Array CGH in patients with developmental delay or intellectual disability: are there phenotypic clues to pathogenic copy number variants?

Abstract

Array comparative genomic hybridization (array CGH) is now widely adopted as a first-tier clinical diagnostic test in individuals with unexplained developmental delay/intellectual disability (DD/ID) and congenital anomalies. Our study aimed at enlarging the phenotypic spectrum associated with clinically relevant copy number variants (CNVs) as well as delineating clinical criteria, which may help separating patients with pathogenic CNVs from those without pathogenic CNVs. We performed a retrospective review of clinical and array CGH data of 342 children with unexplained DD/ID. The phenotypic features of patients with clinically significant CNV were compared with those without pathogenic CNVs. Array CGH detected pathogenic CNVs in 13.2% of the patients. Congenital anomalies, especially heart defects, as well as primary microcephaly, short stature and failure to thrive were clearly more frequent in children with pathogenic CNVs compared with children with normal array CGH results. Thus, we assume that in patients with unexplained DD/ID, array CGH will more probably detect a significant CNV if any of these features is part of the patient's phenotype.

Application of chromosomal microarrays in the evaluation of intellectual disability/global developmental delay patients – A study from a tertiary care genetic centre in India

“…In the present study in pathogenic cases a higher prevalence of deletions compared to duplications (13 deletions versus 7 duplications) was found in concordance with previous studies 13,15,16,17 . This could be due to lower frequency of random duplications than deletions in the genome.…”

Predictive diagnostic value for the clinical features accompanying intellectual disability in children with pathogenic copy number variations: a multivariate analysis

“…Our results confirm that severe phenotypes characterized by the presence of malformations and dysmorphisms associated with DD/ID are causally related to the presence of CNVs, as previously demonstrated [10,21]; moreover, the analysis predicts the likelihood to detect a pathogenic genomic alteration, attributing a 3.3-fold increase to the presence of dysmorphic features and a 5.3-fold to the malformations (Table 4), thus reaffirming the importance of a thorough phenotypic characterization of the patients undergoing a-CGH analysis for maximizing the results [10]. …”

The clinical utility of molecular karyotyping for neurocognitive phenotypes in a consanguineous population

“…Unlike a regular karyotype that relies on the microscopic inspection of chromosomes, molecular karyotyping constructs virtual chromosomes based on the copy-number analysis of DNA, which improves its resolution by 100-fold. 5 Like any other test, there are limitations: microarray platforms cannot identify truly balanced chromosomal rearrangements or point mutations, and low-level mosaicism for unbalanced rearrangements and aneuploidy may not be detected. 3 Furthermore, with the increasing recognition of the pervasiveness of copy-number polymorphisms, as well as the recent realization that reduced penetrance of some pathogenic copy-number variants (CNVs) can influence the clinical phenotype, assigning pathogenicity to CNVs that are uncovered at an increasingly high resolution by molecular karyotyping can be very challenging.…”