DMMC Course POPULATION GENETICS & SNP ANALYSIS

Durkan Lecture Theatre, Institute of Molecular Medicine, TCD, St James's Hospital

1700-1745 Thursday 7 June 2007

Plenary Lecture II
Genome-Wide Analysis of Copy Number Variation in Autism
Dr Jonathan Sebat (Cold Spring Harbor Laboratory, NY, USA)

Jonathan Sebat [1], B. Lakshmi [1], Dheeraj Malhotra [1], Christa Lese-Martin [2], Jennifer Troge [1], Tom Walsh [3], Boris Yamrom [1], Seungtai Yoon [1], Alex Krasnitz [1], Jude Kendall [1], Anthony Leotta [1], Deepa Pai [1], Ray Zhang [1], Yoon-Ha Lee [1], James Hicks [1], Sarah J Spence [4], Annette T. Lee [5], Kaija Puura [6], Terho Lehtimäki [7], David Ledbetter [2], Peter K. Gregersen [5], Joel Bregman [8], James S. Sutcliffe [9], Vaidehi Jobanputra [10], Dorothy Warburton [10], Mary-Claire King [3], David Skuse [11], Daniel H Geschwind [12], T. Conrad Gilliam [13], Kenny Ye [14], Michael Wigler [1]

[1] Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, [2] Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, [3] Department of Medicine and Genome Sciences, University of Washington, Seattle, WA 98195-7720, [4] Pediatrics and Neurodevelopmental Psychiatry Branch/NIMH, Bethesda MD 20892-1255, [5] Feinstein Institute for Medical Research, North Shore LIJ Health System, Manhasset, NY 11030, [6] Department of Child Psychiatry, University of Tampere, Medical School, Finland, [7] Department of Clinical Chemistry, University Hospital of Tampere and Tampere University, Medical School, [8] Fay J. Lindner Center for Autism and Developmental Disorders, North Shore-Long Island Jewish Health System, 4300 Hempstead Turnpike, Bethpage, NY 11714, [9] Center for Molecular Neuroscience, Vanderbilt University, Nashville, Tennessee 37232-8548 [10] Departments of Genetics and Development, and Pediatrics, Columbia University, New York, [11] Behavioural and Brain Sciences Unit, Institute of Child Health, University College London, 30 Guilford Street, London WCIN 1EH, UK, [12] Interdepartmental Program in the Neurosciences, Program in Neurogenetics, Neurology Department, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California 90095-1769, [13] Department of Human Genetics, The University of Chicago, 920 East 58th Street, Chicago, Illinois 60637, [14] Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY 10461.

Autism spectrum disorders (ASDs) are characterized by language impairments, social and communicative deficits and repetitive behaviors. Due in part to a high degree of genetic and phenotypic heterogeneity, traditional gene mapping approaches have had little success in identifying loci that have an effect on autism susceptibility. Cytogenetic techniques have been used to identify chromosomal abnormalities in 5-7 % of patients, but these microscopic lesions contain many genes and it is uncertain which are clinically relevant. It is plausible that submicroscopic chromosomal variants contribute to the genetic basis of autism. Therefore, new methodologies with increased sensitivity to detect genomic imbalances are a promising approach to identifying genetic risk factors. We tested the hypothesis that spontaneous copy number variation (CNV) is associated with autism spectrum disorders (ASD). We performed comparative genomic hybridization (CGH) on a large sample of families with idiopathic ASD, and examined the genomes of patients and unaffected subjects for CNVs not present in their parents. Candidate regions were validated by higher resolution CGH, paternity testing, cytogenetics, FISH analysis and micro-satellite genotyping. Confirmed de novo CNVs were significantly associated with autism (P=0.0005). Such CNVs were identified in 12/118 (10 %) of sporadic cases and in 2/77 (2 %) of patients with an affected first-degree relative. De novo CNVs were detected in 2/196 (1.0 %) of unaffected controls. Spontaneous variants identified in this study ranged in size from 99 kb to 10 Mb, and included mutations of single genes. These findings implicate novel genes in the pathophysiology of autism.