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Objective: To test the hypothesis that chromosomal microarray analysis frequently diagnoses conditions that require specific medical follow-up and that referring physicians respond appropriately to abnormal test results., Methods: A total of 46,298 postnatal patients were tested by chromosomal microarray analysis for a variety of indications, most commonly intellectual disability/developmental delay, congenital anomalies, dysmorphic features, and neurobehavioral problems. The frequency of detection of abnormalities associated with actionable clinical features was tallied, and the rate of physician response to a subset of abnormal tests results was monitored., Results: A total of 2088 diagnoses were made of more than 100 different disorders that have specific clinical features that warrant follow-up. The detection rate for these conditions using high-resolution whole-genome microarrays was 5.4%, which translates to 35% of all clinically significant abnormal test results identified in our laboratory. In a subset of cases monitored for physician response, appropriate clinical action was taken more than 90% of the time as a direct result of the microarray finding., Conclusions: The disorders diagnosed by chromosomal microarray analysis frequently have clinical features that need medical attention, and physicians respond to the diagnoses with specific clinical actions, thus arguing that microarray testing provides clinical utility for a significant number of patients tested.

Objective: The aim of this study is to understand the diagnostic utility of comparative genomic hybridization (CGH)-based microarrays for pregnancies with abnormal ultrasound findings., Methods: We performed a retrospective analysis of 2858 pregnancies with abnormal ultrasounds and normal karyotypes (when performed) tested in our laboratory using CGH microarrays targeted to known chromosomal syndromes with later versions providing backbone coverage of the entire genome. Abnormalities were stratified according to organ system involvement. Detection rates for clinically significant findings among these categories were calculated., Results: Clinically significant genomic alterations were identified in cases with a single ultrasound anomaly (n = 99/1773, 5.6%), anomalies in two or more organ systems (n = 77/808, 9.5%), isolated growth abnormalities (n = 2/76, 2.6%), and soft markers (n = 2/77, 2.6%). The following anomalies in isolation or with additional anomalies had particularly high detection rates: holoprosencephaly (n = 9/85, 10.6%), posterior fossa defects (n = 21/144, 14.6%), skeletal anomalies (n = 15/140, 10.7%), ventricular septal defect (n = 14/132, 10.6%), hypoplastic left heart (n = 11/68, 16.2%), and cleft lip/palate (n = 14/136, 10.3%)., Conclusions: Microarray analysis identified clinically significant genomic alterations in 6.5% of cases with one or more abnormal ultrasound findings; the majority were below the resolution of karyotyping. Larger data sets such as this allow for sub-stratification by specific anomalies to determine risks for genomic alterations detectable by microarray analysis., (© 2012 John Wiley & Sons, Ltd.)

Objective: To develop a novel, rapid prenatal assay for pregnancies with high likelihood of normal karyotypes, using BACs-on-Beads(™) technology, a suspension array-based multiplex assay that employs Luminex(®) xMAP(®) technology, for the detection of gains and losses in chromosomal DNA., Methods: Fifteen relatively common microdeletions were selected that are not detectable, or may be missed, by karyotyping and usually do not present with abnormal ultrasound findings. Chromosomes 13, 18, 21, X, and Y were included. We validated the assay with 430 samples., Results: All microdeletions and aneuploidies were correctly identified, except for a 69,XXX incorrectly identified as a normal female and a male with ∼20% maternal cell contamination (MCC) that could not be distinguished from 69,XXY. MCC became apparent at 20 to 30%. Mosaicism was identified at 30 to 35% abnormal cells., Conclusion: We have developed an alternative to fluorescence in situ hybridization (FISH) aneuploidy screening and microarray analysis in otherwise normal pregnancies undergoing invasive testing. We demonstrated that the assay will detect all microdeletions and aneuploidies of regions covered on the assay. We developed analytical software that displays results for well-characterized syndromes but not abnormalities of unclear clinical significance. This assay is likely to be preferred by women seeking testing beyond routine karyotyping but who desire more information than provided by aneuploidy FISH., (Copyright © 2011 John Wiley & Sons, Ltd.)

Objective: To determine the detection rates of whole-genome microarray technology compared to targeted microarray analysis for chromosome abnormalities in prenatal samples submitted for diagnostic testing., Methods: Microarray analysis using either whole-genome bacterial artificial chromosome (BAC)-based and oligonucleotide (oligo)-based microarrays or targeted BAC microarrays was performed on 182 and 62 prenatal cases, respectively, from North American healthcare providers without previously known chromosome abnormalities or family history of a parent with a known chromosome rearrangement., Results: Microarray analysis identified clinically significant chromosome alterations in 7 out of 182 (3.8%) prenatal specimens, two of which each had two unrelated abnormalities. After excluding two of the cases in which the abnormality would have been identified by routine karyotyping, the diagnostic yield of clinically significant findings was 5 out of 182 (2.7%). One case had a finding of unclear significance (0.5%) and 16 cases had benign copy number variants (CNVs) (8.8%). Targeted microarray analysis combined with previously published data demonstrated detection rates of 0.9% for clinically significant results, 0.5% for results of unclear significance, and 8.0% for benign CNVs., Conclusions: Whole-genome prenatal aCGH detected clinically significant submicroscopic chromosome abnormalities in addition to chromosome abnormalities that could be identified by concurrent karyotyping without an increase in unclear results or benign CNVs compared to targeted aCGH.