Gene on Chromosome 7 Associated With Autism : Three studies show that the integrity of neuroligin-neurexin axis is critical for normal development.

Three independent studies implicate the CNTNAP2 gene on chromosome 7 as an autism-susceptibility gene, researchers reported.

The three studies used different strategies to examine the possible genetic basis for autism, and all independently arrived at the same conclusion: Variations–some common and some rare–in the CNTNAP2 gene predispose carriers to autism.

“It will be important to begin to characterize the genotype-phenotype correlations across this gene so that we may begin to use CNTNAP2 as a diagnostic and prognostic tool,” Dr. Dietrich A. Stephan said in an editorial comment accompanying the three reports (Am. J. Hum. Genet. 2008;82:7-9).

“These preliminary findings lead one to speculate whether early detection of CNTNAP2 mutation carriers, coupled with early intervention, could coax children through a critical period in development (12-24 months of age) and allow them to emerge undamaged and continue to develop normally thereafter,” said Dr. Stephan of the Translational Genomics Research Institute, Phoenix.

In the first study, Maricela Alarcón, Ph.D., of the University of California, Los Angeles, Center for Autism Research and Treatment and her associates built on their previous finding linking a region of chromosome 7q35 that contains approximately 200 known genes with language deficits and autism spectrum disorders. They first genotyped the region in 172 parent-child trios from the Autism Genetics Research Exchange database on 2,758 single nucleotide polymorphisms. This narrowed the search to four likely candidate genes, including CNTNAP2.

This gene was already suspected of being involved in autism since it is a member of the neurexin superfamily; in case studies, mutations in these genes have been linked to severe autism, temporal lobe seizures, language regression, and repetitive behaviors.

The researchers then tested a different set of 304 parent-child trios and confirmed that only the CNTNAP2 gene significantly correlated with a delay in language acquisition–specifically, the age at which carriers used their first word. The investigators then identified a rare microdeletion within CNTNAP2 that was present in an autistic child and his father but not in 1,000 control chromosomes.

Dr. Alarcón and her associates also examined regional gene expression in human fetal brains, and found that CNTNAP2 was highly restricted to areas “known to contribute to complex human behaviors including speech and language, reward, frontal executive function, as well as joint attention, a core deficit in autism spectrum disorders.”

“Our demonstration of the developmental expression of CNTNAP2 being confined to brain circuitry known to be disrupted in autism spectrum disorders provides, to our knowledge for the first time, a link between genetic risk for language dysfunction in autism and specific brain regions known to underlie core processes impaired in this disorder,” the investigators noted (Am. J. Hum. Genet. 2008;82:150-9).

In the second study, Dan E. Arking, Ph.D., of Johns Hopkins University, Baltimore, and his associates genotyped 72 families with multiple affected children in the National Institute of Mental Health Autism Genetics Initiative database.

They confined their analysis to the most strict phenotypic inclusion criteria ever used in a sample of that size, “which allowed [the] subtle association to be detected without genomewide background noise,” Dr. Stephan said.

Dr. Arking and his associates identified one common single nucleotide polymorphism, rs7794745, in the CNTNAP2 gene that was significantly associated with autism. They then confirmed the finding by genotyping a separate sample of 1,295 parent-child trios from the database. The researchers also found that transmission frequency was significantly greater from mothers than from fathers.

“It is likely that additional genetic variants in this gene that contribute to autism susceptibility remain to be discovered,” Dr. Arking and his associates said (Am. J. Hum. Genet. 2008;82:160-4).

In the third study, Dr. Betul Bakkaloglu of Yale University, New Haven, Conn., and associates mapped balanced rearrangements in children who had social and cognitive delays “as a means of identifying candidate genes that may harbor rare disease alleles.” They found an inversion of chromosome 7 in a mentally retarded child with autistic features, and further analysis showed disruption in the CNTNAP2 gene at 7q35.

Dr. Bakkaloglu and associates then resequenced all 24 exons of CNTNAP2 in a sample of 635 subjects with autism spectrum disorders and 942 controls. They found eight rare variants predicted to have an adverse effect on the gene's function. These variants occurred twice as often in affected subjects as in controls.

One particular deleterious variant, I869T, was found in four autistic children from three different families, but was not present in more than 4,000 chromosomes assessed in controls, Dr. Bakkaloglu and associates said (Am. J. Hum. Genet. 2008;82:165-73).

“Now that we have definitive evidence from several perspectives that integrity of the neuroligin-neurexin axis is critical for normal development, we must launch into a candidate gene-resequencing effort to fully describe mutations in the other members of these gene families in autism spectrum disorders,” Dr. Stephan noted.