scholarly journals GP.03 Diagnostic yield of next generation sequencing and myositis autoantibody panels in patients with axial myopathy

2019 ◽  
Vol 46 (s1) ◽  
pp. S6
Author(s):  
A Parks ◽  
J Karamchandani ◽  
Y Troyanov ◽  
R Massie ◽  
EK O’Ferrall
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Muscle Biopsy ◽  
Diagnostic Yield ◽  
Neuromuscular Disorder ◽  
Next Generation ◽  
Antibody Testing ◽  
Initial Manifestation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

Background: Axial myopathy is a rare neuromuscular disorder of variable etiology characterised by preferential involvement of the paraspinal muscles. We reviewed clinical features of patients with axial myopathies and the diagnostic yield of myositis-associated antibodies and targeted next generation sequencing panels. Methods: We performed a retrospective review of patients presenting with axial myopathy at the Montreal Neurological Hospital from 2011-2018. Data collection included clinical presentation, disease course, results of electromyography, imaging, laboratory and genetic testing, and histopathology on muscle biopsy. Results: Twenty-five patients were identified. Initial manifestation of axial weakness was head drop (15), camptocormia (8), and rigid spine (2). Autoimmune myositis was diagnosed in 9 patients, seropositive in 7 out of 7 tested for myositis-associated antibodies. Genetic testing was consistent with oculopharyngeal muscular dystrophy in one patient and RYR-1 (ryanodine receptor 1) related core myopathy in another. Local radiotherapy or spine surgery preceded the onset of axial weakness in 1 and 6 patients, respectively. Muscle biopsies were available in 17 patients and revealed myopathic changes (16), inflammatory changes (6), and myopathy with vacuoles (3). Conclusions: Recent advancements in genetic and antibody testing, combined with paraspinal muscle biopsy, allow for more precise classification and identification of potentially treatable axial myopathies.

scholarly journals Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients

2021 ◽  
Author(s):  
Mohamed Z. Alimohamed ◽  
LennartF. Johansson ◽  
Anna Posafalvi ◽  
Ludolf G. Boven ◽  
Krista K. van Dijk ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

High diagnostic yield of syndromic intellectual disability by targeted next-generation sequencing

2016 ◽  
Vol 54 (2) ◽  
pp. 87-92 ◽  
Author(s):  
Francisco Martínez ◽  
Alfonso Caro-Llopis ◽  
Mónica Roselló ◽  
Silvestre Oltra ◽  
Sonia Mayo ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
High Diagnostic Yield ◽  
Generation Sequencing

scholarly journals Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain

Genes ◽  
2020 ◽  
Vol 11 (5) ◽  
pp. 539
Author(s):  
Lidia Gonzalez-Quereda ◽  
Maria Jose Rodriguez ◽  
Jordi Diaz-Manera ◽  
Jorge Alonso-Perez ◽  
Eduard Gallardo ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Neuromuscular Disorders ◽  
Neuromuscular Disorder ◽  
Gene Panel ◽  
Muscular Dystrophies ◽  
Next Generation ◽  
Congenital Myasthenic Syndromes ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing ◽  
Myasthenic Syndromes

The term neuromuscular disorder (NMD) includes many genetic and acquired diseases and differential diagnosis can be challenging. Next-generation sequencing (NGS) is especially useful in this setting given the large number of possible candidate genes, the clinical, pathological, and genetic heterogeneity, the absence of an established genotype-phenotype correlation, and the exceptionally large size of some causative genes such as TTN, NEB and RYR1. We evaluated the diagnostic value of a custom targeted next-generation sequencing gene panel to study the mutational spectrum of a subset of NMD patients in Spain. In an NMD cohort of 207 patients with congenital myopathies, distal myopathies, congenital and adult-onset muscular dystrophies, and congenital myasthenic syndromes, we detected causative mutations in 102 patients (49.3%), involving 42 NMD-related genes. The most common causative genes, TTN and RYR1, accounted for almost 30% of cases. Thirty-two of the 207 patients (15.4%) carried variants of uncertain significance or had an unidentified second mutation to explain the genetic cause of the disease. In the remaining 73 patients (35.3%), no candidate variant was identified. In combination with patients’ clinical and myopathological data, the custom gene panel designed in our lab proved to be a powerful tool to diagnose patients with myopathies, muscular dystrophies and congenital myasthenic syndromes. Targeted NGS approaches enable a rapid and cost-effective analysis of NMD- related genes, offering reliable results in a short time and relegating invasive techniques to a second tier.

scholarly journals Targeted next generation sequencing identifies a genetic spectrum of DNA variants in patients with hemiplegic migraine

2019 ◽  
Vol 2 ◽  
pp. 251581631988163 ◽  
Author(s):  
Neven Maksemous ◽  
Robert A Smith ◽  
Heidi G Sutherland ◽  
Bridget H Maher ◽  
Omar Ibrahim ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Next Generation ◽  
Hemiplegic Migraine ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance ◽  
High Mutation Frequency ◽  
Unknown Significance ◽  
Atp1a2 Gene ◽  
Generation Sequencing

Objective: Hemiplegic migraine in both familial (FHM) and sporadic (SHM) forms is a rare subtype of migraine with aura that can be traced to mutations in the CACNA1A, ATP1A2 and SCN1A genes. It is characterised by severe attacks of typical migraine accompanied by hemiparesis, as well as episodes of complex aura that vary significantly between individuals. Methods: Using a targeted next generation sequencing (NGS) multigene panel, we have sequenced the genomic DNA of 172 suspected hemiplegic migraine cases, in whom no mutation had previously been found by Sanger sequencing (SS) of a limited number of exons with high mutation frequency in FHM genes. Results: Genetic screening identified 29 variants, 10 of which were novel, in 35 cases in the three FHM genes ( CACNA1A, ATP1A2 and SCN1A). Interestingly, in this suspected HM cohort, the ATP1A2 gene harboured the highest number of variants with 24/35 cases (68.6%), while CACNA1A ranked the second gene, with 5 variants identified in 7/35 cases (20%). All detected variants were confirmed by SS and were absent in 100 non-migraine healthy control individuals. Assessment of variants with the American College of Medical Genetics and Genomics guidelines classified 8 variants as pathogenic, 3 as likely pathogenic and 18 as variants of unknown significance. Targeted NGS gene panel increased the diagnostic yield by fourfold over iterative SS in our diagnostics facility. Conclusion: We have identified 29 potentially causative variants in an Australian and New Zealand cohort of suspected HM cases and found that the ATP1A2 gene was the most commonly mutated gene. Our results suggest that screening using NGS multigene panels to investigate ATP1A2 alongside CACNA1A and SCN1A is a clinically useful and efficient method.

scholarly journals Next-generation sequencing in childhood-onset epilepsies: Diagnostic yield and impact on neuronal ceroid lipofuscinosis type 2 (CLN2) disease diagnosis

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0255933
Author(s):  
Kimberly Gall ◽  
Emanuela Izzo ◽  
Eija H. Seppälä ◽  
Kirsi Alakurtti ◽  
Lotta Koskinen ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Next Generation ◽  
Childhood Onset ◽  
Ceroid Lipofuscinosis ◽  
Generation Sequencing

Epilepsy is one of the most common childhood-onset neurological conditions with a genetic etiology. Genetic diagnosis provides potential for etiologically-based management and treatment. Existing research has focused on early-onset (<24 months) epilepsies; data regarding later-onset epilepsies is limited. The goal of this study was to determine the diagnostic yield of a clinically available epilepsy panel in a selected pediatric epilepsy cohort with epilepsy onset between 24–60 months of life and evaluate whether this approach decreases the age of diagnosis of neuronal ceroid lipofuscinosis type 2 (CLN2). Next-generation sequencing (NGS)-based epilepsy panels, including genes associated with epileptic encephalopathies and inborn errors of metabolism (IEMs) that present with epilepsy, were used. Copy-number variant (CNV) detection from NGS data was included. Variant interpretation was performed per American College of Medical Genetics and Genomics (ACMG) guidelines. Results are reported from 211 consecutive patients with the following inclusion criteria: 24–60 months of age at the time of enrollment, first unprovoked seizure at/after 24 months, and at least one additional finding such as EEG/MRI abnormalities, speech delay, or motor symptoms. Median age was 42 months at testing and 30 months at first seizure onset; the mean delay from first seizure to comprehensive genetic testing was 10.3 months. A genetic diagnosis was established in 43 patients (20.4%). CNVs were reported in 25.6% diagnosed patients; 27.3% of CNVs identified were intragenic. Within the diagnosed cohort, 11 (25.6%) patients were diagnosed with an IEM. The predominant molecular diagnosis was CLN2 (14% of diagnosed patients). For these patients, diagnosis was achieved 12–24 months earlier than reported by natural history of the disease. This study supports comprehensive genetic testing for patients whose first seizure occurs ≥ 24 months of age. It also supports early application of testing in this age group, as the identified diagnoses can have significant impact on patient management and outcome.

scholarly journals Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation

BMJ Open ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. e021632 ◽  
Author(s):  
Juliette Bacquet ◽  
Tanya Stojkovic ◽  
Amandine Boyer ◽  
Nathalie Martini ◽  
Frédérique Audic ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Sanger Sequencing ◽  
Diagnostic Yield ◽  
Motor Neuropathy ◽  
Peripheral Neuropathies ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Generation Sequencing

PurposeInherited peripheral neuropathies (IPN) represent a large heterogenous group of hereditary diseases with more than 100 causative genes reported to date. In this context, targeted next-generation sequencing (NGS) offers the opportunity to screen all these genes with high efficiency in order to unravel the genetic basis of the disease. Here, we compare the diagnostic yield of targeted NGS with our previous gene by gene Sanger sequencing strategy. We also describe several novel likely pathogenic variants.Design and participantsWe have completed the targeted NGS of 81 IPN genes in a cohort of 123 unrelated patients affected with diverse forms of IPNs, mostly Charcot-Marie-Tooth disease (CMT): 23% CMT1, 52% CMT2, 9% distal hereditary motor neuropathy, 7% hereditary sensory and autonomic neuropathy and 6.5% intermediate CMT.ResultsWe have solved the molecular diagnosis in 49 of 123 patients (~40%). Among the identified variants, 26 variants were already reported in the literature. In our cohort, the most frequently mutated genes are respectively:MFN2,SH3TC2,GDAP1,NEFL,GAN,KIF5AandAARS. Panel-based NGS was more efficient in familial cases than in sporadic cases (diagnostic yield 49%vs19%, respectively). NGS-based search for copy number variations, allowed the identification of three duplications in three patients and raised the diagnostic yield to 41%. This yield is two times higher than the one obtained previously by gene Sanger sequencing screening. The impact of panel-based NGS screening is particularly important for demyelinating CMT (CMT1) subtypes, for which the success rate reached 87% (36% only for axonal CMT2).ConclusionNGS allowed to identify causal mutations in a shorter and cost-effective time. Actually, targeted NGS is a well-suited strategy for efficient molecular diagnosis of IPNs. However, NGS leads to the identification of numerous variants of unknown significance, which interpretation requires interdisciplinary collaborations between molecular geneticists, clinicians and (neuro)pathologists.

scholarly journals Targeted next-generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma

2019 ◽  
Vol 56 (8) ◽  
pp. 513-520 ◽  
Author(s):  
Laurène Ben Aim ◽  
Pascal Pigny ◽  
Luis Jaime Castro-Vega ◽  
Alexandre Buffet ◽  
Laurence Amar ◽  
...  
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Retrospective Cohort ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Genetic Mechanisms ◽  
Large Rearrangements ◽  
Next Generation Sequencing Ngs ◽  
Genetic Events ◽  
Generation Sequencing

BackgroundKnowing the genetic status of patients affected by paragangliomas and pheochromocytomas (PPGL) is important for the guidance of their management and their relatives. Our objective was to improve the diagnostic performances of PPGL genetic testing by next-generation sequencing (NGS).MethodsWe developed a custom multigene panel, which includes 17 PPGL genes and is compatible with both germline and tumour DNA screening. The NGS assay was first validated in a retrospective cohort of 201 frozen tumour DNAs and then applied prospectively to 623 DNAs extracted from leucocytes, frozen or paraffin-embedded PPGL tumours.ResultsIn the retrospective cohort, the sensitivity of the NGS assay was evaluated at 100% for point and indels mutations and 86% for large rearrangements. The mutation rate was re-evaluated from 65% (132/202) to 78% (156/201) after NGS analysis. In the prospective cohort, NGS detected not only germline and somatic mutations but also co-occurring variants and mosaicism. A mutation was identified in 74% of patients for whom both germline and tumour DNA were available.ConclusionThe analysis of 824 DNAs from patients with PPGL demonstrated that NGS assay significantly improves the performances of PPGL genetic testing compared with conventional methods, increasing the rate of identified mutations and identifying rare genetic mechanisms.

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