Please use this identifier to cite or link to this item:
Title: Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization
Author: Schlüter, Agatha
Rodríguez Palmero, Agustí
Verdura, Edgard
Vélez Santamaría, Valentina
Ruiz, Montserrat
Fourcade, Stephane
Planas Serra, Laura
Martínez, Juan José
Guilera, Cristina
Girós, Marisa
Artuch, 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
Gutiérrez Solana, Luis G.
López de Munain, Adolfo
Casasnovas Pons, Carlos
Aguilera Albesa, Sergio
Macaya, Alfons
Pujol, Aurora
GWMD working group
Keywords: Malalties hereditàries
Genoma humà
Malalties del sistema nerviós central
Genetic diseases
Human genome
Central nervous system diseases
Issue Date: 10-Jan-2022
Publisher: Lippincott, Williams & Wilkins. Wolters Kluwer Health
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Neurology, 2022, vol. 92, num. 9, p. e912-e923
Related resource:
ISSN: 0028-3878
Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
Articles publicats en revistes (Ciències Clíniques)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

Files in This Item:
File Description SizeFormat 
721874.pdf943.67 kBAdobe PDFView/Open

This item is licensed under a Creative Commons License Creative Commons