Clinical application of 2.7M Cytogenetics array for CNV detection in subjects with idiopathic autism and/or intellectual disability

Abstract

Higher resolution whole-genome arrays facilitate the identification of smaller copy number variations (CNVs) and their integral genes contributing to autism and/or intellectual disability (ASD/ID). Our study describes the use of one of the highest resolution arrays, the Affymetrix(®) Cytogenetics 2.7M array, coupled with quantitative multiplex polymerase chain reaction (PCR) of short fluorescent fragments (QMPSF) for detection and validation of small CNVs. We studied 82 subjects with ASD and ID in total (30 in the validation and 52 in the application cohort) and detected putatively pathogenic CNVs in 6/52 cases from the application cohort. This included a 130-kb maternal duplication spanning exons 64-79 of the DMD gene which was found in a 3-year-old boy manifesting autism and mild neuromotor delays. Other pathogenic CNVs involved 4p14, 12q24.31, 14q32.31, 15q13.2-13.3, and 17p13.3. We established the optimal experimental conditions which, when applied to select small CNVs for QMPSF confirmation, reduced the false positive rate from 60% to 25%. Our work suggests that selection of small CNVs based on the function of integral genes, followed by review of array experimental parameters resulting in highest confirmation rate using multiplex PCR, may enhance the usefulness of higher resolution platforms for ASD and ID gene discovery.

Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis

“…DNA was extracted from peripheral blood using the ArchivePure DNA blood kit (5 PRIME, #2300740). Chromosome microarray analysis for new cases was performed using commercial arrays (e.g., Signature Genomics), and, whenever possible, high-resolution 2.7 M or Cytoscan array analysis was repeated according to Affymetrix protocols and as previously described (56). DNA from the case reported previously by Chabchoub et al (18) was obtained courtesy of Thomy de Ravel (University of Leuven, Leuven, Belgium) for higher-resolution array analysis.…”

A high-resolution copy-number variation resource for clinical and population genetics

“…While these cover the entire genome, the densest representation is within genes and even denser in known OMIM genes. In a recent study, high resolution array assays in a small cohort of ASD and intellectual disability (ID) samples showed higher diagnostic yields and the capability to detect clinically relevant, smaller CNVs 12 . Moreover, in North America alone, over 100 cytogenetic labs are now using the CytoScan-HD platform both for constitutional and cancer DNA testing.…”

Report on a Patient with a 12q24.31 Microdeletion Inherited from an Insulin-Dependent Diabetes Mellitus Father

“…4. Comparison between the genes deleted in the proband (ind3, red track) and the genes deleted in the patients described by Baple et al [2010] (ind1, blue track) and Qiao et al [2012] (ind2, brown track).…”

“…Among these, only 2 patients with a de novo deletion limited to the band 12q24.31 have been described [Baple et al, 2010;Qiao et al, 2012]. The patient described by Baple et al [2010] has a more proximal deletion than the one described by Qiao et al [2012] with a small overlapping region. We report herein a female patient with an inherited proximal interstitial deletion of band 12q24.31 overlying the microdeletion described by Baple et al [2010].…”