April 5, 2012: Critical findings from three independent studies, released April 4 in the journal Nature, identify rare genetic mutations called "de novo mutations" in a handful of biologically unrelated autistic children whose parents have no signs of autism; de novo means these mutations occur spontaneously around conception and are not inherited.
In addition, all three studies found the risk of this type of genetic mutation increases as the father ages, reports Benedict Carey for the New York Times. The studies provide the first evidence of a genetic basis for "sporadic" autism.
Autism Spectrum Disorder (ASD) is a generic term for a broad category of related but biologically distinct conditions that fall on a wide spectrum.
The three studies, encompassing 663 families, link six genes to autism: two had not been associated with the disorder before and two had only been weakly linked to autism in previous studies. Researchers also identified many more potential mutations to investigate in future studies and estimate that about 400 to 1,000 genes are involved in the disorder.
The gene mutations are extremely rare and together account for a tiny fraction of autism cases. But the odds that two or more people in any small group will have such problems in the same genetic location are vanishingly small, strongly suggesting that the mutations are related to the diagnosis.
Matthew W. State M.D., above, professor of Genetics and of Psychiatry, Child Study Center, Yale School of Medicine, and his team found two unrelated children with autism in the study with de novo mutations in the same gene.
“That is like throwing a dart at a dart board with 21,000 spots and hitting the same once twice,” Dr. State said. “The chances that this gene is related to autism risk is something like 99.9999 percent.”
The team found that a third child had a de novo mutation in another gene suspected of a possible link to autism risk — but one such mutation is not enough to make the case.
But the team led Evan E. Eichler Ph.D., professor of genome sciences, Howard Hughes Medical Center, University of Washington School of Medicine, independently found that same high risk gene mutation in child with autism. (read the study here)
All three studies also found evidence that the risk of de novo mutations increases with parental age. In an analysis of 51 de novo mutations, Dr. Eichler’s group found that glitches were four times more likely to originate in DNA from the male than from the female. The risk is higher in fathers at age 35 than at age 25 and seems to creep upward with age
Two of the studies, led by State and Eichler are based on data from the Simons Simplex Collection (SSC), a project of SFARI. The SSC contains genetic and other information, such as cognitive and behavioral data, from 2,700 families who have a single child with autism and their unaffected parents and siblings, and is funded by the Simons Foundation. They examined a total of 447 family trios — an affected child and unaffected parents — and 250 unaffected siblings.
The third study, headed by Mark Daly Ph.D., professor of medicine at Harvard Medical School, sequenced exomes (protein coding in a genome) from 175 family trios that are part of the Autism Consortium in Boston. Unlike the SSC, this group includes families with a history of autism, but Daly says that 70% of the families in this cohort have no family history of the disorder.
Written for California's Children by Elizabeth J Carlyle.