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Clinical applications in the area of neurology, neurodegeneration, and psychiatric disease are still limited to the diagnosis of rare or early-onset disorders and using pharmacogenomic markers to predict efficacy of treatments. Research aimed at using genomics to predict idiopathic causes of dementia, movement disorders, and many psychiatric conditions is one of the hottest fields in medicine and undoubtedly this chapter will be considerably longer in future editions. A few areas are worthy of consideration here.


It has been recognized for decades that neurodegenerative disorders can occur in families, in a dominant or recessive fashion, and identifying the genetic underpinnings has been pivotal in the current understanding of the pathophysiology of these disorders. There is clearly much in common between rare heritable forms of neurodegenerative disease and the more common so-called idiopathic or late-onset disease. A discussion of each single-gene disorder is beyond the scope of this text, but what has changed in the genomics era is the discovery of many more Mendelian causes of a variety of dementia, movement disorders, ataxia, and other neurodegenerative diseases. Thanks to whole-exome sequencing, identifying causative mutations in early-onset neurodegeneration families has been greatly accelerated, and even single individuals with atypical neurodegeneration can sometimes yield novel genetic insight.

At this time, absent a family history, there are no formal recommendations for screening healthy individuals for early-onset neurodegenerative disease. The clearly monogenic forms of these conditions are sufficiently rare, and too few treatments are available, that broad screening would not be cost-effective or likely to provide actionable information. Nevertheless, as sequencing becomes less expensive and is available direct-to-consumer, screening for early-onset neurodegeneration is likely to occur indirectly and must be dealt with thoughtfully. Neurodegeneration is particularly challenging from a screening standpoint because individuals in the same family with the same mutation can have very different ages of onset and severity of disease. Further, the prospect of loss of cognitive or motor function can be the most disturbing to a person of any possible health outcome.

For patients with early-onset dementia or movement disorders, investigation for monogenic causes is appropriate and should start with a detailed family history. Often a neurologist rather than a geneticist will undertake this evaluation and many neurologists specialize in dementia and movement disorders. Single gene and panel testing is available for known Alzheimer and Parkinson genes, though new genes are being discovered all the time (refer to Appendix 5 for guidance finding and selecting available tests).


One particular neurodegeneration risk factor bears special mention. The E4 allele of apolipoprotein E (ApoE4) certainly confers an increased lifetime risk of developing Alzheimer disease, and at a younger age than individuals without this allele. Persons carrying one copy have a 1.5 to twofold increased odds of developing Alzheimer disease ...

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