Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Friedman, Jan M.; Adam, Shelin; Arbour, Laura; Armstrong, Linlea; Baross, Ágnes; Birch, Patricia; Boerkoel, Cornelius F.; Chan, Susanna; Chai, David; Delaney, Allen; Flibotte, Stéphane; Gibson, William T.; Langlois, Sylvie; Lemyre, Emmanuelle; Li, H. Irene; MacLeod, Patrick; Mathers, Joan; Michaud, Jacques L.; McGillivray, Barbara; Patel, Millan S.; Qian, Hong; Rouleau, Guy A.; Allen, Margot I. Van; Yong, Siu Li; Zahir, Farah; Eydoux, Patrice; Marra, Marco A.

doi:10.1186/1471-2164-10-526

Cited by 31 publications

(26 citation statements)

References 79 publications

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“…This is illustrated by the findings of Buysse et al [2009], who detected pathogenic deletions, sized 57-81 kb and affecting only 1 gene, using an array-CGH platform containing 44,000 oligonucleotide probes. The limited contribution of an increment in the number of probes to ϳ 500,000 is also illustrated by the finding of Friedman et al [2009] that among 44 MR/MCA patients who tested negative on a 100,000 SNP genotyping platform, only 1 tested positive when all 44 were reanalyzed using a 500,000 SNP platform. Similarly, Bernardini et al [2009] reanalyzed 51 patients, who scored normal using a 44,290 oligonucleotide array-CGH platform, on a SNP genotyping platform containing 1,800,000 probes, and a pathogenic imbalance was detected in only 3 of these patients.…”

Section: Idiopathic Mental Retardation With or Without Congenital Abnmentioning

confidence: 99%

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

Hochstenbach

Buizer-Voskamp²,

Vorstman

et al. 2011

Cytogenet Genome Res

104

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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.

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Section: Idiopathic Mental Retardation With or Without Congenital Abnmentioning

confidence: 99%

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

Hochstenbach

Buizer-Voskamp²,

Vorstman

et al. 2011

Cytogenet Genome Res

104

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“…The wide-spread use of chromosomal microarray analysis (CMA) led to a new frontier in clinical diagnosis, with the ability to detect causative submicroscopic chromosomal imbalances, also called pathogenic copy-number variants (CNVs), in at least 10-15% of affected individuals in whom conventional cytogenetic analysis is normal. [1][2][3] A few years ago, the number of genes recognized to contribute to ID was reported as B300. 4,5 Currently, the estimated number of ID genes is at least 900-950, based on the evidence that there are 91 pathogenic X-linked genes that account for 10-15% of ID in males.…”

Section: Introductionmentioning

confidence: 99%

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

et al. 2013

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Intellectual disability affects about 3% of individuals globally, withB50% idiopathic. We designed an exonic-resolution array targeting all known submicroscopic chromosomal intellectual disability syndrome loci, causative genes for intellectual disability, and potential candidate genes, all genes encoding glutamate receptors and epigenetic regulators. Using this platform, we performed chromosomal microarray analysis on 165 intellectual disability trios (affected child and both normal parents). We identified and independently validated 36 de novo copy-number changes in 32 trios. In all, 67% of the validated events were intragenic, involving only exon 1 (which includes the promoter sequence according to our design), exon 1 and adjacent exons, or one or more exons excluding exon 1. Seventeen of the 36 copy-number variants involve genes known to cause intellectual disability. Eleven of these, including seven intragenic variants, are clearly pathogenic (involving STXBP1, SHANK3 (3 patients), IL1RAPL1, UBE2A, NRXN1, MEF2C, CHD7, 15q24 and 9p24 microdeletion), two are likely pathogenic (PI4KA, DCX), two are unlikely to be pathogenic (GRIK2, FREM2), and two are unclear (ARID1B, 15q22 microdeletion). Twelve individuals with genomic imbalances identified by our array were tested with a clinical microarray, and six had a normal result. We identified de novo copynumber variants within genes not previously implicated in intellectual disability and uncovered pathogenic variation of known intellectual disability genes below the detection limit of standard clinical diagnostic chromosomal microarray analysis.

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“…4), but quantitative PCR (qPCR) testing showed PRKG2 loss (Supplemental eTable I and eFig. 1-See Supporting Information online) [Friedman et al, 2009].…”

Section: Genetic Investigationsmentioning

confidence: 99%

“…A critical region including only PRKG2 and RASGEF1B was delineated by overlapping the affected genomic regions of 13 patients, including a patient we previously reported [Friedman et al, 2006;Friedman et al, 2009]. Our patient was first assessed using a 100 K Affymetrix Ò Array Genomic Hybridization (AGH) [Friedman et al, 2006] and subsequently re-tested using the higher resolution 500 K Affymetrix Ò AGH platform [Friedman et al, 2009].…”

Section: Introductionmentioning

confidence: 99%

Life‐history chronicle for a patient with the recently described chromosome 4q21 microdeletion syndrome

Tsang¹,

Rupps²,

McGillivray³

et al. 2012

American J of Med Genetics Pt A

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[Bonnet et al. (2010); J Med Genet 47: 377-384] recently suggested a 4q21 microdeletion syndrome with several common features, including severe intellectual disability, lack of speech, hypotonia, significant growth restriction, and distinctive facial features. Overlap of the deleted regions of 13 patients, including a patient we previously reported, delineates a critical region, with PRKG2 and RASGEF1B emerging as candidate genes. Here we provide a detailed clinical report and photographic life history of our previously reported patient. Previous case reports of this new syndrome have not described the prognosis or natural history of these patients.

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Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization

Cited by 31 publications

References 79 publications

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

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

Single exon-resolution targeted chromosomal microarray analysis of known and candidate intellectual disability genes

Life‐history chronicle for a patient with the recently described chromosome 4q21 microdeletion syndrome

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