Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder - implications of a copy number variation involving dpp10 (CGX-12)

ABSTRACT: Background: Array-Comparative-Genomic-Hybridization (aCGH) is recommended as first-tier genetic test for children with autism spectrum disorder (ASD). However, result interpretation can be challenging as copy number variants (CNVs) in non-European ASD patients is not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. Methods DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. Results: Ten pathogenic and one likely-pathogenic CNVs were found in nine patients, with an overall diagnostic yield of 3.5%. A 138kb duplication involving 3â exons of DPP10 (hg[19]chr2:116534689-116672358), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of unknown significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified amongst our ancestry-matched control with frequency of 6/653 (0.92%) as well as from literature and genomic databases. Conclusions: DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings.

ORGANISM(S): Homo sapiens

SUBMITTER: Dr. Brian Hon-Yin Chung

PROVIDER: E-MTAB-5665 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Structural and functional impacts of copy number variations (CNVs) on livestock genomes are not yet well understood. In this study, we have identified 1853 CNV regions (CNVRs) using population-scale sequencing data generated from 75 cattle of 8 breeds (Holstein, Angus, Jersey, Limousin, Romagnola, Brahman, Gir and Nelore). Individual genome sequence coverage ranged from 4 to 30 fold, with a mean of 11.8 fold. A total of 3.1% (87.5 Mb) of the cattle genome is predicted to be copy number variable, representing a substantial increase over the previous estimates (~2%). This dataset was highly correlated with array CGH data (r2 = 0.761) and was validated to be accurate with an estimated 12% false positive rate and a 19% false negative rate based on qPCR and array CGH, respectively. Hundreds of CNVs were found to be either breed specific or differentially variable across breeds, including the RICTOR gene in dairy breeds and the PNPLA3 gene in the beef breeds. In contrast, clusters of the PRP and PAG genes are duplicated in all sequenced animals, implicating that subfunctionalization, neofunctionalization or overdominance play a role in diversifying these fertility related genes. Further population-genetic analyses based on CNVs revealed the population structures of these taurine and indicine breeds and uncovered hundreds of positively selected CNV candidates near important functional genes. These CNV results provide a new glimpse of diverse selections during cattle speciation, domestication, breed formation, and recent genetic improvement. 25 animals were analyzed using a custom Nimblegen aCGH chip with 2.1 million probes. The reference animal chosen was L1 Dominette, a Hereford cow of European ancestry. The array was subjected to a dye-swap with the reference sample to test probe intensity fidelity. Single channel intensity data from the array was used in a digital aCGH analysis to compare aCGH copy number estimates to copy number estimates derived from sequence data. Briefly, the reference signal from all analyzed arrays was collected and a median signal intensity was calculated from probe intensities within the BTF3 gene. The copy number of the reference animal was then inferred by division of single channel probe intensities with the median intensity of the BTF3 gene. Next, test sample intensities were normalized by taking the log2 ratio of the test intensity divided by the normalized reference copy number for the probe. CN values derived from sequence data were also normalized in this fashion by taking the log2 of the ratio of NGS CN divided by aCGH reference copy number.

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Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder - implications of a copy number variation involving dpp10 (CGX-12)

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