36 Child/Adolescent Psychiatry C LINICAL P SYCHIATRY N EWS • February 2008 on 7 Associated With Autism

Three studies show that the integrity of neuroligin- behaviors including speech and language, frequency was significantly greater from reward, frontal executive function, as well mothers than from fathers. axis is critical for normal development. as joint attention, a core deficit in autism “It is likely that additional genetic vari- spectrum disorders.” ants in this gene that contribute to autism BY MARY ANN MOON mosome 7q35 that contains approximate- “Our demonstration of the develop- susceptibility remain to be discovered,” Dr. Contributing Writer ly 200 known with language deficits mental expression of CNTNAP2 being Arking and his associates said (Am. J. and autism spectrum disorders. They first confined to brain circuitry known to be Hum. Genet. 2008;82:160-4). hree independent studies implicate genotyped the region in 172 parent-child disrupted in autism spectrum disorders In the third study, Dr. Betul Bakkaloglu the CNTNAP2 gene on chromo- trios from the Autism Genetics Research provides, to our knowledge for the first of Yale University, New Haven, Conn., and Tsome 7 as an autism-susceptibility Exchange database on 2,758 single nu- time, a link between genetic risk for lan- associates mapped balanced rearrange- gene, researchers reported. cleotide polymorphisms. This narrowed guage dysfunction in autism and specific ments in children who had social and cog- The three studies used different strate- the search to four like- brain regions known nitive delays “as a means of identifying gies to examine the possible genetic basis ly candidate genes, in- ‘Early detection of to underlie core candidate genes that may harbor rare dis- for autism, and all independently arrived cluding CNTNAP2. processes impaired in ease alleles.” They found an inversion of at the same conclusion: Variations—some This gene was al- CNTNAP2 mutation carriers, this disorder,” the in- in a mentally retarded common and some rare—in the CNT- ready suspected of coupled with early vestigators noted child with autistic features, and further NAP2 gene predispose carriers to autism. being involved in (Am. J. Hum. Genet. analysis showed disruption in the CNT- “It will be important to begin to char- autism since it is a intervention, could coax 2008;82:150-9). NAP2 gene at 7q35. acterize the genotype-phenotype correla- member of the neur- children through a critical In the second Dr. Bakkaloglu and associates then rese- tions across this gene so that we may be- exin superfamily; in study, Dan E. Arking, quenced all 24 exons of CNTNAP2 in a gin to use CNTNAP2 as a diagnostic and case studies, muta- period in development.’ Ph.D., of Johns Hop- sample of 635 subjects with autism spec- prognostic tool,” Dr. Dietrich A. Stephan tions in these genes kins University, Balti- trum disorders and 942 controls. They said in an editorial comment accompany- have been linked to severe autism, tem- more, and his associates genotyped 72 found eight rare variants predicted to have ing the three reports (Am. J. Hum. Genet. poral lobe seizures, language regression, families with multiple affected children in an adverse effect on the gene’s function. 2008;82:7-9). and repetitive behaviors. the National Institute of Mental Health These variants occurred twice as often in “These preliminary findings lead one to The researchers then tested a different Autism Genetics Initiative database. affected subjects as in controls. speculate whether early detection of set of 304 parent-child trios and confirmed They confined their analysis to the most One particular deleterious variant, I869T, CNTNAP2 mutation carriers, coupled that only the CNTNAP2 gene significant- strict phenotypic inclusion criteria ever was found in four autistic children from with early intervention, could coax chil- ly correlated with a delay in language ac- used in a sample of that size, “which al- three different families, but was not present dren through a critical period in develop- quisition—specifically, the age at which lowed [the] subtle association to be de- in more than 4,000 assessed ment (12-24 months of age) and allow carriers used their first word. The investi- tected without genomewide background in controls, Dr. Bakkaloglu and associates them to emerge undamaged and contin- gators then identified a rare microdeletion noise,” Dr. Stephan said. said (Am. J. Hum. Genet. 2008;82:165-73). ue to develop normally thereafter,” said within CNTNAP2 that was present in an Dr. Arking and his associates identified “Now that we have definitive evidence Dr. Stephan of the Translational Ge- autistic child and his father but not in one common single nucleotide polymor- from several perspectives that integrity of nomics Research Institute, Phoenix. 1,000 control chromosomes. phism, rs7794745, in the CNTNAP2 gene the neuroligin-neurexin axis is critical for In the first study, Maricela Alarcón, Dr. Alarcón and her associates also ex- that was significantly associated with normal development, we must launch into Ph.D., of the University of California, Los amined regional gene expression in hu- autism. They then confirmed the finding a candidate gene-resequencing effort to Angeles, Center for Autism Research and man fetal brains, and found that CNT- by genotyping a separate sample of 1,295 fully describe mutations in the other mem- Treatment and her associates built on their NAP2 was highly restricted to areas parent-child trios from the database. The bers of these gene families in autism spec- previous finding linking a region of chro- “known to contribute to complex human researchers also found that transmission trum disorders,” Dr. Stephan noted. ■ Two Mutations on Chromosome 16 May Cause 1% of Autism

BY MARY ANN MOON of 512 children with autism, develop- seen in any Icelandic subjects who had lection is acting against transmission of Contributing Writer mental delay, or mental retardation from autism but was found in two people with this deletion (as might be expected from Children’s Hospital Boston. They found bipolar disorder and in five unscreened an allele that increases the risk of autism novel, recurrent microdeletion, as identical deletions with exactly the same control subjects. by as much as a factor of 100), given how Awell as a reciprocal microduplication, boundaries in five autistic boys. Interestingly, a separate study of the Ice- often it arises de novo in a single genera- on a specific region of chromosome 16 ap- In contrast, they found no such dele- landic cohort showed that the deletion oc- tion,” added the researchers, whose study pears to confer substantial susceptibility to tions in a sample of 434 Children’s Hos- curred “at a markedly increased rate” in was funded by several organizations, in- autism, researchers have reported in the pital patients who had undergone genetic people who had various language or psy- cluding the Autism Consortium. The re- New England Journal of Medicine. testing because of dysmorphic features, chiatric disorders. It was found in one searchers reported no conflicts of interest. The two mutations might account for multiple congenital anomalies, congenital subject each with schizophrenia; bipolar In an accompanying editorial, Evan E. approximately 1% of cases of autism, a heart disease, seizures, or other disorders disorder; attention-deficit hyperactivity Eichler, Ph.D., and Dr. Andrew W. Zim- frequency that is the same as that for the unrelated to autism. Similarly, there were disorder; panic disorder, anxiety, depres- merman said that after larger case-control most common known cause of autism identical duplications at 16p11.2 in four sion, or addiction; and dyslexia. groups have undergone genotyping, it is (duplication of the Prader-Willi/Angel- children in the sample with autism, de- “In total, we have observed the identi- possible that some of the 50 other large de man region), according to Lauren A. velopmental delay, or mental retardation, cal deletion of nearly 600 kb [kilobase] in novo events observed by Dr. Weiss and her Weiss, Ph.D., of Massachusetts General but none in the sample of children with 13 subjects with autism or developmental colleagues and other events described in Hospital’s Center for Human Genetic Re- disorders unrelated to autism. or language delay (10 confirmed de novo recent studies might be specifically asso- search, Boston, and her associates. Dr. Weiss and her associates then tried mutations, 2 confirmed inherited muta- ciated with autism. Dr. Eichler is affiliat- The investigators conducted a genome- to replicate their findings in a genetic data- tions from parents with ADHD or mental ed with the University of Washington, wide analysis of a sample of families in the base of more than 19,000 members of the retardation, and 1 mutation of unknown Seattle; Dr. Zimmerman is with the Autism Genetic Resource Exchange to general population in Iceland. They found inheritance), with the reciprocal duplica- Kennedy Krieger Institute and Johns Hop- identify any recurrent deletions or dupli- three cases of the 16p11.2 deletion in the tion of the same region documented in 11 kins University, Baltimore. cations that conferred risk of autism in mul- subgroup of 299 subjects who had autism additional subjects,” said Dr. Weiss, also “The discovery of significant associa- tiple families. One region on chromosome or developmental disorders, “a finding that with the Autism Consortium, and her as- tions for the rarer loci may require the 16p11.2 carried deletions in four indepen- was consistent with the 1% frequency ob- sociates (N. Engl. J. Med. 2008 Jan. 9 screening of tens of thousands of DNA dent families with five autistic children. served” in the Children’s Hospital cohort [doi:10.1056/NEJMoa075974]). samples from patients rather than a few The same region showed duplication rather with autism or developmental disorders. “The fact that [the deletion mutation] is thousand,” they wrote [doi:10.1056/ than deletion in another three indepen- In contrast, only two cases of the dele- seen extremely rarely in the general pop- NEJMe0708756]). dent families with seven autistic children. tion were found in the 18,834 Icelandic ulation not only establishes a significant “Deeper sample collection and new The researchers then attempted to con- control subjects, a rate that was 1/100th difference between rates in autism and cost-effective genomic techniques may be firm their findings by searching for the of that in the autistic Icelanders. control populations, but also unambigu- needed to peel away the remaining layers same microdeletion in a genetic database The microduplication mutation was not ously establishes that strong natural se- of the onion,” they added. ■

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