Array comparative genomic hybridization (a-CGH): state of the art and perspective

Abstract

There is convincing evidence suggesting a potential benefit of chromosomal microarray analysis for fetal abnormalities beyond conventional fetal karyotyping [1][2][3][4][5] . Microarray chromosomal genomic hybridization (a-CGH) may provide submicroscopic rearrangements especially duplicated or deleted portion of the DNA also known as copy number variants (CNVs). A limitation of chromosomal microarray analysis is the potential to identify variants of unknown clinical significance (VOUS). This occurred in 3.4% of cases in the NICHD trial. Such results were classified as "likely benign" in 1.8% of cases and "likely pathogenic" in 1.6% 6 . The result may be uncertain because the CNVs may be rare, novel or characterized by variable penetrance. Furthermore, in such cases, a parental search is mandatory to detect a carrier state or a de novo mutation and to calculate recurrent risk in a genetic counseling. Is genetic counseling advice before testing with a-CGH? Should an informed consent be obtained?Pre as well as post-test genetic counseling is mandatory when karyotyping is performed with a-CGH. Patients must be counseled concerning the incidence of VOUS, identification of diseases with variable clinical presentation, identification of consanguinity and/or non-paternity as well as adult-onset diseases. It is mandatory that healthcare givers do not performed the testing before genetic counseling and signed informed consent. In addition, as the amount of information depends by the type of array technique used and laboratory policy 7 , it is essential that doctors as well as patients be informed about this. Notwithstanding, the NICHD trial have demonstrated that women who received abnormal results reported a need for extensive support and counseling while referring a lack of good understanding of the potential for uncertain results 8 . Is there evidence to indicate that a-CGH should be performed in all cases as integrated prenatal karyotyping testing when fetal malformations are detected on ultrasound?Array chromosomal genomic hybridization (a-CGH) studies performed in fetuses with sonographic anomalies and normal karyotype have demonstrated to detect clinically significant CNVs in 2% of cases 9 . Moreover, when rapid fetal karyotyping is clinically indicated, oligonucleotide a-CGH for direct analysis of uncultured amniocytes has shown to be feasible. The use of oligonucleotide arrays increases the sensitivity and accuracy of detection over previous bacterial artificial chromosome (BAC)-based arrays and shorter reporting time 10 . In a series of 162 fetuses with sonographic anomalies of whom 6.8% had abnormal karyotype and 23.7% had abnormal

408 kb 15q11.2 microduplication by array comparative genomic hybridization in a fetus presenting with exomphalos, micrognathia, tetralogy ofFallot and normal karyotype: A genetic counseling dilemma in paternal carrier status

“…In Italy, the laboratory costs are approximately 283 € for a genetic amniocentesis, 553 € for chorionic villus sampling (CVS) and 1013 € for a‐CGH (Tonni et al. ).…”

“…In those cases that finding could be associated with parental anxiety and problematic genetic counseling (McGillivray et al 2012). In Italy, the laboratory costs are approximately 283 € for a genetic amniocentesis, 553 € for chorionic villus sampling (CVS) and 1013 € for a-CGH (Tonni et al 2014).…”