Abstract
Purpose. To design and validate a prenatal chromosomal microarray testing strategy that moves away from size-based detection thresholds, towards a more clinically relevant analysis, providing higher resolution than G-banded chromosomes but avoiding the detection of copy number variants (CNVs) of unclear prognosis that cause parental anxiety.Methods. All prenatal samples fulfilling our criteria for karyotype analysis (n = 342) were tested by chromosomal microarray and only CNVs of established deletion/duplication syndrome regions and any other CNV >3 Mb were detected and reported. A retrospective full-resolution analysis of 249 of these samples was carried out to ascertain the performance of this testing strategy.Results. Using our prenatal analysis, 23/342 (6.7%) samples were found to be abnormal. Of the remaining samples, 249 were anonymized and reanalyzed at full-resolution; a further 46 CNVs were detected in 44 of these cases (17.7%). None of these additional CNVs were of clear clinical significance.Conclusion. This prenatal chromosomal microarray strategy detected all CNVs of clear prognostic value and did not miss any CNVs of clear clinical significance. This strategy avoided both the problems associated with interpreting CNVs of uncertain prognosis and the parental anxiety that are a result of such findings.
Highlights
Implementation of chromosomal microarray analysis (CMA) for prenatal testing continues to be debated and no international consensus has been reached
We feel that the advantage of increased resolution offered by CMA over G-banded karyotype analysis must be balanced against the potential distress and anxiety caused to a couple by reporting copy number variants (CNVs) of unknown significance, and/or incidental findings of clinical significance but of no relevance to the fetal abnormalities
A recent survey of prenatal genetic counselors showed that the majority (57%) were uncomfortable helping patients decide about pregnancy termination following uncertain results (Bernhardt et al, 2014)
Summary
Implementation of chromosomal microarray analysis (CMA) for prenatal testing continues to be debated and no international consensus has been reached. We feel that the advantage of increased resolution offered by CMA over G-banded karyotype analysis must be balanced against the potential distress and anxiety caused to a couple by reporting CNVs of unknown significance, and/or incidental findings of clinical significance but of no relevance to the fetal abnormalities. This stance holds true within the context of a state-funded healthcare system such as that in the UK, where funds are limited and there is an emphasis on clinical and cost effectiveness of any diagnostic test, within the context of the whole healthcare service. This is not the only study to highlight the issues around unclear results and to suggest that more training and education is required (Mikhaelian et al, 2013)
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