Prenatal Cytogenetic Diagnosis by Array-based Copy Number Analysis

The first important goal of this proposal is to learn the natural history and full phenotype of specific copy number variants when discovered during prenatal diagnosis. This information is critical to provide accurate counseling when these findings are discovered in-utero. While phenotypes of many microdeletions and duplications have been described in postnatal case reports, registries or cohort studies, these are inadequate to provide prenatal guidance because the known occurrence of incomplete penetrance and variable expressivity limits accurate and quantitative prenatal prediction since most of the reported cases were identified because of preexisting pathologic phenotypes. The pathologic potential of other prenatally identified copy number variants remains uncertain, since their occurrence in both phenotypically normal and abnormal individuals makes determination of a true biologic effect or a random association difficult to differentiate. This evaluation is further hampered by the strong ascertainment bias that occurs since clinical arrays have been performed predominantly on affected individuals. To answer these questions, we plan to identify and follow individuals with copy number variants identified during prenatal testing. This relatively unbiased ascertainment of array findings will provide the most accurate description of the full spectrum of associated phenotypes and their natural history and will result in the development of the data resources necessary for appropriate counseling. To ascertain the frequency of specific copy number variants in the general prenatal population, results of all prenatal array results (both normal and abnormal) will be ascertained from 10 of the largest prenatal diagnostic centers offering CNA as part of their routine prenatal diagnostic program. Participating clinical centers will keep daily logs of all prenatal testing performed, aCNAs offered, those performed, the indications, and the results. To facilitate infant follow-up, patients with abnormal array results from these centers will be informed of the follow-up study and consented for participation. Using this approach, we will develop a cohort of fetuses who have been identified in-utero to have copy number variants of known or uncertain clinical significance. These infants will be recruited by the clinical center to participate in a follow-up program from birth using a standardized protocol which includes both physical and neurocognitive development. The follow-up program will be coordinated through Columbia University. The second goal of our application is to understand the patient, and provider expectations of prenatal testing of the fetal genome. Prenatal array analysis raises important new questions about the approaches to transmission of genetic information. By the nature of the technology findings of uncertain significance, predictions of adult onset disorders and unanticipated results will occur. It is important to prospectively understand the impact of such findings on both patients and providers and the appropriate requirements for pre and post test counseling. The results of this evaluation will have important implications on prenatal array designs, guidelines for information transmission, and for the development of clinical approaches to minimize patient anxiety. These findings will not only be valuable for prenatal arrays but will form a basis as newer and more detailed testing such as that offered by sequencing moves into clinical care. To understand the educational, counseling and psychosocial requirements