Parental Studies of 2,248 Chromosomal Microarray Analysis (CMA) Cases -Role of parental studies in facilitating the interpretation of copy number variants. W. Bi, J. Pham, J. Denham, E. Roney, A. N. Pursley, P. Stankiewicz, A. Breman, S. Lalani, J. Smith, C. Bacino, A. Patel, S. W. Cheung Baylor College of Medicine, Houston, TX.
Background: As the resolution of clinical arrays has increased, the number of copy number variants (CNVs) of unclear clinical significance (UCS) detected is also increasing. Performing parental studies on every CNV of UCS is not cost-effective; therefore, a systematic study is needed to develop guidelines to determine the type of CNV for which parental studies are most useful for result interpretation. Methods: We retrospectively identified 1710 of the 2248 CMA cases with parental study results where a single CNV was detected from over 16,000 cases evaluated by a V8.1 array with exonic coverage of >1,700 genes and back bone coverage of 30kb/probe. We examined the correlation between the clinical significance, size, and gene content of these CNVs and whether they were inherited or de novo. Results: The CNVs were located on an autosomal chromosome in 1546 cases: 559 abnormal CNVs, many of which have reduced penetrance, 975 variants of UCS, and 12 heterozygous carrier changes. For abnormal CNVs, 56% (80/142) of the gains were inherited, whereas 39% (162/417) of losses were inherited. In contrast, for UCS variants, 96% (627/654) of the gains were familial while 92% (294/321) of the losses were inherited. The UCS CNVs were divided into 2 groups based on size: <0.5 Mb or >0.5 Mb. Of the 405 gains <0.5 Mb, 98% were familial events while 93% were familial for the gains >0.5 Mb. UCS deletions <0.5 Mb were seen in 274 cases, of which 93% were inherited, whereas only 87% of the deletions >0.5 Mb were inherited. Notably, one parent carried the same CNV for 4 of the 5 gains >2 Mb and all 4 of the losses >1 Mb in regions with a paucity of genes. For the 164 CNVs involving chromosome X, 47 abnormal changes, 116 UCS variants, and 1 heterozygous carrier change were detected. Similar to the findings for autosomal chromosomes, the vast majority of UCS variants were inherited (97/100=97% for gains and 16/16=100% for losses). Detailed analysis of the various categories of CNVs will be presented. Conclusions: Our data shows that the vast majority of single UCS gains (<1 Mb) and losses (<0.5 Mb) in both autosomal chromosomes and chromosome X are inherited. Most of these CNVs are within non-disease associated regions and likely represent benign CNVs. Therefore, for single UCS CNVs, one should first consider the size of the CNV and gene content before requesting parental studies as larger gene-rich gains and losses >0.5Mb are most likely to yield informative results.