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Abstract
Purpose
Within the Solve-RD project (https://solve-rd.eu/), the ERN-ITHACA (European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies) aimed to investigate whether a reanalysis of exomes from unsolved cases based on ClinVar annotations could establish additional diagnoses. We present the results of the “ClinVar low-hanging fruit” reanalysis, reasons for the failure of previous analyses and lessons learned.
Methods
Data from the first 3,576 exomes (1,522 probands and 2,054 relatives) collected from ERN-ITHACA was reanalyzed by the Solve-RD consortium by evaluating for the presence of SNV/indel already reported as (likely) pathogenic in ClinVar. Variants were filtered on frequency, genotype and mode of inheritance and reinterpreted.
Results
We identified causal variants in 59 cases (3.9%), 50 of them also raised by other approaches and 9 leading to new diagnoses, highlighting interpretation challenges: variants in genes not known to be involved in human disease at the time of the first analysis, misleading genotypes or variants undetected by local pipelines (variants in off-target regions, low quality filters, low allelic balance or high frequency).
Conclusion
The “ClinVar low-hanging fruit” analysis represents an effective, fast and easy approach to recover causal variants from exome sequencing data, herewith contributing to the reduction of the diagnostic deadlock.
Keywords
Article info
Publication history
Accepted:
January 12,
2023
Received in revised form:
January 12,
2023
Received:
March 14,
2022
Publication stage
In Press Accepted ManuscriptIdentification
Copyright
© 2023 Published by Elsevier Inc. on behalf of American College of Medical Genetics and Genomics.
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