Array CGH In prenatal diagnosis

Chromosomal abnormalities are the cause of many human genetic disorders. Karyotyping has been for decades the golden standard method for prenatal diagnosis and for the diagnosis of numerical and large structural abnormalities (<3-10Mb). These, if present may result in congenital anomalies, dysmorphism, intellectual disability, autism or other neurological abnormalities. With the introduction of array Comparative Genomic Hybridization (CGH) analysis in postnatal analysis and its use as a first-tier test in cases of Intellectual disabilities, it has been postulated that it might also become the first-tier test in prenatal diagnosis as well. Array CGH, a high throughput, comprehensive and fast technology, has proven its ability to detect subtle copy number changes that can go undetected by light microscopy. Array CGH is a valuable tool for the determination of copy number changes in children with congenital abnormalities and has even replaced karyotyping for certain reasons for referral. Array CGH provides valuable information for phenotypegenotype correlation, as well as more accurate information regarding the clinical significance and the risk in the current and future pregnancy of the respective patient. Another critical factor for accurate Copy Number Variation (CNV) classification is parental testing to determine between familial and de novo CNVs. Appropriate pre and post- test genetic counceling offer the prospective parents tools to decide on the management of their pregnancy. However, one of the problems posing dilemmas to genetic councelors is the fact that it can detect coincidental findings, variants of unknown significance as well as variants with variable expressivity. Array CGH could potentially be used in POC/intrauterine death/stillbirths samples where malformations exist in the fetuses, using the same platform as in prenatal cases, as it offers an increase in detection rate in this category of samples. Furthermore, this method has the advantage to circumvent technical problems associated with tissue culturing which may result in failure of providing results by classical cytogenetics. In prenatal diagnosis chromosomal analysis is still the primary choice of testing; for array CGH to replace it, it has to overcome some of its limitations, such as the detection of CNVs, coincidental or of unclear significance findings. The detection rate in clinically significant copy number changes increases with the application of array CGH in cases where the karyotype is normal and there are sonographic malformations in the fetus. It therefore may be used more extensively in prenatal diagnosis as well. Currently there is a lot of debate whether array CGH should also be introduced in the routine prenatal setting. However, there are still many technical challenges to be overcome such as: .the resolution .the type of platform to be used . ethical issues including coincidental and of unclear significance findings A shared database specifically dedicated to prenatal diagnosis coupled with the growing amount of data regarding CNVs and dosage sensitive genes could make it easier to interpret genomic arrays. Currently international consensus guidelines for the use of array CGH in prenatal diagnosis are still missing.