作者
Koh Ichi Nagata,Anne‐Sophie Denommé‐Pichon,Camille Engel,Frédéric Tran Mau‐Them,Ange‐Line Bruel,Antonio Vitobello,Hana Safraou,Arthur Sorlin,Sophie Nambot,Julian Delanne,Aurore Garde,Estelle Colin,Sébastien Moutton,Julien Thévenon,Nolwenn Jean-Marçais,Marjolaine Willems,David Geneviève,Lucile Pinson,Laurence Perrin,Fanny Laffargue,James Lespinasse,Elodie Lacaze,Arnaud Molin,Marion Gérard,Laëtitia Lambert,Charlotte Benigni,Olivier Patat,Valentin Bourgeois,Charlotte Poé,Martin Chevarin,Victor Couturier,Philippine Garret,Christophe Philippe,Yannis Duffourd,Laurence Faivre,Christel Thauvin‐Robinet
摘要
Wide access to clinical exome/genome sequencing (ES/GS) enables the identification of multiple molecular diagnoses (MMDs), being a long-standing but underestimated concept, defined by two or more causal loci implicated in the phenotype of an individual with a rare disease. Only few series report MMDs rates (1.8% to 7.1%). This study highlights the increasing role of MMDs in a large cohort of individuals addressed for congenital anomalies/intellectual disability (CA/ID).From 2014 to 2021, our diagnostic laboratory rendered 880/2658 positive ES diagnoses for CA/ID aetiology. Exhaustive search on MMDs from ES data was performed prospectively (January 2019 to December 2021) and retrospectively (March 2014 to December 2018).MMDs were identified in 31/880 individuals (3.5%), responsible for distinct (9/31) or overlapping (22/31) phenotypes, and potential MMDs in 39/880 additional individuals (4.4%).MMDs are frequent in CA/ID and remain a strong challenge. Reanalysis of positive ES data appears essential when phenotypes are partially explained by the initial diagnosis or atypically enriched overtime. Up-to-date clinical data, clinical expertise from the referring physician, strong interactions between clinicians and biologists, and increasing gene discoveries and improved ES bioinformatics tools appear all the more fundamental to enhance chances of identifying MMDs. It is essential to provide appropriate patient care and genetic counselling.