Reproductive Fitness and Genetic Transmission of Tetralogy of Fallot in the Molecular Age

Abstract

Background-Individuals with tetralogy of Fallot (TOF) now routinely survive to reproductive age and beyond. Reproductive fitness of adults with TOF and recurrence risks to offspring are of increasing interest in the modern era, especially given recent molecular genetic discoveries. Methods and Results-After excluding individuals with known genetic syndromes, 543 unrelated adults with TOF underwent a detailed family history assessment and molecular characterization for rare copy number variations using high-resolution genome-wide microarrays. Men and women with TOF had significantly fewer offspring compared with an age-matched comparison group without congenital heart disease (CHD; P=0.0004). No aspect of rare copy number variation burden was a predictor of decreased reproductive fitness. Corresponding with the advent of modern surgical repairs, reproductive fitness of women began to exceed that of men (P=0.0490). Recurrence risk for CHD in offspring was 4.8%, with no significant differences between men and women with TOF. The risk of severe CHD in offspring (2.3%) far exceeded population expectations (relative risk, 15.6; 95% confidence interval, 7.9-31.0). Most cases of vertical transmission of CHD were not explained by the transmission of a large rare copy number variation. Although conotruncal lesions (31.5%) were the most commonly reported CHD in relatives, the familial spectrum of disease included many anatomically discordant lesions. Conclusions-Men

The importance of copy number variation in congenital heart disease

“…89,100 One study of reproductive fitness in adults with TOF and without 22q11.2DS showed that syndromal subjects were more likely to be childless, but failed to identify any association with the rare CNV profile. 19 A smaller adult cohort with TGA, ascertained and studied in a similar manner, showed comparable results. 53 A majority of deaths in adults with CHD are a consequence of cardiovascular complications, including heart failure, arrhythmias and sudden death.…”

“…With improved childhood survival, there is growing interest in issues germane to adults with CHD, 10–12 including offspring recurrence. 19,88 Irrespective of informative molecular genetic findings, surveillance during pregnancy, including fetal echocardiography, is the standard of care for offspring of both women and men with CHD. In the setting of a putative susceptibility CNV in either parent, there may be opportunities for pre-implantation genetic diagnosis or prenatal genetic diagnosis (with chorionic villus sampling or amniocentesis).…”

“…Estimating these parameters is challenging, and can be confounded by ascertainment bias and reproductive fitness effects. 19,67,89,90 The individual rarity of non-recurrent CNVs has meant that there is often insufficient evidence (be it epidemiology, cell biology or model organism-based) to conclude causality. Large human sample sizes including the wealth of data generated from clinical use of CMA, high-throughput model organism screening, 106 and targeted mutagenesis using CRISPR/Cas9 technology will all help in this endeavour.…”

Proportion of selected congenital heart defects attributable to recognized risk factors

“…We included nonmodifiable risk factors (male sex [58,59], family history of a first-degree relative with CHD [24,25], and nulliparity [having no previous pregnancies] [59,69]) to estimate the proportion attributable to the full set of recognized risk factors. Although not included as a risk factor in the final model, maternal smoking in B1-P3 was included as a potential confounder.…”

The Genetic Workup for Congenital Structural Heart Disease: From Clinical to Genetic Evaluation

“…data suggest additional undiscovered genetic components based on the increased recurrence risk of CHD for couples with an affected child [5] , the increased risk of CHD in the offspring of individuals with CHD [6,7] , the rare families with multigenerational occurrence of CHD, parental consanguinity associated with a 2-to 3-fold increased offspring risk of CHD [8,9] , and differences in the frequency of specific CHD among populations [10,11] . In Scandinavia, where congenital malformations have been registered for decades and linked to populationbased data sets with pedigree information, inferences about the genetic components of CHD can be made.…”