A hybrid qPCR/SNP array approach allows cost efficient assessment of KIR gene copy numbers in large samples.

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A hybrid qPCR/SNP array approach allows cost efficient assessment of KIR gene copy numbers in large samples.

BMC Genomics. 2014 Apr 11;15(1):274

Authors: Pontikos N, Smyth DJ, Schuilenburg H, Howson JM, Walker NM, Burren OS, Guo H, Onengut-Gumuscu S, Chen WM, Concannon P, Rich SS, Jayaraman J, Jiang W, Traherne JA, Trowsdale J, Todd JA, Wallace C

Abstract
BACKGROUND: Killer Immunoglobulin-like Receptors (KIRs) are surface receptors of natural killer cells that bind to their corresponding Human Leukocyte Antigen (HLA) class I ligands, making them interesting candidate genes for HLA-associated autoimmune diseases, including type 1 diabetes (T1D). However, allelic and copy number variation in the KIR region effectively mask it from standard genome-wide association studies: single nucleotide polymorphism (SNP) probes targeting the region are often discarded by standard genotype callers since they exhibit variable cluster numbers. Quantitative Polymerase Chain Reaction (qPCR) assays address this issue. However, their cost is prohibitive at the sample sizes required for detecting effects typically observed in complex genetic diseases.
RESULTS: We propose a more powerful and cost-effective alternative, which combines signals from SNPs with more than three clusters found in existing datasets, with qPCR on a subset of samples. First, we showed that noise and batch effects in multiplexed qPCR assays are addressed through normalisation and simultaneous copy number calling of multiple genes. Then, we used supervised classification to impute copy numbers of specific KIR genes from SNP signals. We applied this method to assess copy number variation in two KIR genes, \textit{KIR3DL1} and \textit{KIR3DS1}, which are suitable candidates for T1D susceptibility since they encode the only KIR molecules known to bind with HLA-Bw4 epitopes. We find no association between \textit{KIR3DL1/3DS1} copy number and T1D in 6744 cases and 5362 controls; a sample size twenty-fold larger than in any previous KIR association study. Due to our sample size, we can exclude odds ratios larger than 1.1 for the common \textit{KIR3DL1/3DS1} copy number groups at the 5% significance level.
CONCLUSION: We found no evidence of association of \textit{KIR3DL1/3DS1} copy number with T1D, either overall or dependent on HLA-Bw4 epitope. Five other KIR genes, \textit{KIR2DS4}, \textit{KIR2DL3}, \textit{KIR2DL5}, \textit{KIR2DS5} and \textit{KIR2DS1}, in high linkage disequilibrium with \textit{KIR3DL1} and \textit{KIR3DS1}, are also unlikely to be significantly associated. Our approach could potentially be applied to other KIR genes to allow cost effective assaying of gene copy number in large samples.

PMID: 24720548 [PubMed - as supplied by publisher]

Prenatal diagnosis of congenital heart defect by genome-wide high resolution SNP array.

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Prenatal diagnosis of congenital heart defect by genome-wide high resolution SNP array.

Prenat Diagn. 2014 Apr 9;

Authors: Can L, Li R, Fu F, Xie G, Zhang Y, Pan M, Li J, Li D

Abstract
OBJECTIVE: To detect genomic imbalances in fetuses with congenital heart defect (CHD) by high resolution SNP array.
METHODS: A total of 99 fetuses with CHDs with or without other ultrasound anomalies (including structural anomalies and soft markers) but normal karyotypes were investigated using Affymetrix CytoScan HD array.
RESULTS: Clinical significant copy number variations (CNVs) were detected in 19 fetuses (19.2%). The proportion for variants of unknown significance was 3% after parental analysis. Five known microdeletion/microduplication syndromes were identified. The detection rate in CHD plus structural anomaly (27.8%) or soft marker (25%) group was higher than but not statistically different from isolated CHD group (15.9%). There was no significant difference between the detection rates in simple and complex CHD groups (20.7% vs 16.7%). The detection rate in fetuses with CHD and neurologic defect was significantly higher than those with other types of structural anomaly (75% vs 14.3%, P < 0.05).
CONCLUSIONS: Our results demonstrated the value of high resolution SNP arrays in prenatal diagnosis of CHD, it should become an integral aspect in clinically molecular diagnosis and genetic counseling. The complexity of the cardiac defect was not related to the frequency of clinical significant CNV, but the presence of neurologic defect was related. This article is protected by copyright. All rights reserved.

PMID: 24718970 [PubMed - as supplied by publisher]

Identification of multiple diagnostic SNP loci for differentiation of three salmonid species using SNP-arrays.

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Identification of multiple diagnostic SNP loci for differentiation of three salmonid species using SNP-arrays.

Mar Genomics. 2014 Apr 2;

Authors: Drywa A, Poćwierz-Kotus A, Dobosz S, Kent MP, Lien S, Wenne R

Abstract
This paper reports the use of SNP-array technology in a cross-species study for non-ambiguous species identifications. Based on an existing SNP-array for Atlantic salmon (cross)hybridisations with samples of salmon, brown trout and rainbow trout were analyzed to identify species-specific diagnostic markers. In total 566 SNP loci were identified to be highly polymorphic across the three salmonid species providing the molecular basement for various monitoring applications in aquaculture and food industries.

PMID: 24703883 [PubMed - as supplied by publisher]

Detection of an activated JAK3 variant and a Xq26.3 microdeletion causing loss of PHF6 and miR-424 expression in myelodysplastic syndromes by combined targeted next generation sequencing and SNP array analysis.

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Detection of an activated JAK3 variant and a Xq26.3 microdeletion causing loss of PHF6 and miR-424 expression in myelodysplastic syndromes by combined targeted next generation sequencing and SNP array analysis.

Pathol Res Pract. 2014 Feb 23;

Authors: Kunze K, Gamerdinger U, Leßig-Owlanj J, Sorokina M, Brobeil A, Tur MK, Blau W, Burchardt A, Käbisch A, Schliesser G, Kiehl M, Rosenwald A, Rummel M, Grimminger F, Hain T, Chakraborty T, Bräuninger A, Gattenlöhner S

Abstract
Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis and progression to acute leukemia. In patients ineligible for hematopoietic stem cell transplantation, azacitidine is the only treatment shown to prolong survival. However, with the availability of a growing compendium of cancer biomarkers and related drugs, analysis of relevant genetic alterations for individual MDS patients might become part of routine evaluation. Therefore and in order to cover the entire bone marrow microenvironment involved in the pathogenesis of MDS, SNP array analysis and targeted next generation sequencing (tNGS) for the mostly therapy relevant 46 onco- and tumor-suppressor genes were performed on bone marrow biopsies from 29 MDS patients. In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified. Moreover, a recurrent microdeletion was detected in Xq26.3 (n=2), causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. Finally, combined genetic aberrations affecting the VEGF/VEGFR pathway were found in the majority of cases demonstrating the diversity of mutations affecting different nodes of a particular signaling network as an intrinsic feature in MDS patients. We conclude that combined SNP array analyses and tNGS can identify established and novel therapy relevant genomic aberrations in MDS patients and track them in a clinical setting for individual therapy selection.

PMID: 24674452 [PubMed - as supplied by publisher]

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