Detection rates of clinically significant genomic alterations by microarray analysis for specific anomalies detected by ultrasound

Abstract

ObjectiveThe aim of this study is to understand the diagnostic utility of comparative genomic hybridization (CGH)-based microarrays for pregnancies with abnormal ultrasound findings.MethodsWe 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.ResultsClinically 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%).ConclusionsMicroarray 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.

ACOG and SMFM guidelines for prenatal diagnosis: Is karyotyping really sufficient?

“…Our data show that at least 4.7% of patients with 1 or more fetal structural abnormalities have a clinically significant microarray abnormality that would have been missed by karyotype analysis, similar to previous reports 3, 5, 6, 7. Additionally, at least 2.5% of patients whose indication did not include a structural fetal abnormality had a CSCA detected by CMA that would have been missed by karyotyping alone.…”

Limited Clinical Utility of Non-invasive Prenatal Testing for Subchromosomal Abnormalities

“…A previous study showed that microarray analysis detected clinically significant CNVs,~75% of which were smaller than 10 Mb, in up to 6.5% of fetuses with an ultrasound abnormality and normal karyotype. 2 No comprehensive data currently give the true incidence of pathogenic CNVs < 6 Mb, and thus it is difficult to determine exactly what proportion of CNVs would be missed, but it is clear that a significant number would not be detected. Comparing the efficacy of the different diagnostic techniques and determining the limits of detection would require a very large prospective study comparing NIPT and microarray analysis.…”

“…[6][7][8] Over the same time period, there has been a move to replace traditional karyotyping following invasive testing with microarray analysis 9 , which increases detection of pathogenic chromosomal rearrangements to include microdeletion and microduplication syndromes. 1,2,4 There are concerns that widespread implementation of NIPT stands to decrease the detection of these other pathogenic rearrangements. 10 However, in principle, sequencing of cfDNA can also be used for detecting other unbalanced chromosomal rearrangements prenatally, and a number of proof-of-concept studies using a variety of sequencing depths and bioinformatics approaches have detected a range of fetal subchromosomal abnormalities in maternal plasma.…”

“…Although the overall incidence is unknown, it is thought that the combined incidence might approach that of Down syndrome (trisomy 21 [MIM 190685]). 1,2 The majority of cases occur randomly, but some, for example, those in DiGeorge syndrome (22q11.2 deletion [MIM: 188400]), Cri du chat syndrome (5p deletion [MIM: 123450]), and Charcot-Marie-Tooth type 1A disease (17p11.2 duplication [MIM: 118220]), are recurrent. Unlike Down syndrome, these other rearrangement disorders do not have a universal prenatal screening program, although they might be found more commonly in fetuses with an increased nuchal translucency or other fetal abnormalities.…”

Prenatal SNP array testing in 1000 fetuses with ultrasound anomalies: causative, unexpected and susceptibility CNVs

“…Fetuses with ultrasound abnormalities are known to carry not only the highest percentage of microscopically visible chromosome abnormalities 1-3 but also submicroscopic aberrations. [4][5][6][7][8][9][10][11] Before array implementation, these submicroscopic chromosome aberrations could only be detected if targeted testing was requested in case of specific ultrasound anomalies, for example, 22q11 deletion in fetuses with cardiac defects. 12 However, based on prenatal phenotyping by ultrasound examination, it is not always easy to obtain a clinical diagnosis and to determine which locus/loci should be investigated.…”