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Hopkins Team Identifies Autism Susceptibility Gene - 01/22/2008

Hopkins Team Identifies Autism Susceptibility Gene

mother-to-son transmission may be critical to inheriting susceptibility
Release Date: January 22, 2008

Researchers at Johns Hopkins have identified a common genetic alteration that appears to be associated with autism only when inherited by sons from their mother. 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,” says Aravinda Chakravarti, Ph.D., professor of medicine, pediatrics and molecular biology and genetics and member of the McKusick-Nathans Institute of Genetic Medicine at Hopkins.

Using samples collected by the National Institute of Mental Health Autism Genetics Initiative, the 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.

“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,” says Dan Arking, Ph.D., an assistant professor at the McKusick-Nathans Institute. “Using a broader definition of autism, we were then able to replicate the initial finding in one of the largest-ever group 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 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 genome-wide analysis, the team first analyzed DNA from 292 individuals, including 148 affected offspring. They compared single nucleotide polymorphisms, or SNPs, the differences in single chemical’s 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 chromosome.

To validate their finding, the team then repeated their approach with a separate group of samples consisting of 1,295 parent-child trios. They 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 gene, short for contactin-associated protein-like 2, which codes for a protein that’s thought to mediate cell communication in the nervous system.

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,” says Chakravarti. “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 Health.

Authors on the paper are Dan Arking, David Cutler, Tanya Teslovich, Kristen West, Morna Ikeda, Alexis Rea, Moltu Guy, Shin Lin and Chakravarti of Hopkins, and Camille Brune and Edwin Cook Jr. of the Institute for Juvenile Research at the University of Illinois, Chicago.

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