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The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost.

ABSTRACT: In newborns, severe congenital heart defects are rarer than mild ones. This epidemiological relationship between heart defect severity and incidence lacks explanation. Here, an analysis of ~10,000 Nkx2-5^+/- mice from two inbred strain crosses illustrates the fundamental role of epistasis. Modifier genes raise or lower the risk of specific defects via pairwise (G×G_Nkx) and higher-order (G×G×G_Nkx) interactions with Nkx2-5. Their effect sizes correlate with the severity of a defect. The risk loci for mild, atrial septal defects exert predominantly small G×G_Nkx effects, while the loci for severe, atrioventricular septal defects exert large G×G_Nkx and G×G×G_Nkx effects. The loci for moderately severe ventricular septal defects have intermediate effects. Interestingly, G×G×G_Nkx effects are three times more likely to suppress risk when the genotypes at the first two loci are from the same rather than different parental inbred strains. This suggests the genetic coadaptation of interacting G×G×G_Nkx loci, a phenomenon that Dobzhansky first described in Drosophila. Thus, epistasis plays dual roles in the pathogenesis of congenital heart disease and the robustness of cardiac development. The empirical results suggest a relationship between the fitness cost and genetic architecture of a disease phenotype and a means for phenotypic robustness to have evolved.

SUBMITTER: Akhirome E

PROVIDER: S-EPMC8467714 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Children with congenital heart disease (CHD) are often restricted from some types of physical activity (PA) despite the lack of evidence regarding the need to restrict recreational PA, apart from those with rhythm disorders. This study retrospectively investigated the associations between parent-reported activity restrictions (on-going need to restrict exertion, body contact or competition) and measures of health-related fitness among 236 children (8.2 ± 2.1 years, range 4−12 years) treated for single ventricle (n = 104), tetralogy of Fallot (n = 48), transposition of the great arteries (n = 47) or atrial septal defect (n = 37). Body mass index (BMI), moderate-to-vigorous physical activity (MVPA; 7 day accelerometry), strength, flexibility, and movement skill assessment results were collected from the baseline assessment research records for two studies completed in Ontario, Canada. A subset of 62 children also had physician-reported activity restrictions. Regression models empirically tested the goodness of fit between the dependent and independent variables. Participants with body contact restrictions from both parents and physicians had significantly higher BMI z-scores (0.23 ± 1.19 vs. −0.32 ± 0.85; t = 2.55; p = 0.04 and 0.66 ± 1.33 vs. −0.02 ± 0.98; t = 2.25; p = 0.02 for CDC and WHO scores, respectively). Otherwise, BMI z-score was not associated with patient variables (p > 0.36; sex, cardiac diagnosis, age, or activity restriction). Children with any type of parent-reported restriction (0.98 ± 2.06 vs. −0.08 ± 1.99; t = 3.77; p = 0.0002) were less flexible. Movement skill (TGMD-2) scores were 50% lower (25.1 ± 31.2 vs. 52.6 ± 28.6; F = 6.93; p = 0.009) among children with parent-reported competitive sport restrictions. Weekly MVPA (p > 0.18) and strength (p > 0.05) were not associated with activity restriction. Children whose parents reported PA restrictions were less flexible, and had decreased movement skill and increased BMI z-scores if the restrictions impacted competitive sport or body contact, respectively. Future research is recommended to confirm these results among larger samples of children who have both parent- and physician-specified PA restrictions.

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The Genetic Architecture of a Congenital Heart Defect Is Related to Its Fitness Cost.

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