulated into an enhanced ability to diagnose and treat inborn errors of immunity, in some cases with precision therapy. Nonetheless, many questions remain regarding the genetic and environmental contributions to phenotypic variation both within and among families. The purpose of this review is to provide an updated summary of key concepts in genetic and environmental contributions to phenotypic variation within inborn errors of immunity, conceptualized as including dynamic, reciprocal interplay among factors unfolding across the key dimension of time. The associated findings, potential gaps, and implications for research are discussed in turn for each major influencing factor. The substantial challenge ahead will be to organize and integrate information in such a way that accommodates the heterogeneity within inborn errors of immunity to arrive at a more comprehensive and accurate understanding of how the immune system operates in health and disease. And, crucially, to translate this understanding into improved patient care for the millions at risk for serious infection and other immune-related morbidity.
KW - environment
KW - genetics
KW - inborn error of immunity
KW - penetrance
KW - phenotypic variation
KW - time
UR - http://www.scopus.com/inward/record.url?scp=85173058603&partnerID=8YFLogxK
U2 - https://doi.org/10.3389/fcimb.2023.1183142
DO - https://doi.org/10.3389/fcimb.2023.1183142
M3 - Review article
C2 - 37780853
SN - 2235-2988
VL - 13
JO - Frontiers in cellular and infection microbiology
JF - Frontiers in cellular and infection microbiology
M1 - 1183142
ER -