High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

2021 ◽  
pp. jmedgenet-2020-107369
Author(s):  
Quentin Thomas ◽  
Antonio Vitobello ◽  
Frederic Tran Mau-Them ◽  
Yannis Duffourd ◽  
Agnès Fromont ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurological Disorders ◽  
High Efficiency ◽  
Neuromuscular Disorders ◽  
Daily Practice ◽  
Pathogenic Variants ◽  
Complex Phenotypes ◽  
Cerebellar Ataxias ◽  
Mitochondrial Origin ◽  
Second Tier

ObjectiveTo assess the efficiency and relevance of clinical exome sequencing (cES) as a first-tier or second-tier test for the diagnosis of progressive neurological disorders in the daily practice of Neurology and Genetic Departments.MethodsSixty-seven probands with various progressive neurological disorders (cerebellar ataxias, neuromuscular disorders, spastic paraplegias, movement disorders and individuals with complex phenotypes labelled ‘other’) were recruited over a 4-year period regardless of their age, gender, familial history and clinical framework. Individuals could have had prior genetic tests as long as it was not cES. cES was performed in a proband-only (60/67) or trio (7/67) strategy depending on available samples and was analysed with an in-house pipeline including software for CNV and mitochondrial-DNA variant detection.ResultsIn 29/67 individuals, cES identified clearly pathogenic variants leading to a 43% positive yield. When performed as a first-tier test, cES identified pathogenic variants for 53% of individuals (10/19). Difficult cases were solved including double diagnoses within a kindred or identification of a neurodegeneration with brain iron accumulation in a patient with encephalopathy of suspected mitochondrial origin.ConclusionThis study shows that cES is a powerful tool for the daily practice of neurogenetics offering an efficient (43%) and appropriate approach for clinically and genetically complex and heterogeneous disorders.

scholarly journals Diagnostic utility of exome sequencing for inherited peripheral neuropathies

2020 ◽  
Vol 10 (4) ◽  
pp. 12-26
Author(s):  
O. A. Shchagina ◽  
O. P. Ryzhkova ◽  
A. L. Chukhrova ◽  
T. V. Milovidova ◽  
P. Gundorova ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Neuromuscular Disorders ◽  
Congenital Muscular Dystrophy ◽  
Gene Mutations ◽  
Research Centre ◽  
Congenital Myasthenic Syndrome ◽  
Hereditary Motor ◽  
Pathogenic Variants ◽  
Whole Exome

Introduction. Hereditary motor and sensory neuropathies, a highly genetic heterogeneous group of disorders, have a phenotype caused by peripheral nerve damage.Purpose of the study – to assess the extent of genetic heterogeneity of hereditary motor and sensory neuropathies in Russian patients and to evaluate the diagnostic effectiveness of using full-exome research methods to find the genetic cause of hereditary motor and sensory neuropathies.Materials and methods. The material for the study was DNA samples from 51 patients and their family members referred for whole exome sequencing to the DNA-diagnostics laboratory of Research Centre for Medical Genetics in 2017–2019. Methods: whole exome sequencing, Sanger sequencing, restriction fragment length polymorphism.Results. Whole exome sequencing in combination with segregation analysis of the pathogenic variants in families allowed to determine the cause of the disease in 41 % of cases. In another 16 % of cases, candidate genetic variants as a possible cause of the disease were revealed, but additional studies are needed to confirm it. The most frequently mutated gene was MFN2 caused neuropathy in 6 unrelated families. MPZ gene mutations were detected in two families, AARS gene mutations were revealed in another two families, and mutations in GJB1, HINT1, INF2, LRSAM1, LITAF, MME, NEFL, WWOX were detected once. Among the causal variants, mutations in B4GALNT1 caused spastic paraplegia, in COL6A1 led to Bethlem’s congenital muscular dystrophy, and in SYT2 caused congenital myasthenic syndrome indicating difficulties in differential diagnosis of inherited neuromuscular disorders. A PMP22 duplication was detected in 2 families prior to whole exome sequencing.Conclusion. Whole exome sequencing is very important for finding the molecular cause of hereditary motor and sensory neuropathies. In most cases, additional methods should be used to clarify the pathogenicity of variants detected by whole exome sequencing. However, it is necessary to remember that the most common cause of the disease is a large duplication of the region 17p11.2.

scholarly journals Diagnostic utility of exome sequencing in the evaluation of neuromuscular disorders

2018 ◽  
Vol 4 (1) ◽  
pp. e212 ◽  
Author(s):  
Gloria T. Haskell ◽  
Michael C. Adams ◽  
Zheng Fan ◽  
Krunal Amin ◽  
Roberto J. Guzman Badillo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Molecular Diagnosis ◽  
Diagnostic Yield ◽  
Neuromuscular Disorders ◽  
Gene List ◽  
Disease Genes ◽  
Causative Gene ◽  
Pathogenic Variants ◽  
Prior Testing ◽  
Genome Scale

ObjectiveTo evaluate the diagnostic yield and workflow of genome-scale sequencing in patients with neuromuscular disorders (NMDs).MethodsWe performed exome sequencing in 93 undiagnosed patients with various NMDs for whom a molecular diagnosis was not yet established. Variants on both targeted and broad diagnostic gene lists were identified. Prior diagnostic tests were extracted from the patient's medical record to evaluate the use of exome sequencing in the context of their prior diagnostic workup.ResultsThe overall diagnostic yield of exome sequencing in our cohort was 12.9%, with one or more pathogenic or likely pathogenic variants identified in a causative gene associated with the patient's disorder. Targeted gene lists had the same diagnostic yield as a broad NMD gene list in patients with clear neuropathy or myopathy phenotypes, but evaluation of a broader set of disease genes was needed for patients with complex NMD phenotypes. Most patients with NMD had undergone prior testing, but only 10/16 (63%) of these procedures, such as muscle biopsy, were informative in pointing to a final molecular diagnosis.ConclusionsGenome-scale sequencing or analysis of a panel of relevant genes used early in the evaluation of patients with NMDs can provide or clarify a diagnosis and minimize invasive testing in many cases.

scholarly journals The utility of whole exome sequencing in diagnosing pediatric neurological disorders

2020 ◽  
Vol 23 (2) ◽  
pp. 17-24
Author(s):  
OY Muthaffar
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Neurological Disorders ◽  
Diagnostic Yield ◽  
Wide Spectrum ◽  
Retrospective Chart Review ◽  
Signs And Symptoms ◽  
Pathogenic Variants ◽  
Whole Exome ◽  
Tertiary Center

Abstract Pediatric neurological disorders have a wide spectrum of clinical presentations and can be challenging to diagnose. Whole exome sequencing (WES) is increasingly becoming an integral diagnostic tool in medicine. It is cost-effective and has high diagnostic yield, especially in consanguineous populations. This study aims to review WES results and its value in diagnosing neurological disorders. A retrospective chart review was performed for WES results between the period of January 2018 to November 2019. Whole exome sequencing was requested for children with unexplained neurological signs and symptoms such as epilepsy, developmental delay, visual impairment, spasticity, hypotonia and magnetic resonance imaging (MRI) brain changes. It was conducted for children in a pediatric neurology clinic of a tertiary center at Jeddah, Saudi Arabia. Twenty-six children with undiagnosed neurological conditions were identified and underwent WES diagnosis. Nineteen patients (73.0%) of the cohort were diagnosed with pathogenic variants, likely pathogenic variants or variants of unknown significance (VUS). Consanguinity was positive in 18 families of the cohort (69.0%). Seven patients showed homozygous mutations. Five patients had heterozygous mutations. There were six patients with VUS and six patients had negative WES results. Whole exome sequencing showed a high diagnostic rate in this group of children with variable neurological disorders.

High efficiency and clinical relevance of exome sequencing in the daily practice of neurogenetics

2021 ◽  
Vol 429 ◽  
pp. 117855
Author(s):  
Quentin Thomas ◽  
Antonio Vitobello ◽  
Frédéric Tran Mau-Them ◽  
Yannis Duffourd ◽  
Agnès Fromont ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Clinical Relevance ◽  
High Efficiency ◽  
Daily Practice

scholarly journals First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery

2020 ◽  
Vol 28 (8) ◽  
pp. 1034-1043 ◽  
Author(s):  
Holger Hengel ◽  
Rebecca Buchert ◽  
Marc Sturm ◽  
Tobias B. Haack ◽  
Yvonne Schelling ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurological Disorders ◽  
Disease Gene ◽  
Gene Discovery ◽  
First Line ◽  
Disease Gene Discovery ◽  
Israeli Arabs

scholarly journals Whole-exome sequencing with targeted analysis and epilepsy after acute symptomatic neonatal seizures

2021 ◽  
Author(s):  
Adam L. Numis ◽  
Gilberto da Gente ◽  
Elliott H. Sherr ◽  
Hannah C. Glass
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
De Novo ◽  
List Type ◽  
Sequencing Analysis ◽  
Neonatal Seizures ◽  
Pathogenic Variants ◽  
Targeted Analysis ◽  
Whole Exome ◽  
Epilepsy Gene

Abstract Background The contribution of pathogenic gene variants with development of epilepsy after acute symptomatic neonatal seizures is not known. Methods Case–control study of 20 trios in children with a history of acute symptomatic neonatal seizures: 10 with and 10 without post-neonatal epilepsy. We performed whole-exome sequencing (WES) and identified pathogenic de novo, transmitted, and non-transmitted variants from established and candidate epilepsy association genes and correlated prevalence of these variants with epilepsy outcomes. We performed a sensitivity analysis with genes associated with coronary artery disease (CAD). We analyzed variants throughout the exome to evaluate for differential enrichment of functional properties using exploratory KEGG searches. Results Querying 200 established and candidate epilepsy genes, pathogenic variants were identified in 5 children with post-neonatal epilepsy yet in only 1 child without subsequent epilepsy. There was no difference in the number of trios with non-transmitted pathogenic variants in epilepsy or CAD genes. An exploratory KEGG analysis demonstrated a relative enrichment in cell death pathways in children without subsequent epilepsy. Conclusions In this pilot study, children with epilepsy after acute symptomatic neonatal seizures had a higher prevalence of coding variants with a targeted epilepsy gene sequencing analysis compared to those patients without subsequent epilepsy. Impact We performed whole-exome sequencing (WES) in 20 trios, including 10 children with epilepsy and 10 without epilepsy, both after acute symptomatic neonatal seizures. Children with post-neonatal epilepsy had a higher burden of pathogenic variants in epilepsy-associated genes compared to those without post-neonatal epilepsy. Future studies evaluating this association may lead to a better understanding of the risk of epilepsy after acute symptomatic neonatal seizures and elucidate molecular pathways that are dysregulated after brain injury and implicated in epileptogenesis.

Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Emily Breidbart ◽  
Liyong Deng ◽  
Patricia Lanzano ◽  
Xiao Fan ◽  
Jiancheng Guo ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Exome Sequencing ◽  
Large Scale ◽  
Age Of Onset ◽  
Family Members ◽  
Ethnically Diverse ◽  
Monogenic Diabetes ◽  
Diabetes Diagnosis ◽  
Pathogenic Variants ◽  
Atypical Diabetes

Abstract Objectives There have been few large-scale studies utilizing exome sequencing for genetically undiagnosed maturity onset diabetes of the young (MODY), a monogenic form of diabetes that is under-recognized. We describe a cohort of 160 individuals with suspected monogenic diabetes who were genetically assessed for mutations in genes known to cause MODY. Methods We used a tiered testing approach focusing initially on GCK and HNF1A and then expanding to exome sequencing for those individuals without identified mutations in GCK or HNF1A. The average age of onset of hyperglycemia or diabetes diagnosis was 19 years (median 14 years) with an average HbA1C of 7.1%. Results Sixty (37.5%) probands had heterozygous likely pathogenic/pathogenic variants in one of the MODY genes, 90% of which were in GCK or HNF1A. Less frequently, mutations were identified in PDX1, HNF4A, HNF1B, and KCNJ11. For those probands with available family members, 100% of the variants segregated with diabetes in the family. Cascade genetic testing in families identified 75 additional family members with a familial MODY mutation. Conclusions Our study is one of the largest and most ethnically diverse studies using exome sequencing to assess MODY genes. Tiered testing is an effective strategy to genetically diagnose atypical diabetes, and familial cascade genetic testing identified on average one additional family member with monogenic diabetes for each mutation identified in a proband.

scholarly journals Refining Genotypes and Phenotypes in KCNA2-Related Neurological Disorders

2021 ◽  
Vol 22 (6) ◽  
pp. 2824
Author(s):  
Jan H. Döring ◽  
Julian Schröter ◽  
Jerome Jüngling ◽  
Saskia Biskup ◽  
Kerstin A. Klotz ◽  
...  
Keyword(s):  
Neurological Disorders ◽  
Transmembrane Domain ◽  
Potassium Conductance ◽  
Epileptic Encephalopathy ◽  
Clinical Spectrum ◽  
The Novel ◽  
Developmental Abnormalities ◽  
Pathogenic Variants ◽  
Infantile Seizures ◽  
Early Developmental

Pathogenic variants in KCNA2, encoding for the voltage-gated potassium channel Kv1.2, have been identified as the cause for an evolving spectrum of neurological disorders. Affected individuals show early-onset developmental and epileptic encephalopathy, intellectual disability, and movement disorders resulting from cerebellar dysfunction. In addition, individuals with a milder course of epilepsy, complicated hereditary spastic paraplegia, and episodic ataxia have been reported. By analyzing phenotypic, functional, and genetic data from published reports and novel cases, we refine and further delineate phenotypic as well as functional subgroups of KCNA2-associated disorders. Carriers of variants, leading to complex and mixed channel dysfunction that are associated with a gain- and loss-of-potassium conductance, more often show early developmental abnormalities and an earlier onset of epilepsy compared to individuals with variants resulting in loss- or gain-of-function. We describe seven additional individuals harboring three known and the novel KCNA2 variants p.(Pro407Ala) and p.(Tyr417Cys). The location of variants reported here highlights the importance of the proline(405)–valine(406)–proline(407) (PVP) motif in transmembrane domain S6 as a mutational hotspot. A novel case of self-limited infantile seizures suggests a continuous clinical spectrum of KCNA2-related disorders. Our study provides further insights into the clinical spectrum, genotype–phenotype correlation, variability, and predicted functional impact of KCNA2 variants.

RHOBTB2 p.Arg511Trp Mutation in Early Infantile Epileptic Encephalopathy-64: Review and Case Report

2021 ◽  
Author(s):  
J Fonseca ◽  
C Melo ◽  
C Ferreira ◽  
M Sampaio ◽  
R Sousa ◽  
...  
Keyword(s):  
Case Report ◽  
Intellectual Disability ◽  
Status Epilepticus ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Epileptic Encephalopathy ◽  
Btb Domain ◽  
Pathogenic Variants ◽  
Severe Intellectual Disability ◽  
Whole Exome

AbstractEarly infantile epileptic encephalopathy-64 (EIEE 64), also called RHOBTB2-related developmental and epileptic encephalopathy (DEE), is caused by heterozygous pathogenic variants (EIEE 64; MIM#618004) in the Rho-related BTB domain-containing protein 2 (RHOBTB2) gene. To date, only 13 cases with RHOBTB2-related DEE have been reported. We add to the literature the 14th case of EIEE 64, identified by whole exome sequencing, caused by a heterozygous pathogenic variant in RHOBTB2 (c.1531C > T), p.Arg511Trp. This additional case supports the main features of RHOBTB2-related DEE: infantile-onset seizures, severe intellectual disability, impaired motor functions, postnatal microcephaly, recurrent status epilepticus, and hemiparesis after seizures.

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