Details

Autor(en) / Beteiligte

• 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, Rafael
• Yoldi, María Eugenia
• O'Callaghan, Mar
• García-Cazorla, Angels
• Armstrong, Judith
• Marti, Itxaso
• Mondragón Rezola, Elisabet
• Redin, Claire
• Mandel, Jean Louis
• Conejo, David
• Sierra-Córcoles, Concepción
• Beltrán, Sergi
• Gut, Marta
• Vázquez, Elida
• Del Toro, Mireia
• Troncoso, Mónica
• Pérez-Jurado, Luis A
• Gutiérrez-Solana, Luis G
• López de Munain, Adolfo
• Casasnovas, Carlos
• Aguilera-Albesa, Sergio
• Macaya, Alfons
• Pujol, Aurora

Titel

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

Ist Teil von

• Neurology, 2022-03, Vol.98 (9), p.e912

Ort / Verlag

United States

Erscheinungsjahr

2022

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 , , , and , 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.