Curation and reporting of pathogenic genome-wide copy-number variants in a prenatal cell-free DNA screen.

PURPOSE

Advances in fetal fraction amplification in prenatal cell-free DNA screening now allow for high-resolution detection of copy-number variants (CNVs). However, approaches to interpreting CNVs as part of a primary screen are still evolving and require consensus. Here, we present a conservative, patient-centered framework for reporting fetal CNVs.

METHODS

Syndromes described in the literature were evaluated for inclusion based on a definable minimal critical region, disease severity, penetrance, and age of onset. The reporting framework required that a CNV overlap a defined minimal critical region and/or that it be ≥5 Mb and contain at least 1 OMIM disease-associated gene. This framework was then applied to CNVs identified from a cohort of 313,544 prenatal cfDNA screening patient samples. Patient-friendly terminology describing syndrome phenotypes was developed by scientists with training in genetic counseling.

RESULTS

65 syndromes met criteria for inclusion and represented the second most common class of CNVs in a retrospective cohort, more so than an established panel of microdeletions (1p36, 4p, 5p, 15q11.2-q13, and 22q11.2). Frequencies were concordant with reported syndrome incidence rates. The most common CNVs were those ≥5 Mb encompassing an OMIM disease gene(s).

CONCLUSION

This framework for genome-wide fetal-CNV reporting carefully prioritizes findings with the potential to affect reproductive decision making.