scholarly journals Paroxysmal Movement Disorders

2021 ◽  
Vol 12 ◽  
Author(s):  
Susan Harvey ◽  
Mary D. King ◽  
Kathleen M. Gorman
Keyword(s):  
Next Generation Sequencing ◽  
Movement Disorders ◽  
Clinical Phenotype ◽  
Single Gene ◽  
Copy Number Variant ◽  
Genomic Research ◽  
Next Generation ◽  
Causative Gene ◽  
Gene Testing ◽  
Generation Sequencing

Paroxysmal movement disorders (PxMDs) are a clinical and genetically heterogeneous group of movement disorders characterized by episodic involuntary movements (dystonia, dyskinesia, chorea and/or ataxia). Historically, PxMDs were classified clinically (triggers and characteristics of the movements) and this directed single-gene testing. With the advent of next-generation sequencing (NGS), how we classify and investigate PxMDs has been transformed. Next-generation sequencing has enabled new gene discovery (RHOBTB2, TBC1D24), expansion of phenotypes in known PxMDs genes and a better understanding of disease mechanisms. However, PxMDs exhibit phenotypic pleiotropy and genetic heterogeneity, making it challenging to predict genotype based on the clinical phenotype. For example, paroxysmal kinesigenic dyskinesia is most commonly associated with variants in PRRT2 but also variants identified in PNKD, SCN8A, and SCL2A1. There are no radiological or biochemical biomarkers to differentiate genetic causes. Even with NGS, diagnosis rates are variable, ranging from 11 to 51% depending on the cohort studied and technology employed. Thus, a large proportion of patients remain undiagnosed compared to other neurological disorders such as epilepsy, highlighting the need for further genomic research in PxMDs. Whole-genome sequencing, deep-sequencing, copy number variant analysis, detection of deep-intronic variants, mosaicism and repeat expansions, will improve diagnostic rates. Identifying the underlying genetic cause has a significant impact on patient care, modification of treatment, long-term prognostication and genetic counseling. This paper provides an update on the genetics of PxMDs, description of PxMDs classified according to causative gene rather than clinical phenotype, highlighting key clinical features and providing an algorithm for genetic testing of PxMDs.

Analysis of a large cohort of non-small cell lung cancers submitted for somatic variant analysis demonstrates that targeted next-generation sequencing is fit for purpose as a molecular diagnostic assay in routine practice

2018 ◽  
Vol 71 (11) ◽  
pp. 1001-1006 ◽  
Author(s):  
David Allan Moore ◽  
Kevin Balbi ◽  
Alexander Ingham ◽  
Hendrik-Tobias Arkenau ◽  
Philip Bennett
Keyword(s):  
Next Generation Sequencing ◽  
Single Gene ◽  
Small Cell ◽  
Molecular Diagnostic ◽  
Next Generation ◽  
Small Cell Lung ◽  
Targeted Next Generation Sequencing ◽  
Gene Testing ◽  
The Impact ◽  
Generation Sequencing

AimsTargeted next-generation sequencing (tNGS) is increasingly being adopted as an alternative to single gene testing in some centres. Our aim was to assess the overall fitness and utility of tNGS as a routine clinical test in non-small cell lung cancer (NSCLC).MethodsAll NSCLC cases submitted to a single laboratory for tNGS analysis over a 3-year period were included. Rejection/failure rates and turnaround times were calculated. For reportable cases, data relating to observed genetic changes likely to be driving tumour growth and/or contributing to therapeutic resistance were extracted. The impact of varied referral site practices (tissue processing and sample format submitted) on analytical outcomes was also considered.ResultsA total of 2796 cases were submitted, of which 217 (7.8%) were rejected and 131 (5.1%) failed. The median turnaround time was seven working days. Of 2448 reported cases, KRAS, EGFR or other recognised driver mutations were observed in 35%, 17% and 5.4%, respectively. Of the remaining cases, 3.5% demonstrated significant incidental evidence of gene amplification. In 15% of EGFR-driven cases, evidence of an EGFR tyrosine kinase inhibitor resistance mechanism was observed. Potential concerns around the provision of slides or precut ‘rolls’ only (cf, formalin fixed paraffin embedded (FFPE) tissue blocks) as standard practice by certain referral sites were identified.ConclusionsA tNGS panel approach is practically achievable, with acceptable success rates and turnaround times, in the context of a routine clinical service. Furthermore, it provides additional clinically and analytically relevant information, which is not available from single gene testing alone.

Next generation sequencing for detection of EGFR alterations in NSCLC: is more better?

2020 ◽  
pp. jclinpath-2020-207212
Author(s):  
Ullas Batra ◽  
Shrinidhi Nathany ◽  
Mansi Sharma ◽  
Parveen Jain ◽  
Anurag Mehta
Keyword(s):  
Next Generation Sequencing ◽  
Kinase Inhibitor ◽  
Single Gene ◽  
Next Generation ◽  
Cell Lung Carcinoma ◽  
Molecular Features ◽  
Gene Testing ◽  
Clinical Records ◽  
Egfr Mutated ◽  
Generation Sequencing

AimsThe emergence of sophisticated next generation sequencing (NGS) based technologies in routine molecular diagnostics has paved the way for robust and accurate detection of variants which may otherwise be missed on single gene testing. This study aims at highlighting the same premise in EGFR mutated non-small cell lung carcinoma (NSCLC).Methods1350 cases of NSCLC were screened, of which 490 EGFR mutated cases were taken. The clinical records and molecular features were evaluated retrospectively to determine those cases which were missed on single gene testing.ResultsAmong these 490 cases, there were 11 (2.2%) cases which tested negative on single gene testing using polymerase chain reaction (therascreen). These were then subjected to NGS based testing and were positive for 13 different EGFR mutations. Five out of the 11 cases received EGFR tyrosine kinase inhibitor (TKI) based on the NGS test outcome. Four cases with exon 20 insertion mutations were not offered TKI as these mutations are known to be intrinsically resistant to TKI therapy. The five patients who have been treated with TKI have shown fair response and have not progressed to date.ConclusionsWe demonstrated a potentially preferable way to profile treatment-naïve patients with NSCLC by NGS and from our early experience in EGFR mutant cases, the advantages of NGS over single gene testing is clearly evident.

scholarly journals Building a Robust Tumor Profiling Program: Synergy between Next-Generation Sequencing and Targeted Single-Gene Testing

PLoS ONE ◽  
2016 ◽  
Vol 11 (4) ◽  
pp. e0152851 ◽  
Author(s):  
Matthew C. Hiemenz ◽  
Stephan Kadauke ◽  
David B. Lieberman ◽  
David B. Roth ◽  
Jianhua Zhao ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Single Gene ◽  
Next Generation ◽  
Gene Testing ◽  
Generation Sequencing ◽  
Tumor Profiling

Next-Generation Sequencing: An Emerging Tool for Drug Designing

2019 ◽  
Vol 25 (31) ◽  
pp. 3350-3357 ◽  
Author(s):  
Pooja Tripathi ◽  
Jyotsna Singh ◽  
Jonathan A. Lal ◽  
Vijay Tripathi
Keyword(s):  
Next Generation Sequencing ◽  
High Throughput ◽  
Large Scale ◽  
Massively Parallel Sequencing ◽  
Genomic Research ◽  
Biological Research ◽  
Next Generation ◽  
Human Welfare ◽  
Drug Designing ◽  
Generation Sequencing

Background: With the outbreak of high throughput next-generation sequencing (NGS), the biological research of drug discovery has been directed towards the oncology and infectious disease therapeutic areas, with extensive use in biopharmaceutical development and vaccine production. Method: In this review, an effort was made to address the basic background of NGS technologies, potential applications of NGS in drug designing. Our purpose is also to provide a brief introduction of various Nextgeneration sequencing techniques. Discussions: The high-throughput methods execute Large-scale Unbiased Sequencing (LUS) which comprises of Massively Parallel Sequencing (MPS) or NGS technologies. The Next geneinvolved necessarily executes Largescale Unbiased Sequencing (LUS) which comprises of MPS or NGS technologies. These are related terms that describe a DNA sequencing technology which has revolutionized genomic research. Using NGS, an entire human genome can be sequenced within a single day. Conclusion: Analysis of NGS data unravels important clues in the quest for the treatment of various lifethreatening diseases and other related scientific problems related to human welfare.

scholarly journals Clinical and neuroimaging phenotypes of genetic parkinsonism from infancy to adolescence

Brain ◽  
2019 ◽  
Vol 143 (3) ◽  
pp. 751-770 ◽  
Author(s):  
Hugo Morales-Briceño ◽  
Shekeeb S Mohammad ◽  
Bart Post ◽  
Alessandro F Fois ◽  
Russell C Dale ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Movement Disorders ◽  
Early Onset ◽  
Genetic Disorders ◽  
Phenotypic Characterization ◽  
Imaging Features ◽  
Next Generation ◽  
Phenotypic Spectrum ◽  
Inherited Mutations ◽  
Generation Sequencing

Abstract Genetic early-onset parkinsonism presenting from infancy to adolescence (≤21 years old) is a clinically diverse syndrome often combined with other hyperkinetic movement disorders, neurological and imaging abnormalities. The syndrome is genetically heterogeneous, with many causative genes already known. With the increased use of next-generation sequencing in clinical practice, there have been novel and unexpected insights into phenotype-genotype correlations and the discovery of new disease-causing genes. It is now recognized that mutations in a single gene can give rise to a broad phenotypic spectrum and that, conversely different genetic disorders can manifest with a similar phenotype. Accurate phenotypic characterization remains an essential step in interpreting genetic findings in undiagnosed patients. However, in the past decade, there has been a marked expansion in knowledge about the number of both disease-causing genes and phenotypic spectrum of early-onset cases. Detailed knowledge of genetic disorders and their clinical expression is required for rational planning of genetic and molecular testing, as well as correct interpretation of next-generation sequencing results. In this review we examine the relevant literature of genetic parkinsonism with ≤21 years onset, extracting data on associated movement disorders as well as other neurological and imaging features, to delineate syndromic patterns associated with early-onset parkinsonism. Excluding PRKN (parkin) mutations, >90% of the presenting phenotypes have a complex or atypical presentation, with dystonia, abnormal cognition, pyramidal signs, neuropsychiatric disorders, abnormal imaging and abnormal eye movements being the most common features. Furthermore, several imaging features and extraneurological manifestations are relatively specific for certain disorders and are important diagnostic clues. From the currently available literature, the most commonly implicated causes of early-onset parkinsonism have been elucidated but diagnosis is still challenging in many cases. Mutations in ∼70 different genes have been associated with early-onset parkinsonism or may feature parkinsonism as part of their phenotypic spectrum. Most of the cases are caused by recessively inherited mutations, followed by dominant and X-linked mutations, and rarely by mitochondrially inherited mutations. In infantile-onset parkinsonism, the phenotype of hypokinetic-rigid syndrome is most commonly caused by disorders of monoamine synthesis. In childhood and juvenile-onset cases, common genotypes include PRKN, HTT, ATP13A2, ATP1A3, FBX07, PINK1 and PLA2G6 mutations. Moreover, Wilson’s disease and mutations in the manganese transporter are potentially treatable conditions and should always be considered in the differential diagnosis in any patient with early-onset parkinsonism.

scholarly journals Next-Generation Sequencing Identifies Transportin 3 as the Causative Gene for LGMD1F

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e63536 ◽  
Author(s):  
Annalaura Torella ◽  
Marina Fanin ◽  
Margherita Mutarelli ◽  
Enrico Peterle ◽  
Francesca Del Vecchio Blanco ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Next Generation ◽  
Causative Gene ◽  
Generation Sequencing
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