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.
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.
Copyright © 2023. Published by Elsevier Inc.
About The Expert
Anne-Sophie Denommé-Pichon
Leslie Matalonga
Elke de Boer
Adam Jackson
Elisa Benetti
Siddharth Banka
Ange-Line Bruel
Andrea Ciolfi
Jill Clayton-Smith
Bruno Dallapiccola
Yannis Duffourd
Kornelia Ellwanger
Chiara Fallerini
Christian Gilissen
Holm Graessner
Tobias B Haack
Marketa Havlovicova
Alexander Hoischen
Nolwenn Jean-Marçais
Tjitske Kleefstra
Estrella López-Martín
Milan Macek
Maria Antonietta Mencarelli
Sébastien Moutton
Rolph Pfundt
Simone Pizzi
Manuel Posada
Francesca Clementina Radio
Alessandra Renieri
Caroline Rooryck
Lukas Ryba
Hana Safraou
Martin Schwarz
Marco Tartaglia
Christel Thauvin-Robinet
Julien Thevenon
Frédéric Tran Mau-Them
Aurélien Trimouille
Pavel Votypka
Bert B A de Vries
Marjolein H Willemsen
Birte Zurek
Alain Verloes
Christophe Philippe
Antonio Vitobello
Lisenka E L M Vissers
Laurence Faivre
References
PubMed