Product Description:
Chromosomal microarray has a significantly higher diagnostic yield than conventional cytogenetics among patients with unexplained developmental delay and/or multiple congenital anomalies and has become the first tier testing for this patient cohort. A substantial number of investigations, however, result in novel copy number changes of uncertain clinical significance presenting a formidable challenge in establishing the clinical implications of these findings. For most cases, the standard testing algorithm involves parental studies to determine inheritance patterns. Customarily, the copy number change is interpreted as 'benign' if the aberration is inherited from an 'apparently' normal parent. Our report focuses on cases with initial microarray findings of uncertain clinical significance and subsequent classification of these cases after parental studies. In the past 2 years, our laboratory has performed 2540 post-natal microarray investigations utilizing a customized 44,000 oligonucleotide array. We detected a significant copy number change in 551/2540 (21.6%) cases and 400/2540 (15.7%) were reported as causative for the patient?s phenotype. In 151/2540 (5.9%) cases, the copy number change was associated with uncertain clinical significance. The majority of these aberrations were in regions of genome previously not associated with a known syndrome, contained one or more genes and showed little or no overlap with the public and internal databases. All cases had a normal karyotype and harbored cryptic deletions or duplications ranging in size from 94Kb-2.27 Mb. Parental studies were accomplished in 54 of these 151 cases; 3 were de novo aberrations and in 51 cases, the abnormality was inherited. Of the 51 familial studies, 38 (74.6) had alterations that were classified benign in the proband following parental studies, 6 studies (11.7%) remained uncertain and 7 (13.7%) familial aberrations were subsequently determined to be of probable clinical relevance in the proband because the "carrier" parent and/or other family member(s) had a clinical history of a condition similar to the child. A total of 25.4% of our cases were classified as either uncertain or abnormal after parental studies. Thus, our report underscores the importance of collecting precise family history and accurate clinical information in addition to detailed communication with the provider when interpreting inherited copy number changes of uncertain clinical significance.
