Variants of uncertain significance in prenatal microarrays: a retrospective cohort study

Objective: To categorise the variants of uncertain significance found with prenatal chromosomal microarray and determine the proportion of such variants that are associated with a well-known phenotype in order to establish how often they remain truly of uncertain significance.

Design: Retrospective cohort study.

Setting: The University of California, San Francisco.

Population: All patients with a variant of uncertain significance on prenatal microarray between 2014 and 2018.

Methods: Each variant was classified as a copy number variant that (a) contains Online Mendelian Inheritance in Man (OMIM)-annotated disease-causing genes ('OMIM morbid genes'); (b) confers autosomal recessive carrier status; (c) is associated with incomplete penetrance; (d) is >1 Mb in size without OMIM morbid genes; (e) demonstrates mosaicism; or (f) contains significant regions of homozygosity. For each variant of uncertain significance, we examined the existing literature to determine whether the predicted phenotype(s) was known.

Main outcome measure: Prevalence and classification of variants and how much information is available regarding the likelihood of an affected phenotype.

Results: Of 970 prenatal microarrays, 55 (5.8%) had at least one variant of uncertain significance. The most common were copy number variants containing OMIM morbid genes (36.8%). In all, 48 (84.2%) were associated with a known phenotype; 55 (96.5%) had data available regarding the likelihood of an affected phenotype.

Conclusions: The prevalence of variants of uncertain significance with prenatal microarray was 5.8%. In the large majority of cases, data were available regarding the predicted phenotype.

Tweetable abstract: Variants of uncertain significance occur in 5.8% of prenatal microarrays. In the overwhelming majority of cases, outcome information is available.