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Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization

2022; Lippincott Williams & Wilkins; Volume: 98; Issue: 9 Linguagem: Inglês

10.1212/wnl.0000000000013278

1526-632X

Agatha Schlüter, Agustí Rodríguez‐Palmero, Edgard Verdura, Valentina Vélez-Santamaría, Montserrat Ruíz, Stéphane Fourcade, Laura Planas‐Serra, Juan José Martínez, Cristina Guilera, M. Girós, Rafael Artuch, María Eugenia Yoldi, Mar O’Callaghan, Àngels García‐Cazorla, Judith Armstrong, Itxaso Martí, Elisabet Mondragón Rezola, Claire Redin, Jean‐Louis Mandel, David Conejo, Concepción Sierra-Córcoles, Sergi Beltrán, Marta Gut, Élida Vázquez, Mireia del Toro, Mónica Troncoso, Luis A. Pérez‐Jurado, Luis González Gutiérrez-Solana, Adolfo López de Munaín, Carlos Casasnovas, Sergio Aguilera, Alfons Macaya, Aurora Pujol, H Arroyo, Andr ́es Barrios, Andrea Campo, Tamara Castillo, Rosario Cazorla, Mar ́ıa Asunci ́on Garc ́ıa, Ainhoa Garc ́ıa, Antonio Hedrera-Fernández, Juan Hern ́andez, Nathalie Launay, María Gabriela Lorenzo, Concepci ́on Miranda, Ferm ́ın Moreno, Amaia Muñoz, Juan Narbona, MaSocorro P ́erez, Maria Antonia Ramos, Miquel Raspall‐Chaure, Manel Roig-Quilis, Miguel Urtasun, Mar ́ıa Esther V ́azquez, Juan Francisco V ́azquez,

RNA modifications and cancer

Background and Objectives Genetic white matter disorders (GWMD) are of heterogeneous origin, with >100 causal genes identified to date. Classic targeted approaches achieve a molecular diagnosis in only half of all patients. We aimed to determine the clinical utility of singleton whole-exome sequencing and whole-genome sequencing (sWES-WGS) interpreted with a phenotype- and interactome-driven prioritization algorithm to diagnose GWMD while identifying novel phenotypes and candidate genes. Methods A case series of patients of all ages with undiagnosed GWMD despite extensive standard-of-care paraclinical studies were recruited between April 2017 and December 2019 in a collaborative study at the Bellvitge Biomedical Research Institute (IDIBELL) and neurology units of tertiary Spanish hospitals. We ran sWES and WGS and applied our interactome-prioritization algorithm based on the network expansion of a seed group of GWMD-related genes derived from the Human Phenotype Ontology terms of each patient. Results We evaluated 126 patients (101 children and 25 adults) with ages ranging from 1 month to 74 years. We obtained a first molecular diagnosis by singleton WES in 59% of cases, which increased to 68% after annual reanalysis, and reached 72% after WGS was performed in 16 of the remaining negative cases. We identified variants in 57 different genes among 91 diagnosed cases, with the most frequent being RNASEH2B , EIF2B5 , POLR3A , and PLP1 , and a dual diagnosis underlying complex phenotypes in 6 families, underscoring the importance of genomic analysis to solve these cases. We discovered 9 candidate genes causing novel diseases and propose additional putative novel candidate genes for yet-to-be discovered GWMD. Discussion Our strategy enables a high diagnostic yield and is a good alternative to trio WES/WGS for GWMD. It shortens the time to diagnosis compared to the classical targeted approach, thus optimizing appropriate management. Furthermore, the interactome-driven prioritization pipeline enables the discovery of novel disease-causing genes and phenotypes, and predicts novel putative candidate genes, shedding light on etiopathogenic mechanisms that are pivotal for myelin generation and maintenance.