scholarly journals Randomized Clinical Trial of First‐Line Genome Sequencing in Pediatric White Matter Disorders

2020 ◽  
Vol 88 (2) ◽  
pp. 264-273 ◽  
Author(s):  
Adeline Vanderver ◽  
Geneviève Bernard ◽  
Guy Helman ◽  
Omar Sherbini ◽  
Ryan Boeck ◽  
...  
Keyword(s):  
Clinical Trial ◽  
White Matter ◽  
Randomized Clinical Trial ◽  
Genome Sequencing ◽  
First Line ◽  
White Matter Disorders

scholarly journals Genome sequencing in persistently unsolved white matter disorders

2020 ◽  
Vol 7 (1) ◽  
pp. 144-152 ◽  
Author(s):  
Guy Helman ◽  
Bryan R. Lajoie ◽  
Joanna Crawford ◽  
Asako Takanohashi ◽  
Marzena Walkiewicz ◽  
...  
Keyword(s):  
White Matter ◽  
Genome Sequencing ◽  
White Matter Disorders

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

Neurology ◽  
2022 ◽  
pp. 10.1212/WNL.0000000000013278
Author(s):  
Agatha Schlüter ◽  
Agustí Rodríguez-Palmero ◽  
Edgard Verdura ◽  
Valentina Vélez-Santamaría ◽  
Montserrat Ruiz ◽  
...  
Keyword(s):  
White Matter ◽  
Candidate Genes ◽  
Genome Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Collaborative Study ◽  
Case Series ◽  
Genomic Analysis ◽  
White Matter Disorders ◽  
Whole Exome

Background and Objectives:Genetic white matter disorders (GWMD) are of heterogeneous origin, with more than a hundred causal genes identified to date. Classical targeted approaches achieve a molecular diagnosis in only half of all patients. Here we aim 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 patients, 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 HPO terms of each patient.Results:We received 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 six families, underscoring the importance of genomic analysis to solve these cases. Finally, 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.

scholarly journals No Effects of Cognitive Remediation on Cerebral White Matter in Individuals at Ultra-High Risk for Psychosis—A Randomized Clinical Trial

2020 ◽  
Vol 11 ◽  
Author(s):  
Tina D. Kristensen ◽  
Bjørn H. Ebdrup ◽  
Carsten Hjorthøj ◽  
René C. W. Mandl ◽  
Jayachandra M. Raghava ◽  
...  
Keyword(s):  
Clinical Trial ◽  
White Matter ◽  
High Risk ◽  
Randomized Clinical Trial ◽  
Cognitive Remediation ◽  
Cerebral White Matter ◽  
Ultra High Risk
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