title: Genome arrays for the detection of copy number variations in idiopathic mental retardation, idiopathic generalized epilepsy and neuropsychiatric disorders: lessons for diagnostic workflow and research.
abstract: We review the contributions and limitations of genome-wide array-based identification of copy number variants (CNVs) in the clinical diagnostic evaluation of patients with mental retardation (MR) and other brain-related disorders. In unselected MR referrals a causative genomic gain or loss is detected in 14-18% of cases. Usually, such CNVs arise de novo, are not found in healthy subjects, and have a major impact on the phenotype by altering the dosage of multiple genes. This high diagnostic yield justifies array-based segmental aneuploidy screening as the initial genetic test in these patients. This also pertains to patients with autism (expected yield about 5-10% in nonsyndromic and 10-20% in syndromic patients) and schizophrenia (at least 5% yield). CNV studies in idiopathic generalized epilepsy, attention-deficit hyperactivity disorder, major depressive disorder and Tourette syndrome indicate that patients have, on average, a larger CNV burden as compared to controls. Collectively, the CNV studies suggest that a wide spectrum of disease-susceptibility variants exists, most of which are rare (<0.1%) and of variable and usually small effect. Notwithstanding, a rare CNV can have a major impact on the phenotype. Exome sequencing in MR and autism patients revealed de novo mutations in protein coding genes in 60 and 20% of cases, respectively. Therefore, it is likely that arrays will be supplanted by next-generation sequencing methods as the initial and perhaps ultimate diagnostic tool in patients with brain-related disorders, revealing both CNVs and mutations in a single test.
authors: Division of Biomedical Genetics, Department of Medical Genetics, University Medical Centre Utrecht, Utrecht, The Netherlands. phochste@umcutrecht.nl
authors: R
authors: R
authors: Hochstenbach
authors: J E
authors: JE
authors: Buizer-Voskamp
authors: J A S
authors: JA
authors: Vorstman
authors: R A
authors: RA
authors: Ophoff
mesh_terms: D000818:Animals; D000013:Congenital Abnormalities / Q000235:genetics; D056915:DNA Copy Number Variations; D004827:Epilepsy / Q000175:diagnosis / Q000235:genetics*; D018628:Gene Dosage; D058685:Genetic Pleiotropy; D020022:Genetic Predisposition to Disease; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D001523:Mental Disorders / Q000175:diagnosis / Q000235:genetics*; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D019683:Penetrance