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A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
Genetics in medicine, 2023-04, Vol.25 (4), p.100018-100018, Article 100018
2023
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Autor(en) / Beteiligte
Titel
A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing
Ist Teil von
  • Genetics in medicine, 2023-04, Vol.25 (4), p.100018-100018, Article 100018
Ort / Verlag
United States: Elsevier Inc
Erscheinungsjahr
2023
Quelle
MEDLINE
Beschreibungen/Notizen
  • Within the Solve-RD project (https://solve-rd.eu/), the 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 3576 exomes (1522 probands and 2054 relatives) collected from European Reference Network for Intellectual disability, TeleHealth, Autism and Congenital Anomalies was reanalyzed by the Solve-RD consortium by evaluating for the presence of single-nucleotide variant, and small insertions and deletions already reported as (likely) pathogenic in ClinVar. Variants were filtered according to 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.
Sprache
Englisch
Identifikatoren
ISSN: 1098-3600
eISSN: 1530-0366
DOI: 10.1016/j.gim.2023.100018
Titel-ID: cdi_hal_primary_oai_HAL_hal_04461276v1
Format
–
Schlagworte
Alleles, ClinVar, Developmental disorder, Exome reanalysis, Exome Sequencing, Genetics, Genotype, Humans, Intellectual Disability - diagnosis, Intellectual Disability - genetics, Life Sciences, Rare diseases

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