A Solve-RD ClinVar-based reanalysis of 1,522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing


Within the Solve-RD project (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.


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.


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).


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.


ClinVar; developmental disorder; exome reanalysis; rare diseases.

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