Reproductive Fitness and Genetic Transmission of Tetralogy of Fallot in the Molecular Age
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 (CNVs) using high resolution genome-wide microarrays. Men and women with TOF had significantly fewer offspring compared to an age-matched comparison group without congenital heart disease (CHD) (p=0.0004). No aspect of rare CNV 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 (RR=15.6, 95% CI 7.9-31.0). Most cases of vertical transmission of CHD were not explained by the transmission of a large rare CNV. 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 and women with TOF have reduced reproductive fitness. Their offspring are at significantly elevated risk for severe CHD. These results support the importance of genetic counseling for both men and women with complex CHD. Many inherited genetic variants remain to be discovered.
- reproductive fitness
- tetralogy of Fallot
- heart defects, congenital
- genetic epidemiology
- copy number variant
- Received August 15, 2013.
- Revision received December 15, 2013.
- Accepted January 27, 2014.