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.