Going BAC or oligo microarray to the well: A commentary on Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies


In this issue of the Journal of Human Genetics, Hayashi et al. document the results of their originally designed study of a ‘two-stage screening’ method that uses arraybased comparative genomic hybridization for diagnosing patients who present with both multiple congenital anomalies and mental retardation (MCA/MR).1 They collected DNA samples from 536 patients with MCA/ MR by multicenter cooperation throughout Japan (from Hokkaido to Okinawa). They first screened all samples using the ‘MCG Genome Disorder Array,’ which covers subtelomeric regions and well-known disease-causing regions using 550 or 660 bacterial artificial chromosome (BAC)-based arrays that were originally constructed by them. Next, samples that did not show copy number variation (CNV) in the first stage of screening were screened again using ‘MCG Whole Genome Array-4500,’ which minutely covers all human chromosomes using 4523 bacterial artificial chromosomes at intervals of 0.7 Mb. In the first stage of screening, 54 (10.1%) patients showed CNVs that were confirmed by fluorescence in situ hybridization. In the second stage of screening, 63 (18.0%) of 349 patients demonstrated CNVs, of which 60 cases were confirmed by fluorescence in situ hybridization. The authors classified CNVs found in the second stage of screening into three categories: pathogenic, benign or variant of uncertain clinical significance). Initially, pathogenic CNVs were classified according to the following six criteria: (1) CNVs identified in recently established syndromes; (2) CNVs containing pathogenic gene(s); (3) recurrent CNVs in the same regions; (4) CNVs reported as pathogenic in previous studies; (5) large/gene-rich CNVs or CNVs containing morbid OMIM genes; or (6) de novo CNVs or CNVs that are maternally inherited through the X chromosome. CNVs that did not meet any of these criteria were classified as benign if they were inherited from a parent or as a variant of uncertain clinical significance if parental samples were not available. Consequently, 48 (13.8%) of 349 patients had pathogenic CNVs, 9 (2.6%) had benign CNVs and 6 (1.7%) had a variant of uncertain clinical significance. MR is a highly heterogeneous condition and nearly 2500 syndromes of various congenital abnormalities are associated with MR2 (http://becomerich.lab.u-ryukyu.ac.jp/). It is very difficult to determine the etiology of MR unless characteristic combinations of features can be accurately described, such as upslanted palpebral fissures in Down syndrome, overgrowth in Sotos syndrome, overeating in Prader–Willi syndrome or stereotypical hand movements in Rett syndrome, or unless specific and abnormal findings on laboratory or neuroimaging examinations are found, such as a metabolic screening indicative of phenylketonuria or lysosomal diseases, or brain magnetic resonance imaging indicative of polymicrogyria or lissencephaly. G-banded karyotyping has also been used to diagnose specific syndromes in patients with MCA/MR, and fluorescence in situ hybridizationis also useful for detecting microdeletion or microduplication syndromes; however, it is not easy for general practitioners or even pediatric neurologists to diagnose rare syndromes, such as Potocki– Lupski syndrome (17p11.2 duplication syndrome), Smith–Magenis syndrome (17p11.2 deletion syndrome) or 1p36 deletion syndrome. On the other hand, clinical applications of chromosomal microarrays are rapidly increasing for the diagnosis of congenital anomalies, hematological and solid tumors, and neuropsychological disorders, including MR and autism. In particular, chromosomal microarrays are used to diagnose MCA/MR. The diagnostic yields of chromosomal microarrays for detecting chromosomal aberrations among patients with MCA/MR or MR are only 7–15% in patients with normal G-banded karyotyping, depending on the probe coverage. These yields are much higher than G-banded karyotyping, which shows a yield of less than 3% if Down syndrome and other recognizable chromosomal syndromes are excluded.3 The International Standard Cytogenomic Array Consortium and other groups support the consensus that chromosomal microarray is a first-tier clinical Dr M Kato is at the Department of Pediatrics, Yamagata University Faculty of Medicine, 2-2-2 Iida-nishi, Yamagata 990-9585, Japan. E-mail: mkato@med.id.yamagata-u.ac.jp Journal of Human Genetics (2011) 56, 104–105 & 2011 The Japan Society of Human Genetics All rights reserved 1434-5161/11 $32.00

DOI: 10.1038/jhg.2010.168

Cite this paper

@article{Kato2011GoingBO, title={Going BAC or oligo microarray to the well: A commentary on Clinical application of array-based comparative genomic hybridization by two-stage screening for 536 patients with mental retardation and multiple congenital anomalies}, author={Mitushiro Kato}, journal={Journal of Human Genetics}, year={2011}, volume={56}, pages={104-105} }