Researchers at Johns Hopkins have identified a common
genetic alteration that appears to be
associated with autism only when inherited by sons from
their mothers. The CNTNAP2 gene, also
identified by two other groups publishing jointly in the
January issue of The American Journal of
Human Genetics, is one of the strongest common genetic
links to autism susceptibility found to date.
"While there probably are other, yet unidentified,
gene variants that also contribute to autism
susceptibility, our data clearly show that CNTNAP2 is
associated with an increased risk and an
excellent entry into further study for understanding
autism," said Aravinda Chakravarti, professor of
molecular biology and genetics and a member of the
Institute of Genetic Medicine at Johns Hopkins.
Using samples collected by the National Institute of
Mental Health Autism Genetics Initiative,
the Johns Hopkins team analyzed genetic material from 72
families, each having two or three
affected children who were diagnosed before 36 months of
age by the most stringent clinical
classification of autism disorder.
Dan Arking, assistant professor at the
McKusick-Nathans Institute, said, "We initially limited
ourselves to the samples with the strictest definition of
autism to minimize any heterogeneity, hoping
that if the effects were subtle, they would still stand
out. Using a broader definition of autism, we
were then able to replicate the initial finding in one of
the largest-ever groups of autism samples."
Autism spectrum disorder includes a set of poorly
understood developmental disorders that
vary in severity and symptoms, but all include impaired
social interaction and language development and
restricted and repetitive behavior and interests.
The Johns Hopkins team focused on one region on
chromosome 7 that previously had been
flagged as a possible link to faulty language acquisition
in autism families.
Using genomewide analysis, the team first analyzed DNA
from 292 individuals, including 148
affected offspring. The scientists compared single
nucleotide polymorphisms, or SNPs — the
differences in single-chemical building blocks of the DNA
— at the same point across many people. They
found that autistic individuals tend to inherit the DNA
letter T from their parents much more often
than expected by chance at one particular place on the
To validate its finding, the team repeated its
approach with a separate group of samples
consisting of 1,295 parent-child trios. It again found an
overrepresentation of T, confirming that
inheritance of the T genetic variant is associated with
increased risk of developing autism.
The T genetic variant is found in the middle of the
CNTNAP2 (short for contactin-associated
protein-like 2) gene, which codes for a protein that's
thought to mediate cell communication in the
The researchers then looked at the same data to see if
there were differences in which parent
the T allele is inherited from, and the gender of the
child. They found that autistic individuals are
more likely to get the T allele from mothers than fathers,
and more likely to be boys than girls.
"We know that boys are four times as likely as girls
to be autistic," Chakravarti said. "And now
we have some intriguing evidence suggesting that the gene
may show a parent-of-origin effect."
The research was funded by the National Institutes of
Authors on the paper are Arking, David Cutler, Tanya
Teslovich, Kristen West, Morna Ikeda,
Alexis Rea, Moltu Guy, Shin Lin and Chakravarti, all of
Johns Hopkins; and Camille Brune and Edwin
Cook Jr., both of the Institute for Juvenile Research at
the University of Illinois, Chicago.