Editorial comment on “Whole Exome Sequencing Identifies Compound Heterozygous Mutations in WDR62 in Siblings With Recurrent Polymicrogyria”

Themanuscript on page XXX by Ramocki et al. [2011] represent the first exome sequence data in the American Journal of Medical Genetics. This warrants attention beyond the methodologies and the research utility of the findings, which are at the cutting edge of clinical genomics. Just as importantly, this publication is the beginning of what will be a major shift in clinical genetics; how we think about not only themethods of diagnostic testing, but how we practice the art of diagnosis. Like many readers of the Journal, I was attracted to clinical genetics by the diagnostic challenge of patients with pleiotropic malformation syndromes. Tomake diagnoses for these patients, we approach the problem by acquiring and evaluating many kinds of data; inheritance patterns, embryologic mechanistic analyses, pattern recognition, the timing of onset and natural history, and detailed phenotypic assessments such as clinical laboratory testing, morphologic assessments, and imaging. The integration of these diverse forms of data into a differential diagnosis that informed directed molecular testing was a key intellectual activity of the clinical geneticist. The advent of high throughput molecular assays may change this paradigm. As shown by Ramocki et al. [2011], exome sequencing may mitigate the need for extensive phenotypic assessments to select the one or handful of genes that should be sequenced. The phenotype of polymicrogyria has significant genetic heterogeneity, likely caused by mutations in 20–50 genes (W.B. Dobyns, personal communication). The question could be raised as to whether the clinician’s time is best spent determining which gene(s) should be tested based upon an extensive (and expensive) clinical evaluation or if the exome should be done first, and then the clinical evaluation customized to the patient, as indicated by the mutated gene. This may be regarded as a type of personalized medicine. Why evaluate an individual patient for the general problem of polymicrogyria when one can instead evaluate the patient in a directed way, based on the gene that is mutated in their particular case? This process of using an exome sequence as a diagnostic tool was also put forward in the recent report by Worthey et al. [2011]. They demonstrated the use of an exome sequence to diagnose an infantwithNOD2mutation, showing that the child’s inflammatory bowel disease was a manifestation of X-linked inhibitor of apoptosis deficiency. This exome result allowed a diagnosis to be made, but more importantly, it allowed the treatment of the child to be directed toward bone marrow transplantation, which would have occurred much later, if at all, without the exome diagnosis. This is not to say that diagnostic skills, robust reasoning, and clinical experience are no longer needed or useful. The opposite is the case—these attributes will be as important as ever. What may change is when and how they are deployed. Instead of using 2 hr of a clinician’s time to decide which test to order, we could use that 2 hr of time to interpret the genomic result, determine it’s validity, and deploy appropriate phenotyping efforts to characterize the manifestations in the affectedpatient. Equally important,wemaybe able to serve patients as well with fewer total hours of service—a potential route to reducing health care costs. The center of gravity of clinical geneticist’s activities may shift from phenotyping efforts to determine which test should be ordered toward interpreting genomes and applying focused phenotyping based on that sequence result. The interpretation of genomes and exomes will require new skills for clinical geneticists and will necessitate new modes of training for genetics