Underdiagnoses resulting from variant misinterpretation: Time for systematic reanalysis of whole exome data?

Fathiya AL-Murshedi, Douja Meftah, Patrick Scott*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

18 Citations (Scopus)


Background: Clinical whole exome sequencing (WES) yields a diagnosis in approximately 30% of patients evaluated for presumed genetic disorders. For unsolved cases, periodic reanalysis is usually predicated on the availability of improved bioinformatics tools or new gene discoveries. Methods: Exome data reanalysis was independently performed on unsolved cases that had underwent trio analysis by an external service provider. The retrieved exome data was reannotated using wANNOVAR and reanalysed following standard filtering criteria. Results: Independent reanalysis led to the identification of a disease-causing variation in two families segregating predominantly a neurological phenotype. As the causative genes were relatively well established at the time the WES referral was made, misinterpretation of the functional impact of the variant and/or underappreciation of the gene's associated phenotype are the most probable causes of the discrepancy in reporting. Conclusion: Non-diagnostic clinical exome resulting from variant misinterpretation is probably under appreciated. These results emphasise the relevance of implement a policy for the reanalysis of high-throughput sequencing data, especially in a clinical context given the implications.

Original languageEnglish
JournalEuropean Journal of Medical Genetics
Publication statusAccepted/In press - Jan 1 2018


  • Diagnostic yield
  • Unsolved exomes
  • Variation assessment

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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