A new kind of genetic test that analyzes all of a person’s genes can provide a diagnosis about a quarter of the time for patients whose conditions have baffled doctors, scientists reported Saturday. And for young children with mysterious developmental delays, the test gives a diagnosis more than 40 percent of the time.
The test is called whole-exome sequencing, and it looks at all 20,000 or so genes in the human body. It’s not a whole genome sequence because it leaves out DNA that’s not classified as a gene. But such tests provide a good map of the so-called protein coding sequences.
It was a relief for Audrey Lapidus of Los Angeles, whose baby son Calvin seemed just fine at first. But at 6 months, an osteopath suggested genetic testing. “She said he had some very interesting facial features,” Lapidus told NBC News. Other pediatricians rejected the notion.
“But then he just wasn’t hitting the milestones,” she said. “He wasn’t sitting up or rolling over.”
Still, pediatricians and friends alike reassured her. A basic genetic panel came back clear.
“Everyone wants to tell you about their nephew who didn’t walk until he was 2 and he graduated from Harvard,” Lapidus said. “I was holding on to those stories.”
At the same time, she continued to visit geneticists and neurologists. “Deep down, I knew something was wrong,” she said.
Calvin became the first child at UCLA to get a whole-exome genetic test at UCLA, in 2012. When it came back, it showed Calvin had Pitt-Hopkins Syndrome, a rare genetic disorder affecting only 250 children worldwide.
It’s caused by a single mutation on one gene found on chromosome 18. It causes developmental delays, seizures and, as Calvin’s osteopath suspected, distinctive facial features, such as thin eyebrows and sunken eyes. Children often never learn to speak or walk without help.
“It wasn’t the answer I wanted,” Lapidus admits. She wanted to hear that Calvin was perfectly normal, if a little delayed. But at least it was an answer.
“A diagnosis makes a huge difference,” she said. “At least now I know what to expect.”
And she found other parents. “I talk to these women in North Carolina and Iowa. We write practically every single day.” They compare notes on day-to-day challenges. “Little things, like what meds are you using for seizures, how are you handling school,” she said.
And the former journalist hit the Internet and found a group of parents seeking answers. Now called the Pitt Hopkins Research Foundation, it’s managed to raise $1 million, says Lapidus.
There's no specific treatment, yet, for the condition. But the group is funding research, and Lapidus has invested in speech therapy and physical therapy for Calvin, who's now 3.
“Our study is the first to show that sequencing a child’s genome together with his or her parents’ dramatically improves geneticists’ ability to reach a firm diagnosis in rare disorders,” said Dr. Stan Nelson, vice chair of human genetics at the David Geffen School of Medicine at UCLA, who helped lead the study.
Nelson, Hane Lee and colleagues tested 814 patients with undiagnosed genetic conditions between January 2012 and August 2014 and found whole-exome sequencing gave a cause in 26 percent of them overall. In 138 kids under 5 with developmental delays, the diagnosis rate was 41 percent, they report in the Journal of the American Medical Association.
They say their findings, also released at a meeting of the American Society of Human Genetics, support broader use of the test, which costs about $6,000. Lapidus said in Calvin’s case, health insurance paid 80 percent of the cost.
A second study in JAMA found similar results. Yaping Yang and Christine Eng of the Baylor College of Medicine and colleagues tested 2,000 patients and found a genetic cause in 25 percent of them, including previously unidentified disease-causing mutations.
“All families deserve a clear diagnosis of their child’s condition,” said Dr. Wayne Grody, director of the UCLA Clinical Genomics Center. “This is immediately useful to families and physicians in understanding how the disease occurred, preventing unnecessary testing, and developing the best strategies to treat it.”