A two-hit hypothesis of neurodevelopmental disorders: exploring BDNF val66met polymorphism and environmental prenatal exposures

An individual’s risk of being diagnosed with a neurodevelopmental disorder is multifaceted and involves a complex interaction between their genetic background and their prenatal environment. To uncover the causes of neurodevelopmental disorders, candidate risk genes and potentially adverse prenatal environmental exposures need to be evaluated for their effect on brain development and subsequent behavioural abnormalities in adulthood.

The Val66Met polymorphism is a common genetic mutation present in approximately 25-30% of the population. Human epidemiological studies have implicated a role for the Val66Met polymorphism to mediate the risk and severity of neurodevelopmental disorders such as schizophrenia and autism spectrum disorder.

The two-hit hypothesis model suggests that the Val66Met mutation alone is insufficient to cause neurodevelopmental problems, but an adverse prenatal environment can act as the ‘second hit’ to multiply the risk of and potentially lead to neurodevelopmental disorders. The foetal brain is particularly vulnerable to damage from chemical exposures and infections that can lead to permanent changes in the structure and chemistry of the brain.