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 array-based 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.

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