Next-Generation Neurogenetics: The Future Has Begun

New advances in neurogenetics emerge at an ever-increasing pace, impacting all areas of neurology. The GeneTests website (http://www.ncbi.nlm.nih.gov/sites/GeneTests/), a publicly funded medical genetics information resource, currently (November 6, 2011) lists 1154 clinics involved in the care of patients with hereditary diseases and 604 laboratories testing for 2469 different diseases. Many of these conditions are neurologic in nature or may be complicated by neurologic features. Monogenic causes have been identified even for diseases previously considered textbook examples of nonhereditary conditions, such as Parkinson's disease. For example, the discovery of the LRRK2 gene causing clinically typical, late-onset Parkinson's disease has finally dismantled the dogma of a largely nongenetic origin of the condition and has also clearly shown that monogenic parkinsonism may account for a large number of cases in select populations. Of note, a genetic etiology may be suspected even in patients with a negative family history. Small family size, nonpaternity, adoption, variable expressivity, reduced penetrance, anticipation, and de novo mutations may all account for a “pseudo-” negative family history despite the presence of a genetic disorder. Overall, however, a well-defined genetic origin is found only in a minority of patients with neurologic disorders (reviewed in the chapters on dystonia, dementia, ataxia, hereditary spastic paraplegia, neuropathy, and epilepsy).

Although these fascinating developments in the molecular genetics of numerous neurologic conditions have provided important new insights, they also revealed further complexity of a genetic contribution to neurologic diseases and challenged some of the previously held concepts. Indeed, the etiology of most neurologic diseases remains a complex puzzle of genes, the environment, and an aging brain. In addition, the boundaries between causative genes with classical Mendelian patterns of inheritance versus genetic risk factors conferring disease susceptibility appear to be less well defined than previously thought. Another important area of genetics in neurology is related to the mitochondrial genome and its complex patterns of transmission. Mitochondrial dysfunction as a key element in the etiology of various neurologic conditions, is described in the chapter on mitochondrial diseases.

Perhaps not surprisingly, some of the genes implicated in monogenic disease have also been demonstrated to act as susceptibility factors in idiopathic forms of the condition. As described in the chapter, “Genetics of Complex Neurologic Diseases,” most of these findings are based on a genome-wide association (GWA) approach. Although GWA studies are limited to relatively common types of genetic variation occurring at a frequency of greater than ∼1% in the general population, genetic liability conferred by rare sequence variants has not yet been assessed systematically. So-called next-generation sequencing, a recent technologic breakthrough, now enables the study of whole genomes at base-pair resolution. This approach has not only already led to the discovery of new genes for rare Mendelian neurologic disorders (for example, VPS35 mutations causing dominant Parkinson's disease), but also resulted in a map of human genome variation from population-scale sequencing. This provides the basis for the discovery of (rare) genetic factors causing, contributing to, or modifying complex neurologic diseases.

Further extending the boundaries of Mendelian inheritance and even those of genetic susceptibility to neurologic disease, genetic factors do not act in isolation. Rather, a combination of (commonly unknown) genetic and environmental factors is considered to account for the vast majority of neurologic diseases, including interactions between several genes, modifying effects by susceptibility alleles, the influence of environmental agents on gene expression, and their direct impact on the brain. These important aspects are discussed in the chapters, “Genetics Meets Environment: Evaluating Gene–Environment Interactions in Neurologic Diseases” and “Epigenetics in Nucleotide Repeat Expansion Disorders.”

Of great clinical relevance, an increasing number of genetic tests have become commercially available and call for an informed selection of the right test(s) accompanied by specific genetic counseling. Massive parallel sequencing approaches at affordable costs, widespread availability of diagnostic testing, and the advent of direct-to-consumer testing raise important ethical and legal issues that are reviewed in the chapter on genetic testing for neurologic diseases. For a small number of conditions, treatments or preventive measures can now be offered. Although the past decade has witnessed the molecular genetic revolution of many neurologic disorders, the anticipated next phase will hopefully see a more successful translation of genetic clues into specific and causal therapies for our patients.