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Background <p>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.</p> Results <p>The variants in these cases include a homozygous variant in <i>ATP6V0A2</i> in a trio exome case, heterozygous variants in <i>SLC20A2</i> and in <i>CSF1R</i> in adult proband-only cases, and a heterozygous variant in <i>COL1A1</i> in a family. All variants were associated with aberrant splicing resulting in loss of function or a major alteration to the protein sequence.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月1日

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  • 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

摘要

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.