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 The Increasing Impact of Translational Research in the Molecular Diagnostics of Neuromuscular Diseases

2021 ◽  
Vol 22 (8) ◽  
pp. 4274
Author(s):  
Dèlia Yubero ◽  
Daniel Natera-de Benito ◽  
Jordi Pijuan ◽  
Judith Armstrong ◽  
Loreto Martorell ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Clinical Symptoms ◽  
Neuromuscular Diseases ◽  
Genomic Analysis ◽  
Molecular Diagnostic ◽  
Diagnostic Process ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Referral Hospitals ◽  
Uncertain Significance

The diagnosis of neuromuscular diseases (NMDs) has been progressively evolving from the grouping of clinical symptoms and signs towards the molecular definition. Optimal clinical, biochemical, electrophysiological, electrophysiological, and histopathological characterization is very helpful to achieve molecular diagnosis, which is essential for establishing prognosis, treatment and genetic counselling. Currently, the genetic approach includes both the gene-targeted analysis in specific clinically recognizable diseases, as well as genomic analysis based on next-generation sequencing, analyzing either the clinical exome/genome or the whole exome or genome. However, as of today, there are still many patients in whom the causative genetic variant cannot be definitely established and variants of uncertain significance are often found. In this review, we address these drawbacks by incorporating two additional biological omics approaches into the molecular diagnostic process of NMDs. First, functional genomics by introducing experimental cell and molecular biology to analyze and validate the variant for its biological effect in an in-house translational diagnostic program, and second, incorporating a multi-omics approach including RNA-seq, metabolomics, and proteomics in the molecular diagnosis of neuromuscular disease. Both translational diagnostics programs and omics are being implemented as part of the diagnostic process in academic centers and referral hospitals and, therefore, an increase in the proportion of neuromuscular patients with a molecular diagnosis is expected. This improvement in the process and diagnostic performance of patients will allow solving aspects of their health problems in a precise way and will allow them and their families to take a step forward in their lives.

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 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

The Efficacy of Whole Genome Sequencing and RNA-Seq in the Diagnosis of Whole Exome Sequencing Negative Patients with Complex Neurological Phenotypes

2021 ◽  
Author(s):  
Bianca Blake ◽  
Lauren I. Brady ◽  
Nicholas A. Rouse ◽  
Peter Nagy ◽  
Mark A. Tarnopolsky
Keyword(s):  
Whole Genome Sequencing ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genome Sequencing ◽  
Diagnostic Yield ◽  
Whole Genome ◽  
Rna Seq ◽  
Complete Coverage ◽  
Whole Exome ◽  
Chromosome Microarray

AbstractWhole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease by sequencing both the exome and the remaining 98 to 99% of the genetic code. In addition to more complete coverage, WGS can detect structural variants (SVs) and intronic variants (SNVs) that cannot be identified by whole exome sequencing (WES) or chromosome microarray (CMA). Other multi-omics tools, such as RNA sequencing (RNA-Seq), can be used in conjunction with WGS to functionally validate certain variants by detecting changes in gene expression and splicing. The objective of this retrospective study was to measure the diagnostic yield of duo/trio-based WGS and RNA-Seq in a cohort of 22 patients (20 families) with pediatric onset neurological phenotypes and negative or inconclusive WES results in lieu of reanalysis. WGS with RNA-Seq resulted in a definite diagnosis of an additional 25% of cases. Sixty percent of these solved cases arose from the identification of variants that were missed by WES. Variants that could not be unequivocally proven to be causative of the patients' condition were identified in an additional 5% of cases.

Whole exome sequencing in patients with inherited white matter disorders

2017 ◽  
Vol 21 ◽  
pp. e62
Author(s):  
I. Dorboz ◽  
F. Renaldo ◽  
K. Boussaid ◽  
S. Samaan ◽  
D. Tonduti ◽  
...  
Keyword(s):  
White Matter ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
White Matter Disorders ◽  
Whole Exome

scholarly journals The Clinical and Genotypic Spectrum of Scoliosis in Multiple Pterygium Syndrome: A Case Series on 12 Children

Genes ◽  
2021 ◽  
Vol 12 (8) ◽  
pp. 1220
Author(s):  
Noémi Dahan-Oliel ◽  
Klaus Dieterich ◽  
Frank Rauch ◽  
Ghalib Bardai ◽  
Taylor N. Blondell ◽  
...  
Keyword(s):  
Molecular Diagnosis ◽  
Spinal Instrumentation ◽  
Case Series ◽  
Retrospective Chart Review ◽  
Arthrogryposis Multiplex Congenita ◽  
Prospective Data ◽  
Whole Exome ◽  
Spine Deformities ◽  
Scoliosis Treatment ◽  
Multiple Pterygium Syndrome

Background: Multiple pterygium syndrome (MPS) is a genetically heterogeneous rare form of arthrogryposis multiplex congenita characterized by joint contractures and webbing or pterygia, as well as distinctive facial features related to diminished fetal movement. It is divided into prenatally lethal (LMPS, MIM253290) and nonlethal (Escobar variant MPS, MIM 265000) types. Developmental spine deformities are common, may present early and progress rapidly, requiring regular fo llow-up and orthopedic management. Methods: Retrospective chart review and prospective data collection were conducted at three hospital centers. Molecular diagnosis was confirmed with whole exome or whole genome sequencing. Results: This case series describes the clinical features and scoliosis treatment on 12 patients from 11 unrelated families. A molecular diagnosis was confirmed in seven; two with MYH3 variants and five with CHRNG. Scoliosis was present in all but our youngest patient. The remaining 11 patients spanned the spectrum between mild (curve ≤ 25°) and malignant scoliosis (≥50° curve before 4 years of age); the two patients with MYH3 mutations presented with malignant scoliosis. Bracing and serial spine casting appear to be beneficial for a few years; non-fusion spinal instrumentation may be needed to modulate more severe curves during growth and spontaneous spine fusions may occur in those cases. Conclusions: Molecular diagnosis and careful monitoring of the spine is needed in children with MPS.

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