Chromosomal Microarray Analysis Results From Pregnancies With Various Ultrasonographic Anomalies

Our prenatal genetics group routinely counsels patients with fetal ultrasonographic abnormalities. We read the article on prenatal chromosomal microarrays in the December 2018¹ issue and were reassured that the diagnostic rate was 2.7% above the karyotypic rate in this large and broad cohort of ultrasonographic findings. Although lower than the previously reported 6% diagnostic rate of prenatal microarray in the anomalous fetus,² the diagnostic yield in your cohort provides continued evidence of the benefits of prenatal microarray. Raising concern, however, is the reported variant of uncertain significance rate of 5.8%. One of the most challenging aspects of pretest genetic counseling for patients considering prenatal microarray is the possibility of unclear results and the potential psychological implications of ambiguous findings prenatally. Although the diagnostic benefits of prenatal microarray over karyotype analysis have been well demonstrated in anomalous and nonanomalous prenatal populations alike, the potential psychological harm and pregnancy management implications attributed to variant of uncertain significance results are significant considerations in prenatal genetic counseling. Neither the high variant of uncertain significance rate, how or whether these were disclosed to patients, nor the complexities of posttest counseling in the setting of such results are fully addressed in the Materials and Methods or Discussion sections of the article. In the context of fetal anomalies for which microarray is indicated, this counseling should include discussion of the possibility of a variant of uncertain significance result,³ which Wapner et al² reported as 1.6%. Our cytogenetic laboratory, which follows similar guidelines for reporting variant of uncertain significance of copy number losses greater than 1 Mb or copy number gains greater than 2 Mb, has a 3% prenatal variant of uncertain significance rate.

Several publications have suggested a lower variant of uncertain significance rate owing to the recent generation of phenotypic information that has allowed for reclassification of copy number variants that were previously classified as variant of uncertain significance.^4,5 Because your study spanned from 2013 to 2017, we are curious whether there were trends in variant of uncertain significance frequency throughout the course of your study period. Before publication, were variant of uncertain significance results examined for possible reclassification? Reclassification may affect your rate of pathogenic copy number variants and variant of uncertain significance results to demonstrate a yield more comparable with previously reported diagnostic and variant of uncertain significance rates.