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The Giant Mutations in the Human Genome

Our genomes are a mess—and we're only beginning to understand the societal costs behind such genetic uncertainty.
(Photo: hakandogu/Shutterstock)

(Photo: hakandogu/Shutterstock)

Intellectual disability and developmental delay disorders are surprisingly common, but they're frustratingly mysterious and hard to categorize. Patients often show a baffling mix of symptoms that are sometimes subtle and sometimes severe. Why are developmental disorders so confusing?

It turns out that there is a class of giant DNA mutations that share features of developmental disorders: They are surprisingly common, frustratingly diverse, and hard to categorize. Researchers are now discovering that these mutations play a big role in developmental delay disorders. The baffling symptoms are a consequence of the underlying genetic turmoil.

Despite the tremendous amount of quality control machinery in the cell devoted to making accurate copies of our DNA, our genomes are surprisingly unstable. Mistakes are made, and not just small typos: Entire paragraphs and pages of our genetic text get duplicated or deleted. These large mutations are called "copy number variants" or CNVs, and they add or subtract copies of genes.

Finding these mutations is only the beginning. Understanding why they cause particular effects is the next challenge.

Over the past decade, scientists have discovered CNVs to be shockingly common. One study found that we each carry, on average, about 1,000 CNVs, affecting roughly three percent of our genes. Different individuals have different CNVs, and so across the entire human population, much of the human genome is affected by these radical alterations.

It's hard to know what impact all of this has on our health. We're all walking around with these mutations, and most of us are just fine. In fact, many CNVs have existed in the human population for a long time and are broadly shared; many are relatively benign. But other CNV mutations are very rare, or even unique, and researchers are discovering that these giant mutations have a big medical impact. In fact, as one researcher recently put it, the ability to find CNV mutations was "the most substantial clinical benefit to come directly from the Human Genome Project in the first decade of the twenty-first century."

Why? Because large DNA deletions or duplications explain many cases of developmental delay disorders. The most famous case is Down syndrome, which is caused by an entire extra chromosome. But there are many others disorders turn out to be due, in part, to CNVs, including autism spectrum disorders; more obscure ones like Angelman, DiGeorge, and Williams syndromes; as well as other uncategorized disorders. All together, intellectual disability and developmental delay affect about three percent of children. These disorders are costly to society and a huge challenge to the children and their families. Adding to the parents' frustration is that they're often unexplained: Doctors can't always say what caused them, whether they're likely to recur in siblings, or even how to treat them.

THAT IS NOW CHANGING. Researchers have begun to discover how these confusingly diverse, frustratingly subtle, and surprisingly common disorders are often caused by CNV mutations that are themselves confusingly diverse, frustratingly subtle in their effects, and surprisingly common in the population.

One team of researchers, led by Evan Eichler at the University of Washington, has been building a CNV "morbidity map" of developmental delay disorders. In a 2011 study, Eichler and his colleagues looked for rare, very large CNV mutations in nearly 16,000 children with developmental delay disorders and in 8,300 healthy subjects. While mutations certainly occurred in the healthy subjects—11 percent of them had relatively large mutations in their DNA—they were much more common in the children with developmental delay. The very largest mutations were almost 50 times more likely to occur in children with developmental delay than in the control subjects.

Finding these mutations is only the beginning. Understanding why they cause particular effects is the next challenge. Because these mutations are so varied, and because they often affect multiple genes at once, it can be hard to figure out exactly what went wrong. To get at this question, Eichler and his colleagues completed an even larger study that included nearly 30,000 children with developmental delay. With so many patients, the researchers were able to find patterns among the mutations and symptoms that at first seemed to have little to do with each other.

For example, the researchers found a group of patients whose various mutations had one thing in common: They damaged a gene called ZMYND11. Ordinarily, these patients wouldn't be diagnosed with the same disorder: Some had severe intellectual disability, while others showed normal intelligence. But they all had some symptoms in common, including subtle facial deformities, delayed speech, and behavioral difficulties. The authors noted that one of the male patients had been very hard to categorize. He was diagnosed with "borderline personality disorder, bipolar disorder, psychosis, depression, low frustration tolerance leading to aggression and ADHD." The genetic results show the underlying cause, and by relating his symptoms with other patients who carry ZMYBD11 mutations, they give his physicians a chance to find better ways to treat him.

As geneticists dig into the seismic disruptions caused by CNVs, the confusing landscape of developmental disorders will begin to make more sense. But as one researcher wrote in a comment on Eichler's study, as we learn more about these common mutations, we'll find that many people lie in a gray area. They'll carry mutations "for which the majority of carriers do not meet the criteria for any medical diagnosis or disability," but which clearly cause problems in some people. This will be a challenge to society: "On the one hand, huge numbers of people might be stigmatized." But this might also allow us to help people: "On the other hand, these CNVs might be contributing substantially to societal disability and disparity, and affected individuals might be precisely the group that could benefit from early supportive intervention." Of course, this problem isn't unique to CNVs—it's the ever-present dilemma we continue to face as we learn to better understand human genetics.