Autism Gene Scans Converge on Two Suspect Sites, Two Types of Genetic Risk

March 19, 2008 • Science Update

Four teams of scientists, using resources supported in part by NIMH, have pinpointed two different sites in the genome, each conferring a different type of genetic risk for autism. At one site, risk genes appear to be inherited. At the other, risk stems from spontaneous mutations, not seen in the genetics of the parents. In both examples, evidence suggests the suspect genes are critical for development of brain circuits impaired in autism.

In the inherited form of risk, people with autism were more prone than healthy controls to have certain versions of a gene on Chromosome 7. In the spontaneous form, one percent of autism was traced to a conspicuous "hot spot" of missing or duplicated genes on Chromosome 16.

The new leads help to focus the search for genetic causes of autism spectrum disorders (ASD), which affect 1 in 150 children with language, social and communication deficits and repetitive behaviors. Studies examining the occurrence of ASD in siblings and family members suggest that 90 percent of ASD involves genetic components, yet findings to date account for only about 10 percent of this. Most cases are spontaneous, rather than being passed through families as an inherited feature, suggesting that different rare and possibly multiple mutations likely influence risk in different combinations - and in complex interplay with environmental factors.

"Hot spot" glitch is rare, but notably more prevalent in ASD

In a genome-wide scan, a research team called the Autism Consortium found identical mutations associated with autism at the Chromosome 16 site in three separate samples.¹ In families from the NIMH-funded Autism Genetic Resource Exchange (AGRE), Children's Hospital Boston, and Iceland, about one percent of nearly 1500 people with autism or related developmental delays were either missing, or had duplicate copies of, about 25 genes in the Chromosome 16 area.

Though very rare, the mutations were about 100 times more prevalent in children with ASD, the researchers reported in the New England Journal of Medicine, January 9, 2008.

The Chromosome 16 hot spot may be especially prone to such spontaneous rearrangements of genetic material because it evolved relatively recently and is unique to humans and other primates. "Autism may be a relatively 'young' disease," notes an accompanying editorial.²

"The first widely replicated autism-predisposition gene."

Also drawing upon the AGRE resource, three other teams of researchers independently linked inherited variation in a gene on Chromosome 7, called CNTNAP2, with autism. They reported their findings online January 10, 2008, in the American Journal of Human Genetics. An accompanying editorial heralds this triangulation as "the first widely replicated autism-predisposition gene."³

CNTNAP2 is a member of a gene family that makes proteins called Neurexins that have been previously implicated in autism. Neurexins play a key role during development in building the machinery by which brain cells communicate. CNTNAP2 is also conspicuously located in an area of Chromosome 7 consistently identified as harboring autism risk genes.

In one of the new studies, genetic risk for impaired language in autism was linked to specific circuits known to malfunction in the disorder - but only in males. NIMH grantee Daniel Geschwind, M.D., of the University of California, Los Angeles, and colleagues ultimately focused on CNTNAP2 after a re-examination of all genes in the suspect Chromosome 7 area.⁴ They winnowed their search from four candidate genes that emerged in 172 families and confirmed it in a larger sample of 304 families.

The researchers found that a version of CNTNAP2 influences the age at which boys with autism say their first word. Delayed onset of speech is a hallmark of autism, which affects three times as many boys as girls. Boys also are more prone to attention deficit and language disorders and learning disabilities. The findings suggest that gender is likely an important clue in understanding how variation in the gene increases risk.

"Strikingly," expression of CNTNAP2 was narrowly restricted to only a set of interconnected brain structures responsible for speech, language, reward and other "executive" functions - precisely the circuits that malfunction in autism, researchers said.

"This gene may not only predispose children to autism," said Geschwind. "It also may influence the development of brain structures involved in language, providing a tangible link between genes, the brain and behavior."

Another study reported in the same issue of the journal also linked autism to another version, called the thymine variant, of CNTNAP2.⁵ A research team led by NIMH grantee Aravinda Chakravarti, Ph.D., of Johns Hopkins University, found that children with autism were about 20 percent more likely to have inherited this version from their mothers than their fathers. The risk gene version was first identified in 145 children with autism from families that had two or more children with the disorder, and then confirmed in larger sample of 1295 families with autism, drawn from the NIMH Autism Genetics Initiative.

A third group of researchers turned up several autism-linked rare variants of CNTNAP2.⁶ Matthew State, M.D., Ph.D., of Yale University, and colleagues, became interested in the gene after tracing cognitive and social delays in a child to a spontaneous glitch in a part of the gene. After a thorough search, they found a total of 27 different sites of variation in 635 patients - a relatively larger number than seen in 942 controls. The researchers further determined that 8 of 13 rare variants seen only in patients were likely deleterious to brain development.

All three groups noted that the significance of their findings is amplified by the fact that the other groups also independently implicated CNTNAP2, each using a different approach.

"The three studies together identify a set of common and rare variants that provide unequivocal evidence that the CNTNAP2 gene, when disrupted, leads to a type of ASD," noted Dietrich Stephan, Ph.D., of the Translational Genomics Research Institute, in the accompanying editorial.

In addition to this inherited risk subtype, he suggested that CNTNAP2 likely harbors mutations that confer risk for ASD in some individuals. By understanding these variations, science one day may be able to detect children carrying specific CNTNAP2 mutations and tailor early interventions to assist them during a critical period in brain development (12-24 months), suggested Stephan.

¹Eichler EE, Zimmerman AW.  A Hot Spot of Genetic Instability in Autism. N Engl J Med. 2008 Jan 9; [Epub ahead of print] No abstract available. PMID: 18184953

²Weiss LA, Shen Y, Korn JM, Arking DE, Miller DT, Fossdal R, Saemundsen E, Stefansson H, Ferreira MA, Green T, Platt OS, Ruderfer DM, Walsh CA, Altshuler D, Chakravarti A, Tanzi RE, Stefansson K, Santangelo SL, Gusella JF, Sklar P, Wu BL, Daly MJ; the Autism Consortium.  Association between Microdeletion and Microduplication at 16p11.2 and Autism. N Engl J Med. 2008 Jan 9; [Epub ahead of print] PMID: 18184952

³Stephan DA.  Unraveling autism. Am J Hum Genet. 2008 Jan;82(1):7-9. PMID: 18179879

⁴Alarcón M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, Nelson SF, Cantor RM, Geschwind DH.  Linkage, Association, and Gene-Expression Analyses Identify CNTNAP2 as an Autism-Susceptibility Gene. Am J Hum Genet. 2008 Jan 10;82(1):150-159. PMID: 18179893

⁵Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH Jr, Chakravarti A.  A Common Genetic Variant in the Neurexin Superfamily Member CNTNAP2 Increases Familial Risk of Autism. Am J Hum Genet. 2008 Jan;82(1):160-4. PMID: 18179894

⁶Bakkaloglu B, O'Roak BJ, Louvi A, Gupta AR, Abelson JF, Morgan TM, Chawarska K, Klin A, Ercan-Sencicek AG, Stillman AA, Tanriover G, Abrahams BS, Duvall JA, Robbins EM, Geschwind DH, Biederer T, Gunel M, Lifton RP, State MW.  Molecular Cytogenetic Analysis and Resequencing of Contactin Associated Protein-Like 2 in Autism Spectrum Disorders. Am J Hum Genet. 2008 Jan 10;82(1):165-173. PMID: 18179895