Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Diagnostic Exome Sequencing in Persons with Severe Intellectual Disability Joep de Ligt, M.Sc., Marjolein H. Willemsen, M.D., Bregje W.M. Van Bon, M.D., Ph.D., Tjitske Kleefstra, M.D., Ph.D., Helger G. Yntema, Ph.D., Thessa Kroes, B.Sc., Anneke T. Freemi Upnp Installation Artists here. Vulto-van Silfhout, M.D., David A.

Koolen, M.D., Ph.D., Petra de Vries, B.Sc., Christian Gilissen, Ph.D., Marisol del Rosario, B.Sc., Alexander Hoischen, Ph.D., Hans Scheffer, Ph.D., Bert B.A. De Vries, M.D., Ph.D., Han G. Brunner, M.D., Ph.D., Joris A. Veltman, Ph.D., and Lisenka E.L.M.

Vissers, Ph.D. N Engl J Med 2012; 367:1921-1929 DOI: 10.1056/NEJMoa1206524. Methods We evaluated patients with intellectual disability to exclude known causes of the disorder.

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We then sequenced the coding regions of more than 21,000 genes obtained from 100 patients with an IQ below 50 and their unaffected parents. A data-analysis procedure was developed to identify and classify de novo, autosomal recessive, and X-linked mutations. In addition, we used high-throughput resequencing to confirm new candidate genes in 765 persons with intellectual disability (a confirmation series). All mutations were evaluated by molecular geneticists and clinicians in the context of the patients' clinical presentation.

Results We identified 79 de novo mutations in 53 of 100 patients. A total of 10 de novo mutations and 3 X-linked (maternally inherited) mutations that had been previously predicted to compromise the function of known intellectual-disability genes were found in 13 patients. Potentially causative de novo mutations in novel candidate genes were detected in 22 patients. Additional de novo mutations in 3 of these candidate genes were identified in patients with similar phenotypes in the confirmation series, providing support for mutations in these genes as the cause of intellectual disability. We detected no causative autosomal recessive inherited mutations in the discovery series.

Thus, the total diagnostic yield was 16%, mostly involving de novo mutations. Severe intellectual disability, which is also referred to as cognitive impairment or mental retardation, affects approximately 0.5% of the population in Western countries and represents an important health burden. A clinical diagnosis of severe intellectual disability is generally based on an IQ of less than 50 and substantial limitations in activities of daily living. In early childhood, the diagnosis is based on substantial developmental delays, including motor, cognitive, and speech delays. Children with different nonsyndromic forms of intellectual disability are clinically indistinguishable. Intellectual disability can be caused by nongenetic factors, such as infections and perinatal asphyxia. In developed countries, most severe forms of intellectual disability are thought to have a genetic cause, but the cause remains elusive in 55 to 60% of patients.

An understanding of the genetic cause of intellectual disability can benefit patients and their families, because a diagnosis may provide information on the prognosis, precludes further unnecessary invasive testing, and may lead to appropriate therapy. Moreover, a diagnosis often facilitates access to appropriate medical and supportive care. Family members may benefit from knowledge of the risk of recurrence, reproductive counseling, and possible prenatal diagnosis. We and others have reported evidence supporting the hypothesis that rare de novo point mutations can be a major cause of severe intellectual disability.