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Background <p>Sequencing reanalysis can benefit from the inclusion of new information about the patient and from the literature. We studied approaches needed to make reanalysis part of routine follow-up by clinical geneticists.</p> Methods <p>Reanalysis used the SimulConsult diagnostic decision support software, which generates a pertinence metric for gene zygosities determined from the variant table and the patient’s findings. Twenty patients had routine exome sequencing at St. George’s Hospital (London, UK). Twenty were admitted to the Undiagnosed Diseases Network at Vanderbilt University Medical Center (VUMC) and had all remained undiagnosed despite previous evaluations and sequencing.</p> Results <p>For St. George’s cases, reanalysis picked 7 of the 7 initial diagnoses plus 2 diagnoses found later, and suggested another diagnosis with a gene absent from the variant table. For VUMC, reanalysis picked 5 of 8 diagnoses that were in the variant tables, and suggested a non-coding variant absent from the variant table.</p> Conclusion <p>Rapid reanalysis by clinicians could increase the yield of genetic diagnosis with minimal effort and no new lab expenses. For the routine cases at St. George’s, diagnostic yield increased from 7 to 10 (43%). Capabilities that could further increase yield include joint variant calling, robust phenotyping, clinical correlation after sequencing, and adding CNV data to variant tables.</p>

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Defining an approach to empower clinical geneticists to do genomic reanalysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月5日

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  • Michael M. Segal,
  • Meriel McEntagart,
  • Alexander T. Deng,
  • Andrea Haworth,
  • Brian King,
  • Anthony Rogers,
  • John Filby,
  • John Short,
  • Mary Grace Hash,
  • Lynette C. Rives,
  • Kimberly M. Ezell,
  • John A Phillips III

摘要

Background

Sequencing reanalysis can benefit from the inclusion of new information about the patient and from the literature. We studied approaches needed to make reanalysis part of routine follow-up by clinical geneticists.

Methods

Reanalysis used the SimulConsult diagnostic decision support software, which generates a pertinence metric for gene zygosities determined from the variant table and the patient’s findings. Twenty patients had routine exome sequencing at St. George’s Hospital (London, UK). Twenty were admitted to the Undiagnosed Diseases Network at Vanderbilt University Medical Center (VUMC) and had all remained undiagnosed despite previous evaluations and sequencing.

Results

For St. George’s cases, reanalysis picked 7 of the 7 initial diagnoses plus 2 diagnoses found later, and suggested another diagnosis with a gene absent from the variant table. For VUMC, reanalysis picked 5 of 8 diagnoses that were in the variant tables, and suggested a non-coding variant absent from the variant table.

Conclusion

Rapid reanalysis by clinicians could increase the yield of genetic diagnosis with minimal effort and no new lab expenses. For the routine cases at St. George’s, diagnostic yield increased from 7 to 10 (43%). Capabilities that could further increase yield include joint variant calling, robust phenotyping, clinical correlation after sequencing, and adding CNV data to variant tables.