Long before a child enters school, brain cells are on the move, lining up into carefully wired circuits in preparation for the demanding task of learning to read. Mistakes in this circuit architecture are thought to underlie dyslexia, a reading disability that affects as many as 15 percent of children and runs strongly in families.
In a finding that received worldwide recognition, Yale researchers have discovered a gene that may cause many cases of dyslexia by interfering with early brain development. The gene, DCDC2, is required for neurons to migrate normally and is disrupted in up to 20 percent of people with dyslexia.
“Our results validate and confirm the fact that dyslexia is genetic,” says senior researcher Jeffrey R. Gruen, M.D., associate professor of pediatrics and an investigator at the Yale Child Health Research Center. “Based on brain imaging data, we know that dyslexics seem to have a disrupted brain reading circuit, and we think that variants of DCDC2 could be responsible for disrupting circuit formation during development.”
Besides illuminating the cause of dyslexia, the identification of DCDC2 could lead to genetic tests to identify at-risk children early on, when educational interventions are most effective, Gruen says.
The work, presented at the October meeting of the American Society for Human Genetics, was published in the November 22 issue of the Proceedings of the National Academy of Sciences.
Dyslexia is defined as an impairment in reading ability in people with normal intelligence and adequate educational opportunities. For the last 15 years, researchers have been on the trail of a gene for dyslexia they had traced to human chromosome 6. In 2002, Gruen and colleagues narrowed the search to a stretch of 1.5 million DNA base pairs containing 19 candidate genes, all of which were known to be active in the brain.
To get a closer look at those 19 genes in normal readers and dyslexics, Gruen and his team analyzed 536 parents and children from 153 families, correlating DNA sequences with the children’s scores on a battery of reading and comprehension tests.
They quickly saw that in children with low reading scores, sequence variations clustered most often in the area of DCDC2. The researchers hit pay dirt when they noticed that in some dyslexic subjects, one copy of the DCDC2 gene was missing nearly 2,500 “letters” of DNA code. This deletion is uncommon in the general U.S. population, but it was seen in nearly 20 percent of the study participants with dyslexia.
The DCDC2 deletion does not affect the structure or function of the gene’s protein product, but Gruen and his colleagues believe it reduces the overall amount of messenger RNA, and hence protein, in nerve cells. They then demonstrated that neurons did not migrate properly in the developing brains of fetal rats in which DCDC2 expression was experimentally suppressed.
While the team hasn’t yet confirmed that DCDC2 protein levels are lower in dyslexic people, they did establish that in normal adult humans the gene is most active in brain regions that are involved in reading.
The newly found gene has no relation to IQ, Gruen is quick to point out. And thanks to the flexibility of the brain’s circuitry early in life, he says that, with early intervention, dyslexic children may be able to compensate for their disability by training neural circuits other than those affected by the gene when they learn to read.
“If children with dyslexia can get the right education program early on, they will be successful,” Gruen says. “We’re hoping that someday we can use genetic information to match kids to their ideal intervention as early as possible.”