Autism Connected To Gene Central To Neuron Formation, Study Shows

Autism Connected To Gene Central To Neuron Formation, Study Shows
ScienceDaily (Mar. 20, 2008) — Eli Hatchwell, M.D., Ph.D., Associate Professor of Pathology at Stony Brook University Medical Center, and colleagues have found that a disruption of the Contactin 4 gene on chromosome 3 may be linked to autism spectrum disorder (ASD). What causes ASD, a developmental disorder of the central nervous system, is largely unknown. Dr. Hatchwell’s finding suggests that mutations affecting Contactin 4 may be relevant to ASD pathogenesis, and thus a potential biomarker for some individuals with the disorder.


According to the Centers for Disease Control and Prevention, the prevalence of ASD in the United States may be as high as 1 in 150 children. The disorder is divided into five subtypes, including autism proper. Pathogenesis of ASD may be environmental and/or biological. Experts suspect that many genes may play a role in the etiology of ASD.

“Given the prevalence of ASD, a clearer understanding of its etiology is necessary for both diagnostic and therapeutic purposes,” says Dr. Hatchwell, also Director of Stony Brook University’s Genomics Core Facility and Geneticist at the Cody Center for Autism and Developmental Disabilities at SBU. “Our study implicates Contactin 4 as a candidate gene in ASD, a finding that significantly contributes to our understanding of the biological basis of autism.”

A total of 92 patients with ASD from the Cody Center participated in the genetics study. The participants came from 81 families. Genomic DNA was analyzed from all subjects and, where relevant, from their biological parents. More than 500 normal control patients were included in the analysis.

A whole genome analysis of the 92 subjects revealed that three subjects had chromosome 3 copy number variations that disrupted the same gene, Contactin 4. A deletion was detected in two subjects (siblings), and a duplication was found in a third, unrelated, individual. Subsequent array analysis of parental DNA indicated that both variations were paternally inherited, specifically inherited from fathers without a history of ASD.

According to Dr. Hatchwell, when mutations are found that explain just one percent of a given ASD population, the results are significant, as ASD likely has a multitude of genetic causes. For example, a recent study reported in the New England Journal of Medicine showed that copy number variations of chromosome 16p11.2 accounted for one percent of all cases of the syndrome. Dr. Hatchwell explains that the genetic analysis with the Cody Center patients, detailed in the article entitled “Disruption of Contactin 4 in 3 Subjects with Autism Spectrum Disorder,” is highly significant in that two of 81 families (2.5 percent) presented with a disruption of Contactin 4.

The mutations found in Dr. Hatchwell’s study directly interrupt Contactin 4. The gene codes for an axon-associated cell adhesion molecule that is expressed in the brain and is known to be important in axonal development.

Dr. Hatchwell’s multidisciplinary research team is planning to analyze Contactin 4 in large numbers of patients with ASD and normal controls, in order to identify mutations that might be involved in the pathogenesis of ASD in a subset of affected individuals.

Details of the study are reported in the early online edition of the Journal of Medical Genetics. Dr. Hatchwell’s co-authors from Stony Brook University include: Jasmin Roohi, B.A., Department of Genetics; John C. Pomeroy, M.D., David H. Tegay, D.O., and Carla DeVincent, Ph.D., of the Department of Pediatrics; Lance E. Palmer, Ph.D., Department of Microbiology. Other authors include: Cristina Montagna, Ph.D., Department of Pathology and Molecular Genetics, Albert Einstein College of Medicine; Susan L. Christian, Ph.D., Department of Human Genetics, University of Chicago; and Norma Nowak, Ph.D., Department of Cancer Prevention and Population Sciences, University of Buffalo.

The study was supported in part by grants from the Cody Center for Autism and Developmental Disabilities, National Alliance for Autism Research, National Institute of Neurological Diseases and Stroke, the National Cancer Institute, and the General Clinical Research Center at SBUMC.

Adapted from materials provided by Stony Brook University Medical Center.

CNVs in Contactin 4 and 2.5 percent of Autism

http://news.aol.com/story/_a/gene-for-brain-connections-linked-with/n20080318150209990016



Gene for brain connections linked with autism
By Maggie Fox,
Reuters
Posted: 2008-03-18 15:02:04
WASHINGTON (Reuters) - A gene that helps the brain make connections may underlie a significant number of autism cases, researchers in the United States reported on Tuesday.Disruptions in the gene, called contactin 4, stop the gene from working properly and appear to stop the brain from making proper networks, the researchers reported in the Journal of Medical Genetics.These disruptions, in which the child has either three copies of the gene or just one copy when two copies is normal, could account for up to 2.5 percent of autism cases, said Dr. Eli Hatchwell of Stony Brook University Medical Center in New York, who led the study."That is a significant number," said Hatchwell.



Generally the mistake that people make is they are looking for one unifying cause for autism, and there is no such thing and there never will be," Hatchwell said in a telephone interview.



Hatchwell's team tested 92 patients from 81 families with autism spectrum disorder and compared them to 560 people without autism.They did a whole genome analysis, looking at the entire DNA map, and found three of the patients had deletions or duplications of DNA that disrupted contactin 4.They were all inherited from fathers without a history of autism, which can cause severe social and developmental delays and even mental retardation.

Both genes have been affected by CNVs in patients with autism and mental retardation, but neither has been previously implicated in SZ

1: Hum Mol Genet. 2008 Feb 1;17(3):458-65. Epub 2007 Nov 6. Links
Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia.Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O'Donovan MC, Erdogan F, Owen MJ, Ropers HH, Ullmann R.
Department of Psychological Medicine, Cardiff University, Henry Wellcome Building, Heath Park, Cardiff CF14 4XN, UK.

Copy number variations (CNVs) account for a substantial proportion of human genomic variation, and have been shown to cause neurodevelopmental disorders. We sought to determine the relevance of CNVs to the aetiology of schizophrenia (SZ). Whole-genome, high-resolution, tiling path BAC array comparative genomic hybridization (array CGH) was employed to test DNA from 93 individuals with DSM-IV SZ. Common DNA copy number changes that are unlikely to be directly pathogenic in SZ were filtered out by comparison to a reference dataset of 372 control individuals analyzed in our laboratory, and a screen against the Database of Genomic Variants. The remaining aberrations were validated with Affymetrix 250K SNP arrays or 244K Agilent oligo-arrays and tested for inheritance from the parents. A total of 13 aberrations satisfied our criteria. Two of them are very likely to be pathogenic. The first one is a deletion at 2p16.3 that was present in an affected sibling and disrupts NRXN1. The second one is a de novo duplication at 15q13.1 spanning APBA2. The proteins of these two genes interact directly and play a role in synaptic development and function. Both genes have been affected by CNVs in patients with autism and mental retardation, but neither has been previously implicated in SZ.

PMID: 17989066 [PubMed

Structural variation of chromosomes in autism spectrum disorder

http://www.ncbi.nlm.nih.gov/pubmed/18252227?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum


1: Am J Hum Genet. 2008 Feb;82(2):477-88. Epub 2008 Jan 17. Links
Structural variation of chromosomes in autism spectrum disorder.Marshall CR, Noor A, Vincent JB, Lionel AC, Feuk L, Skaug J, Shago M, Moessner R, Pinto D, Ren Y, Thiruvahindrapduram B, Fiebig A, Schreiber S, Friedman J, Ketelaars CE, Vos YJ, Ficicioglu C, Kirkpatrick S, Nicolson R, Sloman L, Summers A, Gibbons CA, Teebi A, Chitayat D, Weksberg R, Thompson A, Vardy C, Crosbie V, Luscombe S, Baatjes R, Zwaigenbaum L, Roberts W, Fernandez B, Szatmari P, Scherer SW.
The Centre for Applied Genomics, The Hospital for Sick Children, Department of Molecular and Medical Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.

Structural variation (copy number variation [CNV] including deletion and duplication, translocation, inversion) of chromosomes has been identified in some individuals with autism spectrum disorder (ASD), but the full etiologic role is unknown. We performed genome-wide assessment for structural abnormalities in 427 unrelated ASD cases via single-nucleotide polymorphism microarrays and karyotyping. With microarrays, we discovered 277 unbalanced CNVs in 44% of ASD families not present in 500 controls (and re-examined in another 1152 controls). Karyotyping detected additional balanced changes. Although most variants were inherited, we found a total of 27 cases with de novo alterations, and in three (11%) of these individuals, two or more new variants were observed. De novo CNVs were found in approximately 7% and approximately 2% of idiopathic families having one child, or two or more ASD siblings, respectively. We also detected 13 loci with recurrent/overlapping CNV in unrelated cases, and at these sites, deletions and duplications affecting the same gene(s) in different individuals and sometimes in asymptomatic carriers were also found. Notwithstanding complexities, our results further implicate the SHANK3-NLGN4-NRXN1 postsynaptic density genes and also identify novel loci at DPP6-DPP10-PCDH9 (synapse complex), ANKRD11, DPYD, PTCHD1, 15q24, among others, for a role in ASD susceptibility. Our most compelling result discovered CNV at 16p11.2 (p = 0.002) (with characteristics of a genomic disorder) at approximately 1% frequency. Some of the ASD regions were also common to mental retardation loci. Structural variants were found in sufficiently high frequency influencing ASD to suggest that cytogenetic and microarray analyses be considered in routine clinical workup.