disorders. They will need to sequence the entire genomes of patients and their families.
On the second Tuesday of every month, Lupski meets with other clinical geneticists at Baylor to discuss challenging cases. Short video clips of children with a range of strange and disturbing disorders are projected on a screen in the front of the room. One boy has widely set eyes, each a different color, and hearing loss in one ear. One toddler won’t put anything in his mouth and must use a gastric feeding tube. Three brothers suffer from mental retardation of unknown cause. For parents whose children’s mysterious disorders haven’t been identified by traditional genetic testing, genome sequencing might finally bring a diagnosis, and years of medical testing could come to an end.
In a few lucky cases, it could lead to treatment. Last year, researchers at Yale University probably saved the life of a five-month-old infant in Turkey who’d been admitted to the hospital with the catch-all diagnosis of “failure to thrive.” Physicians suspected a kidney disorder. But by sequencing his exome, the portion of the genome that codes for proteins, researchers discovered a genetic mutation linked to congenital chloride diarrhea. This rare disorder can be treated by simply replacing the body’s lost salt.
In most cases, we’re still years away from cures or drugs for the genetic disorders uncovered by sequencing. Still, understanding the genetic causes of a disease is a first step to identifying its molecular mechanisms, which in turn will help researchers develop treatments. And sequencing can greatly speed up the search for disease genes. Once Lupski identified the first genetic variation for Charcot-Marie-Tooth in 1991, researchers used genetic engineering to re-create that mutation in mice and then used those animals to test potential treatments. A drug that emerged from this research is now in clinical trials for Charcot-Marie-Tooth patients who have the duplication that Lupski discovered (it turns out that about 70 percent of sufferers do). He hopes this success can be repeated for rarer disease-linked variations like his own. Another lab has already developed a mouse with a mutation in the SH3TC2 gene.
As the price of sequencing continues to plummet, Lupski believes, genetically guided diagnosis will spur a major transition in medicine by helping to spotlight the complex genetics behind both rare and common diseases.
“At one point, if you had a cough, the doctor said you had pneumonia,” he says. “Now we can distinguish between bacterial and viral pneumonias, and prescribe the right drug for the right type.”
Emily Singer is Technology Review’s Senior Editor for Biomedicine.