Neurogenetics The expanding horizons of diagnosis and disease pathogenesis

To an increasing extent, the desire to catalog and categorize neurologic disorders based on genotype–phenotype correlations is challenged by frequent departures from the syndromic categorizations that were commonplace in the pregenomic era. This challenge is not limited to the recent striking revelations concerning diseases attributable to noncoding, nonconventional mutations, such as repeat expansions in C9ORF72. There are abundant examples of conventional mutations, identified using nonbiased, whole-exome sequencing, that lead to unanticipated phenotypes in the world of hereditary motor system disorders. The report by Pfeffer et al. Further the supports the idea that, as targeted sequencing based on clinical phenotype moves toward nonbiased sequencing, we must be prepared to expect surprises that link genetic abnormalities to unanticipated clinical syndromes.

Neurology 2015