“I immediately contacted the physician to find out the story with that baby,” Rehm says. “And that’s when I found out that the parents had terminated it.”
This story is unusual only in that Rehm is uncommonly open about it. Many geneticists have similar tales where mistakes in the scientific literature have led to wrong—and sometimes harmful—diagnoses.
In one study, Stephen Kingsmore at the National Center for Genome Resources in Santa Fe found that a quarter of mutations that have been linked to childhood genetic diseases are debatable. In some cases, the claims were based on papers that contained extremely weak evidence. In other cases, the claims were plain wrong: The mutations turned out to be common, like the one in Rehm’s anecdote, and couldn’t possibly cause rare diseases.
Daniel MacArthur at Massachusetts General Hospital found a similar trend in a study of over 60,000 people, the results of which have been uploaded to a pre-print server. On average, each of these volunteers is walking around with 53 gene variants that are classified as “pathogenic” in two widely-used databases. When the team took a closer look at 200 of these variants, they found enough evidence to classify just nine of them as pathogenic.
This is an absurd situation, especially given the stakes. Over the last decade, there’s been a lot of talk about reproducibility problems in science—about published results that turn out to be false alarms. In fields like psychology, neuroscience, and cell biology, these errors can send scientists down unproductive paths, waste time and money, and pollute headlines with misleading claims. “But I get much more exercised about reproducibility problems in clinical genetics, because those have massive and real-time consequences for thousands of families,” says MacArthur.
People get abortions on the basis of mutations that are linked to severe congenital diseases. They get mastectomies on the basis of mutations in breast-cancer genes. They get monitoring devices surgically implanted in their chests on the basis of mutations in heart-disease genes. “This is absolutely an issue, and it’s led to all sorts of problematic decision-making,” says Rehm.
How did things get so bad? Everyone I spoke to said that studies used to hew to lower standards. Even just a decade ago, scientists would classify a variant as pathogenic if they found it in a handful of patients with a disease but not in, say, 100 healthy peers. “That’s sooooo not sufficient evidence,” says Rehm. A study that small just won’t tell you how common the variant in question really is in the general population.
“I think none of us really appreciated just how many rare, nasty-looking genetic variants exist in everyone's genome,” admits MacArthur. That only became clear once geneticists acquired enough money, technological power, and collaborative will to do really big sequencing projects, like the 1,000 Genomes Project. Then, “it became abundantly clear that every single one of us is walking around with hundreds of genetic changes that look like they should cause disease, but actually don't. This means that every genome has ‘narrative potential’—material that you could use to tell a story about diseases.”