Most primary medical care relies on a solid knowledge base of human anatomy and biochemistry. If you go to 
your doctor for a routine physical, she may run bloodwork, looking at a standard panel of markers for disease. Likewise, if you go to the emergency room with intense localized pain, the team can use x-rays or other imaging technology, and they will know where to look and what to look for.
Clinical genetics, by contrast, is in many ways still in its infancy. A genetic counselor can offer to test prospective parents for a panel of genetic variants known to cause the most common birth defects and diseases, and individuals whose families have a high incidence of breast and ovarian cancer can be tested for BRCA1 and BRCA2 mutations to guide their medical decisions. But most of the human genome is still uncharted territory, and technology to sequence patients is outpacing our ability to understand what we see. A doctor seeing an x-ray will clearly know what to do with a broken bone, but a doctor looking at a whole exome sequence (WES) - the 1% of a person's genome that encodes their proteins - will mostly see mutations with unknown effect, known as variants of unknown significance (VUS). They will see the analog of broken bones - “broken genes” are known as loss-of-function (LoF) variants - but we all walk around with these, usually with no consequences. At the American Society of Human Genetics (ASHG) meeting this year, scientists and clinicians alike shared their latest work on deciphering the meaning and consequences of genetic variation.
Exomes in the clinic
This rapid change was on display at the session on WES in clinical practice. Whole exome sequencing is increasingly being offered by academic medical centers, and scientists from these centers reported on their work integrating this new data into clinical care. Christine Eng reported on Baylor's sequencing center. Of cases referred to the center, only 25% resulted in a molecular diagnosis from WES; however, from those successes, 30% of the diagnoses were from disease-gene associations only discovered in the past three years. Han Lee reported on UCLA's center, which has a similarly low diagnosis rate, and emphasized how much the diagnosis rate for developmental disorders rises when parents are sequenced along with a child; this is because clinicians can focus on mutations only seen in the child, which are much more likely to be causal. New databases are being developed for application to WES. Bradford Powell from UNC described work of the NCGENES project, which is curating disease-specific gene sets to focus on relevant exome variants; and Lora Bean from Emory showcased EmBase for collecting and coordinating annotations of VUS.
Research insights from personal exomes
Beyond the exome
