For the first time, DNA sequencing leads to diagnosis and treatment

A Turkish boy suffering from dehydration and failure to thrive became the first patient to receive an accurate diagnosis and successful treatment based on the complete sequencing of his protein-coding genes, thanks to the work of Yale researchers.

A team led by Richard P. Lifton, M.D., Ph.D., chair and Sterling Professor of Genetics and professor of internal medicine, used emerging genomics technologies to identify an unexpected and rare genetic mutation in the infant, who had previously defied diagnosis. That information allowed the baby’s doctors to embark on a successful treatment program.

The milestone achievement resulted from a new approach to DNA sequencing known as whole-exome sequencing. This approach zooms in on the 1 to 2 percent of the genome that carries protein coding information, where disease-causing mutations are most likely to occur. Lifton and colleagues at the Yale Center for Genome Analysis—including Murim Choi, Ph.D., a postdoctoral fellow, and Shrikant M. Mane, Ph.D., director of the genome analysis center at West Campus—worked out a method that combines gene chip technology to purify the target DNA along with the latest high-throughput sequencing techniques to decode it. Their approach yields a comprehensive view of an individual’s protein-coding genes for a few thousand dollars—10 to 20 times less costly than sequencing the entire genome.

At the request of a Turkish doctor, the Yale group deployed the technology to investigate the five-month-old baby, who was suspected of having a rare genetic kidney disease known as Bartter syndrome, marked by excessive urination. The baby’s DNA arrived at Yale, and in just ten days, the researchers had their answer. The kidney gene was fine; however, the baby turned out to have an unsuspected mutation in a protein responsible for water and salt absorption in the intestines. That defect led to chronic chloride diarrhea, which in turn caused the child’s dehydration. Armed with that information, Lifton and colleagues then went back to other infants with similar symptoms attributed to Bartter syndrome, and identified five more with mutations in the intestinal transporter.

The results, reported in the Proceedings of the National Academy of Sciences in October, show that the new technology can quickly generate clinically useful results, bringing doctors and patients closer to the day when comprehensive sequencing information will be a routine part of medical care.

“We believe this heralds the dawn of a new era in genetics and personalized medicine,” said Lifton, who is also an investigator for the Howard Hughes Medical Institute. “As the cost of DNA sequencing continues to plummet, it seems clear that this technology will be useful for clinical diagnosis in a number of settings.”