RT Journal Article
T1 Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.
A1 Schlüter, Agatha
A1 Rodríguez-Palmero, Agustí
A1 Verdura, Edgard
A1 Vélez-Santamaría, Valentina
A1 Ruiz, Montserrat
A1 Fourcade, Stéphane
A1 Planas-Serra, Laura
A1 Martínez, Juan José
A1 Guilera, Cristina
A1 Girós, Marisa
A1 Artuch, Rafael
A1 Yoldi, María Eugenia
A1 O'Callaghan, Mar
A1 García-Cazorla, Angels
A1 Armstrong, Judith
A1 Marti, Itxaso
A1 Mondragón Rezola, Elisabet
A1 Redin, Claire
A1 Mandel, Jean Louis
A1 Conejo, David
A1 Sierra-Córcoles, Concepción
A1 Beltrán, Sergi
A1 Gut, Marta
A1 Vázquez, Elida
A1 Del Toro, Mireia
A1 Troncoso, Mónica
A1 Pérez-Jurado, Luis A
A1 Gutiérrez-Solana, Luis G
A1 López de Munain, Adolfo
A1 Casasnovas, Carlos
A1 Aguilera-Albesa, Sergio
A1 Macaya, Alfons
A1 Pujol, Aurora
A1 GWMD working group, 
AB 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. 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. 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. 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.
YR 2022
FD 2022-01-10
LK http://hdl.handle.net/10668/20400
UL http://hdl.handle.net/10668/20400
LA en
DS RISalud
RD Apr 5, 2025