biostudies-literatureUnknown98(9)Schluter A<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.Neurologye912-e923https://www.ebi.ac.uk/biostudies/studies/S-EPMC8901178biostudies-literatureDiagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.PMC8901178Pujol AV Azquez MIEPlanas-Serra LHern Andez JGuilera CArmstrong JGarc Ia AMandel JLGWMD working groupRuiz MSierra-Corcoles CBarrios AEAguilera-Albesa SNarbona JCasasnovas CLorenzo MLopez de Munain AMondragon Rezola EPerez-Jurado LALaunay NArtuch RRodriguez-Palmero ARedin CHedrera ARoig-Quilis MGutierrez-Solana LGSchluter ARamos MAFourcade SGiros MYoldi MEBeltran SArroyo HACastillo TVerdura EGut MMacaya ACazorla RUrtasun MAO'Callaghan MConejo DTroncoso MVelez-Santamaria VMartinez JJMunoz AMarti IV Azquez JFGarcia-Cazorla AMiranda COChaure MRP Erez MDel Toro MGarc Ia MIAOCampo AMoreno FIVazquez EfalseDiagnosis of Genetic White Matter Disorders by Singleton Whole-Exome and Genome Sequencing Using Interactome-Driven Prioritization.<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.2022-01-01T00:00:00Z2022 Mar2025-04-18T12:12:11.388Z2025-04-06T21:48:12.676ZS-EPMC89011783501296410.1212/WNL.0000000000013278