Clinical Implementation of Chromosomal Microarray Analysis: Summary of 2513 Postnatal Cases

Abstract

BackgroundArray Comparative Genomic Hybridization (a-CGH) is a powerful molecular cytogenetic tool to detect genomic imbalances and study disease mechanism and pathogenesis. We report our experience with the clinical implementation of this high resolution human genome analysis, referred to as Chromosomal Microarray Analysis (CMA).Methods and FindingsCMA was performed clinically on 2513 postnatal samples from patients referred with a variety of clinical phenotypes. The initial 775 samples were studied using CMA array version 4 and the remaining 1738 samples were analyzed with CMA version 5 containing expanded genomic coverage. Overall, CMA identified clinically relevant genomic imbalances in 8.5% of patients: 7.6% using V4 and 8.9% using V5. Among 117 cases referred for additional investigation of a known cytogenetically detectable rearrangement, CMA identified the majority (92.5%) of the genomic imbalances. Importantly, abnormal CMA findings were observed in 5.2% of patients (98/1872) with normal karyotypes/FISH results, and V5, with expanded genomic coverage, enabled a higher detection rate in this category than V4. For cases without cytogenetic results available, 8.0% (42/524) abnormal CMA results were detected; again, V5 demonstrated an increased ability to detect abnormality. Improved diagnostic potential of CMA is illustrated by 90 cases identified with 51 cryptic microdeletions and 39 predicted apparent reciprocal microduplications in 13 specific chromosomal regions associated with 11 known genomic disorders. In addition, CMA identified copy number variations (CNVs) of uncertain significance in 262 probands; however, parental studies usually facilitated clinical interpretation. Of these, 217 were interpreted as familial variants and 11 were determined to be de novo; the remaining 34 await parental studies to resolve the clinical significance.ConclusionsThis large set of clinical results demonstrates the significantly improved sensitivity of CMA for the detection of clinically relevant genomic imbalances and highlights the need for comprehensive genetic counseling to facilitate accurate clinical correlation and interpretation.

NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype

“…Microduplication of 17q11.2 may be associated with a nonspecific phenotype; ID/ DD and dysmorphic features were the only clinical features common to a majority of cases in our study and previous studies ( Table 1). 22,23 The only other features present in more than one nonrelated individual in our cohort and the cases in the literature are short stature, failure to thrive, microcephaly, and seizures ( Table 1). 22,23 One of our subjects had small teeth, while the family reported by Grisart et al 22 had dental enamel hypoplasia.…”

“…22,23 The only other features present in more than one nonrelated individual in our cohort and the cases in the literature are short stature, failure to thrive, microcephaly, and seizures ( Table 1). 22,23 One of our subjects had small teeth, while the family reported by Grisart et al 22 had dental enamel hypoplasia. Premature balding, present in the previously reported family, was not present in our cohort, which may be due to the relative younger ages of the subjects.…”

“…No NF1 microduplications have been reported in two different series of Grisart et al 22 Lu et al 23 Age at diagnosis 13 y …”

“…This microduplication has also been reported in one case from a series of 2,513 patients undergoing clinical microarray-based comparative genomic hybridization (aCGH); the individual was referred for DD/ID, failure to thrive, and microcephaly. 23 Here we report the characterization of seven nonrelated individuals with NF1 microduplications to help clarify the clinical significance of these copy-number alterations. L R R C 3 7 B P 1 All 17q11.2 duplications were initially identified by aCGH using various microarray platforms.…”

Comparison of chromosome analysis and chromosomal microarray analysis: what is the value of chromosome analysis in today’s genomic array era?

“…FISH analysis was performed to confirm the CMA results as described previously. 3 For a copy number loss, five metaphase cells were examined. For a copy number gain, 50 nuclei were examined independently by two technologists in addition to an examination of at least one metaphase cell to rule out a translocation or an insertion of the gained material.…”