A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

• Type: Article in International Scientific Journal
• Date: 2023

Authors

Denommé-Pichon A.S. (Author) Other; Bruel A.L. (Author) Other; Bruel A.L. (Author) Other; Duffourd Y. (Author) Other; Duffourd Y. (Author) Other; Safraou H. (Author) Other; Safraou H. (Author) Other; Thauvin-Robinet C. (Author) Other; Thauvin-Robinet C. (Author) Other; Thauvin-Robinet C. (Author) Other; Tran Mau-Them F. (Author) Other; Tran Mau-Them F. (Author) Other; Philippe C. (Author) Other; Philippe C. (Author) Other; Vitobello A. (Author) Other; Vitobello A. (Author) Other; Denommé-Pichon A.S. (Author) Other; Jean-Marçais N. (Author) Other; Jean-Marçais N. (Author) Other; Moutton S. (Author) Other; Thevenon J. (Author) Other; Faivre L. (Author) Other; Matalonga L. (Author) Other; Matalonga L. (Author) Other; de Boer E. (Author) Other; de Boer E. (Author) Other; de Boer E. (Author) Other; Gilissen C. (Author) Other; Gilissen C. (Author) Other; Gilissen C. (Author) Other; Hoischen A. (Author) Other; Hoischen A. (Author) Other; Hoischen A. (Author) Other; Hoischen A. (Author) Other; Kleefstra T. (Author) Other; Kleefstra T. (Author) Other; Kleefstra T. (Author) Other; Kleefstra T. (Author) Other; Pfundt R. (Author) Other; Pfundt R. (Author) Other; de Vries B.B.A. (Author) Other; de Vries B.B.A. (Author) Other; Willemsen M.H. (Author) Other; Willemsen M.H. (Author) Other; Vissers L.E.L.M. (Author) Other; Vissers L.E.L.M. (Author) Other; Jackson A. (Author) Other; Banka S. (Author) Other; Banka S. (Author) Other; Clayton-Smith J. (Author) Other; Clayton-Smith J. (Author) Other; Benetti E. (Author) Other; Fallerini C. (Author) Other; Fallerini C. (Author) Other; Renieri A. (Author) Other; Renieri A. (Author) Other; Renieri A. (Author) Other; Ciolfi A. (Author) Other; Ciolfi A. (Author) Other; Dallapiccola B. (Author) Other; Dallapiccola B. (Author) Other; Pizzi S. (Author) Other; Pizzi S. (Author) Other; Radio F.C. (Author) Other; Tartaglia M. (Author) Other; Ellwanger K. (Author) Other; Ellwanger K. (Author) Other; Graessner H. (Author) Other; Haack T.B. (Author) Other; Haack T.B. (Author) Other; Haack T.B. (Author) Other; Zurek B. (Author) Other; Zurek B. (Author) Other; Graessner H. (Author) Other; Havlovicova M. (Author) Other; Havlovicova M. (Author) Other; Macek M. (Author) Other; Macek M. (Author) Other; Ryba L. (Author) Other; Schwarz M. (Author) Other; Votypka P. (Author) Other; Faivre L. (Author) Other; López-Martín E. (Author) Other; Posada M. (Author) Other; Mencarelli M.A. (Author) Other; Rooryck C. (Author) Other; Trimouille A. (Author) Other; Verloes A. (Author) Other; Verloes A. (Author) Other; Abbott K.M. (Author) Other; Denommé-Pichon A.S. (Author) Other; Faivre L. (Author) Other; Jackson A. (Author) Other; Kerstjens M. (Author) Other; Martín E.L. (Author) Other; Maystadt I. (Author) Other; Morleo M. (Author) Other; Nigro V. (Author) Other; Pinelli M. (Author) Other; Posada M. (Author) Other

Journal

Title: Genetics in Medicine

Vol. 25

ISSN: 1098-3600

Publisher: Springer Nature

Indexing

Scopus - 0 Citations

Other information

Authenticus ID: P-00Z-0RS

DOI: 10.1016/j.gim.2023.100018

Abstract (EN): Purpose: 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. Methods: 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. 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.

Language: English

Type (Professor's evaluation): Scientific