Genetic Mechanisms of Neurodevelopmental Risk in Congenital Heart Disease: Mostly Unknowns

Author(s): Sarah E. Hanna, Tina O. Findley, Jacqueline G. Parchem, Sarah U. Morton

Congenital heart disease (CHD) is the most common major congenital anomaly, occurring in approximately one percent of live births globally^1,2. Yet, an underlying genetic etiology is identified in only 20 to 30 percent of people with CHD^3,4. The role of genetic factors in CHD risk is demonstrated by the high recurrence rate within families and its association with genetic syndromes^5,6. CHD is associated with a higher incidence of neurodevelopmental delay and disability (NDD)^7–11, and there has been recent interest in the contribution of genetics to these outcomes^12,13. As the survival rate for individuals with CHD has significantly improved¹⁴, the excess risk for impairments in motor skills, language abilities, and social-emotional functioning have been become more apparent^11,15–19. Both factors intrinsic to an individual patient, such as genetic variants or structural type of CHD, as well as extrinsic factors, such as nutritional supports and anesthesia exposures, can influence the risk of NDD^20,21. However, as few multicenter trials include patients with known genetic diagnoses or genomic data²², we have a limited understanding of how genetic variation contributes to neurodevelopmental outcomes among individuals with CHD.

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