Usefulness of copy number variant detection following monogenic disease exclusion in prenatal diagnosis

Aim: Families with an adverse history of monogenic disease focus on single-gene diagnosis instead of low-depth whole-genome sequence, during subsequent pregnancies. The aim of this study was to assess the potential usefulness of low-depth whole-genome sequencing (copy number variant sequencing [CNV-seq]) detection following monogenic disease exclusion in prenatal diagnosis.

Methods: A total of 285 families with a history of monogenic disease (of 41 different types; eliminated during the current pregnancy) were recruited and retrospectively analyzed. Low-depth whole-genome sequencing (CNV-Seq, Next-Seq CN500 platform) was performed for all fetuses.

Results: The CNV detection results of the 285 samples were as follows: one case of 18-trisomy chimera (0.35%), one case of pathogenic 3q29 microdeletion syndrome CNV (0.35%), four cases of variant of uncertain significance (VUS) CNVs (1.40%), and four cases of Duchenne muscular dystrophy (DMD) carriers (1.40%); and the remaining samples were normal (96.15%). Of note, 2/285 (0.70%) samples still exhibited pathogenic abnormalities. All positive samples were followed up where the two cases of pathogenic abnormalities elected the pregnancy termination, while the four VUS cases and four DMD-carrier cases were born healthy.

Conclusion: In cases where prenatal fetal monogenic disease has been ruled out, CNV detection is still beneficial and should be performed to prevent missed pathogenic CNVs. However, the costs need to be balanced against benefits, and the research will need to assess other types of testing.