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From the Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle (H.C.M.); and the Departments of Integrative Systems Biology and Pediatrics, Children’s National Medical Center, and George Washington University School of Medicine (M.L.B., E.P.H.) — both in Washington, DC. Address reprint requests to Dr. Mefford at the Department of Pediatrics, 1959 NEPacific St., Box 356320, Seattle, WA 98195, or at email@example.com.N Engl J Med 2012;366:733-43.
W. Gregory Feero, M.D., Ph.D., and Alan E. Guttmacher, M.D., Editors
Genomics, Intellectual Disability, and Autism
Heather C. Mefford, M.D., Ph.D., Mark L. Batshaw, M.D.,
and Eric P. Hoffman, Ph.D.
Intellectual disability, which is characterized by significant limitations in both intellectual functioning and adaptive behavior that begin before the age of 18 years, (1) affects 1.5 to 2% of the population in Western countries. (2) A diagnosis of intellectual disability is usually made when IQ testing reveals an IQ of less than 70, which means that often the diagnosis is not made until late childhood or early adulthood. However, most persons with intellectual disability are identified early in childhood on the basis of concern about developmental delays, which may include motor, cognitive, and speech delays. A genetic underpinning of this disorder has long been recognized in a subset of cases, with trisomy 21 (Down’s syndrome) detectable by chromosomal studies since 1959.(3)
Trisomy 21 remains the most important chromosomal cause of intellectual disability. Single-gene causes have also been identified for a number of intellectual disability syndromes and include both autosomal and X-linked genes, with the fragile X syndrome being the most common of inherited syndromes caused by a single-gene defect leading to this phenotype in male patients. Autism spectrum disorders have been estimated to affect as many as 1 in 100 to 1 in 150 children. (4,5) Disorders on the autism spectrum share features of impaired social relationships, impaired language and communication, and repetitive behaviors or a narrow range of interests. Many children with autism spectrum disorders also have intellectual disability, and approximately 75% have lifelong disability requiring substantial social and educational support.
Thus, autism and intellectual disability together represent an important health burden in the population and are frequent reasons for referral to genetics and developmental pediatrics clinics for a diagnostic workup. During the past decade, advances in genetic research have enabled genomewide discovery of chromosomal copy-number changes and single-nucleotide changes in patients with intellectual disability and autism as well as in those with other disorders. These technological advances — which include array comparative genomic hybridization (CGH), single-nucleotide-polymorphism (SNP) genotyping arrays, and massively parallel sequencing — have transformed the approach to the identification of etiologic genes and genomic rearrangements in the research laboratory and are now being applied in the clinical diagnostic arena. Here we review these techniques and how they have enabled the rapid discovery of chromosomal and single-gene causes of intellectual disability and autism. Read all article.