SPECIAL ARTICLE OFFICIAL JOURNAL www.hgvs.org Genome-Wide Arrays: Quality Criteria and Platforms to be Used in Routine Diagnostics Joris R. Vermeesch, 1 Paul D. Brady, 1 Damien Sanlaville, 2 Klaas Kok, 3 and Rosalind J. Hastings 4 1 Laboratory for Cytogenetics and Genome Research, Centre for Human Genetics, KU Leuven, University Hospital Leuven, Leuven, Belgium; 2 HCL, Cytogenetics Department and INSERM U1028, CNRS UMR5292, TIGER Team, Lyon Neuroscience Research Centre, Lyon, France; 3 Department of Genetics, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands; 4 CEQA and UK NEQAS for Clinical Cytogenetics, Women’s Centre, Oxford University Hospitals NHS Trust, Oxford, United Kingdom For the Focus on CNV Detection with Diagnostic Arrays Received 8 November 2011; accepted revised manuscript 9 February 2012. Published online 13 March 2012 in Wiley Online Library (www.wiley.com/humanmutation).DOI: 10.1002/humu.22076 ABSTRACT: Whole-genome analysis using genome-wide arrays, also called “genomic arrays,” “microarrays,” or “arrays,” has become the first-tier diagnostic test for pa- tients with developmental abnormalities and/or intellec- tual disabilities. In addition to constitutional anomalies, genomic arrays are also used to diagnose acquired dis- orders. Despite the rapid implementation of these tech- nologies in diagnostic laboratories, external quality control schemes (such as CEQA, EMQN, UK NEQAS, and the USA QA scheme CAP) and interlaboratory comparisons show that there are huge differences in quality, interpreta- tion, and reporting among laboratories. We offer guidance to laboratories to help assure the quality of array exper- iments and to standardize minimum detection resolution, and we also provide guidelines to standardize interpreta- tion and reporting. Hum Mutat 33:906–915, 2012. C  2012 Wiley Periodicals, Inc. KEY WORDS: molecular karyotyping; array CGH; SNP array; copy number variation; genomic array; genome- wide array; quality criteria Introduction Following the discovery that specific developmental disorders are associated with chromosomal abnormalities, genome-wide analysis for chromosomal rearrangements and imbalances became a routine test in the genetic diagnosis of patients with developmental dis- orders. For nearly five decades, conventional karyotyping was the only method to perform such an analysis, although over this pe- riod cytogenetics has seen some major improvements. In the 1960s, only whole-chromosomal imbalances or large segmental rearrange- ments could be detected. With the invention of chromosomal band- ing techniques, the resolution increased dramatically, and it became possible to associate smaller imbalances with novel developmental disorders. The introduction of improved banding resolution as well ∗ Correspondence to: Joris Vermeesch, Laboratory for Cytogenetics and Genome Research, Centre for Human Genetics, KU Leuven, UZ Leuven, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail: joris.vermeesch@uzleuven.be as several novel banding techniques has led to different levels of quality in the diagnoses made by different laboratories. This obser- vation led to the development of guidelines and quality criteria for laboratories (e.g., European Cytogenetic Guidelines, 2006; Associa- tion for Clinical Cytogenetics Professional Guidelines, 2007, 2009). Although conventional karyotyping has been the gold standard for many years, this technology has several limitations: (1) the resolu- tion is limited to the level of the banding quality; (2) it requires short-term culture of the patient sample, which is time-consuming and can lead to selective advantage of specific cell lines; and (3) the technical skills required for karyotyping are substantial and the analyses are time-consuming. With the development of genome-wide arrays, these limitations have been largely overcome. DNA is usually isolated from a blood sample, but can also be obtained from other cell types, and the analysis can be performed in less than 5 days. Arrays enable the de- tection of genomic gains and losses with unprecedented resolution, and allow for a higher degree of automation. Most importantly, the use of genome-wide arrays has significantly improved the diagnostic yield over conventional karyotyping in patients with developmen- tal delay, intellectual disability, multiple congenital anomalies, and autism [Menten et al., 2006; Stankiewicz and Beaudet, 2007]. This led to an international consensus statement that genome-wide ar- rays should be used in the diagnostic workup of such patients [Miller et al., 2010] and, as a consequence, more diagnostic laboratories are now introducing genomic microarrays as the first-tier test or as a supplementary test. Although there is consensus that microarrays should be intro- duced, individual laboratories are confronted with many practical questions on how to implement this novel technology. Over the last few years, many different array platforms have been offered commercially by a plethora of providers. Each platform is different and the underlying methodology also differs, affecting the ability to detect different-sized imbalances. Confronted with these differ- ences, it is not easy to choose between the options available. Each laboratory has the freedom to choose a platform, providing that it fulfils their minimum criteria. In addition, each laboratory is re- sponsible for ensuring the analytical validity of the technique used before introducing it into its routine diagnostic service. To assist in the standardization of the tests applied in different genetic cen- ters and to assure a similar quality of interpretation, the American College of Medical Genetics has recently developed standard guide- lines [Kearney et al., 2011a, 2011b]. Our aim here is to complement and reinforce those efforts by presenting a European consensus on the recommended minimum analytical and reporting criteria, C  2012 WILEY PERIODICALS, INC.