{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["98(9)"],"submitter":["Schluter A"],"pubmed_abstract":["<h4>Background and objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 <i>RNASEH2B</i>, <i>EIF2B5</i>, <i>POLR3A</i>, and <i>PLP1</i>, 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.<h4>Discussion</h4>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."],"journal":["Neurology"],"pagination":["e912-e923"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8901178"],"repository":["biostudies-literature"],"pubmed_title":["Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization."],"pmcid":["PMC8901178"],"pubmed_authors":["Pujol A","V Azquez MIE","Planas-Serra L","Hern Andez J","Guilera C","Armstrong J","Garc Ia A","Mandel JL","GWMD working group","Ruiz M","Sierra-Corcoles C","Barrios AE","Aguilera-Albesa S","Narbona J","Casasnovas C","Lorenzo M","Lopez de Munain A","Mondragon Rezola E","Perez-Jurado LA","Launay N","Artuch R","Rodriguez-Palmero A","Redin C","Hedrera A","Roig-Quilis M","Gutierrez-Solana LG","Schluter A","Ramos MA","Fourcade S","Giros M","Yoldi ME","Beltran S","Arroyo HA","Castillo T","Verdura E","Gut M","Macaya A","Cazorla R","Urtasun MA","O'Callaghan M","Conejo D","Troncoso M","Velez-Santamaria V","Martinez JJ","Munoz A","Marti I","V Azquez JF","Garcia-Cazorla A","Miranda CO","Chaure MR","P Erez M","Del Toro M","Garc Ia MIAO","Campo A","Moreno FI","Vazquez E"],"additional_accession":[]},"is_claimable":false,"name":"Diagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.","description":"<h4>Background and objectives</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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 <i>RNASEH2B</i>, <i>EIF2B5</i>, <i>POLR3A</i>, and <i>PLP1</i>, 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.<h4>Discussion</h4>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.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Mar","modification":"2025-04-18T12:12:11.388Z","creation":"2025-04-06T21:48:12.676Z"},"accession":"S-EPMC8901178","cross_references":{"pubmed":["35012964"],"doi":["10.1212/WNL.0000000000013278"]}}