Genomic medicine enters the neurology clinic.

Neurology 2012;79:112–114 Extraordinary advances in genetics and genomics are revolutionizing the practice of medicine. In this issue of Neurology, 3 articles demonstrate the utility of exome sequencing for identifying the genetic cause of neurologic disorders. This issue represents a landmark in neurogenetics: the concurrent publication of 3 such examples highlights the rapidly changing landscape driven by exome and genome sequencing, and presages the widespread application of these methods for the diagnosis of neurologic disease. Landouré et al.1 identify a novel mutation in TRPV4 causing a Charcot-Marie-Tooth (CMT) 2C phenotype, missed by Sanger sequencing. They confirmed the pathogenicity of this dominant mutation using calcium imaging in vitro to show that a TRP antagonist reversed the pathogenic increase in calcium and cell death. Sailer et al.2 used exome sequencing to identify the cause of spinocerebellar ataxia (SCA), another condition with marked locus heterogeneity. Here too, a conventional screen based on previously reported mutations failed to detect the novel mutation in PRKCG causing SCA14. Finally, Pierson et al.3 identified 2 compound heterozygous mutations in GLB1, responsible for recessive juvenile-onset GM1 in a family where initial -galactosidase enzyme analysis was reported as normal. In contrast to whole-genome sequencing, where all 3 billion bases of the human genome are sequenced, exome sequencing consists of the capture by hybridization and targeted sequencing of all the protein-coding regions of the genome. This corresponds to 1%–3% of the human genome, for less than $1,000 in most centers. These advances are due to next-generation sequencing methods that reliably sequence billions of bases in a few days.4 However, it is just a first step; whole-genome sequencing will likely become even faster and less expensive, and may replace exome sequencing. We envision 4 mainstream applications of exome/ genome sequencing in clinical and translational research: 1. Discovery of novel causal genes in mendelian disorders. Although it comprises a few percent of the human genome, the exome is estimated to include the majority of the large-effect size, diseasecausing variants in humans. Indeed, causal mutations in a large number of mendelian conditions have already been found using this technique,5 and the genetic etiology of the estimated 7,000 mendelian diseases is expected to be solved within the next 5 years. 2. Efficient screen of diseases with locus heterogeneity. The utility of this approach is exemplified by the 3 articles published in this issue. For many diseases with marked locus heterogeneity, such as SCAs and CMT, multiple large genes are implicated, making conventional screening for each patient impractical. Exome sequencing provides a cost-efficient alternative to conventional Sangerbased methods. Since the first whole-genome sequencing in CMT,6 examples of extensive targeted resequencing have been reported,7 and we expect this application to soon enter patients’ clinical charts. 3. Identification of genetic modifiers within families with mendelian disorders. Phenotypic studies in large families have shown that, despite the fact that all individuals in a single mendelian family share the same causal mutation, considerable phenotypic heterogeneity is present (e.g., Alzheimer disease due to PSEN1 mutations). Identifying rare and common genetic modifiers of disease course in mendelian diseases is now a tractable problem, and provides a conceptual bridge between mendelian and complex diseases. 4. Genetic characterization of complex heterogeneous disease categories. The “missing heritability” is the single most important problem in complex disease genetics.8 Signals identified in genomewide association studies (GWAS) explain only a fraction of the estimated heritability, and many support the assumption that rare variants have