Variant-specific RNA testing resolves variants of uncertain significance in exome testing.

Authors

Audrey K O'Neill, Grace E VanNoy, Brooklynn Gasser, Jessica Gage, Jessica Grzybowski, Carolyn Horton, Melissa Holman, Claire Watson, Shoji Ichikawa, Changrui Xiao, Dana Mittag, Edwin C Ferren, Erika Levine, Mafalda Barbosa, Joseph Biddle, Laurie Sadler, Melissa Samons, Heather Zimmermann, Marcy E Richardson

Published in

BMC genomics. Volume 27. Issue 1. Jul 01, 2026. Epub Jul 01, 2026.

Abstract

Variants of uncertain significance (VUS) are a substantial barrier to clinical care in genetics, and VUS that are suspected to affect splicing can be particularly difficult to resolve. We used exome sequencing (ES) followed by variant-specific RNA testing to resolve VUS in four separate cases resulting in reclassification to Likely Pathogenic and a positive molecular diagnosis in all cases.
The variants in these cases include a homozygous variant in ATP6V0A2 in a trio exome case, heterozygous variants in SLC20A2 and in CSF1R in adult proband-only cases, and a heterozygous variant in COL1A1 in a family. All variants were associated with aberrant splicing resulting in loss of function or a major alteration to the protein sequence.
These findings demonstrate the power of targeted RNA testing for reclassifying VUS that have limited direct evidence across a broad range of indications for exome testing.

PMID:
42380775
Bibliographic data and abstract were imported from PubMed on 13 Oct 2026.

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