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

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 seque...

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Detalles Bibliográficos
Autores: Schlüter, Agatha, Rodríguez Palmero, Agustí, Verdura, Edgard, Vélez Santamaría, Valentina, Ruiz, Montserrat, Fourcade, Stéphane, Planas Serra, Laura, Martínez, Juan José, Guilera, Cristina, Girós, Marisa, Artuch Iriberri, Rafael, Yoldi, María Eugenia, O'Callaghan, Mar, García Cazorla, Àngels, Armstrong, Judith, Marti, Itxaso, Mondragón Rezola, Elisabet, Redin, Claire, Mandel, Jean Louis, Conejo, David, Sierra Córcoles, Concepción, Beltran, Sergi, Gut, Marta, Vázquez, Elida, Toro, Mireia del, Troncoso, Mónica, Pérez Jurado, Luis A., Gutiérrez Solana, Luis G., López de Munain, Adolfo, Casasnovas Pons, Carlos, Aguilera Albesa, Sergio, Macaya, Alfons, Pujol, Aurora, 1968-, GWMD working group
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/184675
Acceso en línea:https://hdl.handle.net/2445/184675
Access Level:acceso abierto
Palabra clave:Malalties hereditàries
Genoma humà
Genòmica
Fenotip
Malalties del sistema nerviós central
Genetic diseases
Human genome
Genomics
Phenotype
Central nervous system diseases
Descripción
Sumario: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.

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