What question did this study set out to answer?

The study aims to address the challenge of resolving variants of uncertain significance (VUS) in genetic testing.

July 2, 2026BMC Genomics0 citationsOpen Access

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

AOAudrey K. O’Neill GVGrace E. VanNoy BGBrooklynn Gasser

Key Points

The study aims to address the challenge of resolving variants of uncertain significance (VUS) in genetic testing.
Utilized exome sequencing followed by targeted RNA testing for variant classification.
Analyzed variants in four separate cases including ATP6V0A2, SLC20A2, CSF1R, and COL1A1.
Provided reclassification outcomes based on observed splicing effects and protein alterations.
All four cases resulted in reclassification of VUS to likely pathogenic.
Variants were linked to aberrant splicing leading to loss of function or significant protein sequence changes.
Positive molecular diagnosis was achieved for each case after RNA testing.

Abstract

Abstract Background 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. Results 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. Conclusions 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.

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