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 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 Next-Generation Sequencing-Based Genetic Diagnostic Strategies of Inherited Kidney Diseases

2021 ◽  
pp. 425-437
Author(s):  
Jiahui Zhang ◽  
Changming Zhang ◽  
Erzhi Gao ◽  
Qing Zhou
Keyword(s):  
Genetic Testing ◽  
Next Generation Sequencing ◽  
Kidney Diseases ◽  
Genetic Diagnosis ◽  
Life Quality ◽  
Biological Data ◽  
Next Generation ◽  
Diagnostic Strategies ◽  
Wide Range ◽  
Generation Sequencing

<b><i>Background:</i></b> At least 10% of adults and most of the children who receive renal replacement therapy have inherited kidney diseases. These disorders substantially decrease their life quality and have a large effect on the health-care system. Multisystem complications, with typical challenges for rare disorders, including variable phenotypes and fragmented clinical and biological data, make genetic diagnosis of inherited kidney disorders difficult. In current clinical practice, genetic diagnosis is important for clinical management, estimating disease development, and applying personal treatment for patients. <b><i>Summary:</i></b> Inherited kidney diseases comprise hundreds of different disorders. Here, we have summarized various monogenic kidney disorders. These disorders are caused by mutations in genes coding for a wide range of proteins including receptors, channels/transporters, enzymes, transcription factors, and structural components that might also have a role in extrarenal organs (bone, eyes, brain, skin, ear, etc.). With the development of next-generation sequencing technologies, genetic testing and analysis become more accessible, promoting our understanding of the pathophysiologic mechanisms of inherited kidney diseases. However, challenges exist in interpreting the significance of genetic variants and translating them to guide clinical managements. Alport syndrome is chosen as an example to introduce the practical application of genetic testing and diagnosis on inherited kidney diseases, considering its clinical features, genetic backgrounds, and genetic testing for making a genetic diagnosis. <b><i>Key Messages:</i></b> Recent advances in genomics have highlighted the complexity of Mendelian disorders, which is due to allelic heterogeneity (distinct mutations in the same gene produce distinct phenotypes), locus heterogeneity (mutations in distinct genes result in similar phenotypes), reduced penetrance, variable expressivity, modifier genes, and/or environmental factors. Implementation of precision medicine in clinical nephrology can improve the clinical diagnostic rate and treatment efficiency of kidney diseases, which requires a good understanding of genetics for nephrologists.

scholarly journals Genetic Analysis Using a Next Generation Sequencing-Based Gene Panel in Patients With Skeletal Dysplasia: A Single-Center Experience

2021 ◽  
Vol 12 ◽  
Author(s):  
Su Jin Kim ◽  
Sae-Mi Lee ◽  
Jong-Moon Choi ◽  
Ja-Hyun Jang ◽  
Hyun Gi Kim ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Skeletal Dysplasia ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Clinical Manifestations ◽  
Gene Panel ◽  
Next Generation ◽  
Skeletal Involvement ◽  
Diagnosis Rate ◽  
Generation Sequencing

Skeletal dysplasia (SD), a heterogeneous disease group with rare incidence and various clinical manifestations, is associated with multiple causative genes. For clinicians, accurate diagnosis of SD is clinically and genetically difficult. The development of next-generation sequencing (NGS) has substantially aided in the genetic diagnosis of SD. In this study, we conducted a targeted NGS of 437 genes – included in the nosology of SD published in 2019 – in 31 patients with a suspected SD. The clinical and genetic diagnoses were confirmed in 16 out of the 31 patients, and the diagnostic yield was 51.9%. In these patients, 18 pathogenic variants were found in 13 genes (COL2A1, MYH3, COMP, MATN3, CTSK, EBP, CLCN7, COL1A2, EXT1, TGFBR1, SMAD3, FIG4, and ARID1B), of which, four were novel variants. The diagnosis rate was very high in patients with a suspected familial SD and with radiological evidence indicating clinical SD (11 out of 15, 73.3%). In patients with skeletal involvement and other clinical manifestations including dysmorphism or multiple congenital anomalies, and various degrees of developmental delay/intellectual disability, the diagnosis rate was low (5 out of 16, 31.2%) but rare syndromic SD could be diagnosed. In conclusion, NGS-based gene panel sequencing can be helpful in diagnosing SD which has clinical and genetic heterogeneity. To increase the diagnostic yield of suspected SD patients, it is important to categorize patients based on the clinical features, family history, and radiographic evidence.

scholarly journals High Diagnostic Yield of Targeted Next-Generation Sequencing in a Cohort of Patients With Congenital Hypothyroidism Due to Dyshormonogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Athanasia Stoupa ◽  
Ghada Al Hage Chehade ◽  
Rim Chaabane ◽  
Dulanjalee Kariyawasam ◽  
Gabor Szinnai ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Congenital Hypothyroidism ◽  
Diagnostic Yield ◽  
Genetic Defect ◽  
Genetic Diagnosis ◽  
Compound Heterozygous ◽  
Next Generation ◽  
Hormone Production ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

ObjectiveTo elucidate the molecular cause in a well-characterized cohort of patients with Congenital Hypothyroidism (CH) and Dyshormonogenesis (DH) by using targeted next-generation sequencing (TNGS).Study designWe studied 19 well-characterized patients diagnosed with CH and DH by targeted NGS including genes involved in thyroid hormone production. The pathogenicity of novel mutations was assessed based on in silico prediction tool results, functional studies when possible, variant location in important protein domains, and a review of the recent literature.ResultsTNGS with variant prioritization and detailed assessment identified likely disease-causing mutations in 10 patients (53%). Monogenic defects most often involved TG, followed by DUOXA2, DUOX2, and NIS and were usually homozygous or compound heterozygous. Our review shows the importance of the detailed phenotypic description of patients and accurate analysis of variants to provide a molecular diagnosis.ConclusionsIn a clinically well-characterized cohort, TNGS had a diagnostic yield of 53%, in accordance with previous studies using a similar strategy. TG mutations were the most common genetic defect. TNGS identified gene mutations causing DH, thereby providing a rapid and cost-effective genetic diagnosis in patients with CH due to DH.

scholarly journals Rapid Exome Sequencing for Critically Ill Children: Implementation and Challenges in the Asian Context

2021 ◽  
Author(s):  
Nikki Fong ◽  
Jiin Ying Lim ◽  
Breana Cham ◽  
Sylvia Kam ◽  
Chew Yin Goh ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Critically Ill ◽  
Diagnostic Yield ◽  
Genetic Disorders ◽  
Genetic Diagnosis ◽  
Critically Ill Children ◽  
Diagnostic Study ◽  
Next Generation ◽  
Paediatric Patients ◽  
Generation Sequencing

Abstract Objective: Use rapid next-generation sequencing (NGS) to improve our diagnostic yield in critically ill paediatric patients with suspected genetic disorders in the Asian setting.Design: A diagnostic study conducted between April 2018 and January 2019.Methods: Next-generation sequencing was performed with the TruSight One gene panel (targeting 4813 genes) followed by MiSeq sequencing on 10 patients who presented with suspected genetic disorders as assessed by their attending physicians. Results: In 4 of the 10 cases (40%), a genetic diagnosis was achieved, with one further case diagnosed on re-analysis of data 2 years later. The median turn-around time (TAT) for results was 9.5 working days (range 5-19 days). Challenges faced during implementation included sample availability, managing parental and primary physician expectations, cost of testing, and bioinformatic resources.Conclusion: RapidSeq is an effective method for diagnosing patients with rare diseases, which aids in shortening the diagnostic odyssey, while allowing clinicians to appropriately tailor management for the underlying disorder, and provide accurate genetic counselling for families. However, challenges such as cost and insurance implications still remain a barrier to more widespread use of genomic testing in the local setting, and continued efforts will be required to optimise RapidSeq for use in paediatric patients in the ICU.

scholarly journals Next-Generation Sequencing Facilitates Genetic Diagnosis And Improves The Management Of Patients With Hearing Loss In Clinical Practice

2021 ◽  
Author(s):  
Chang Liu ◽  
Yanlin Huang ◽  
Yan Zhang ◽  
Hongke Ding ◽  
Lihua Yu ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Clinical Practice ◽  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Study Cohort ◽  
Inheritance Pattern ◽  
Next Generation ◽  
Effective Manner ◽  
Generation Sequencing

Abstract Background: Hearing loss (HL) is a prevalent sensorineural disorder, and is among the most etiologically heterogeneous disorders. With the advent of next-generation sequencing (NGS) technologies, hundreds of candidate genes can be analyzed simultaneously in a cost-effective manner. Methods: 94 patients from 87 families diagnosed with non-syndromic or syndromic hearing loss were enrolled. A custom-designed HL panel and clinical exome sequencing (CES) were applied to explore molecular etiology in the cohort, and the efficacy of the two panels was examined. Results: The etiologic diagnosis for hearing loss has been arrived at 40 out of 94 patients (42.6%), 28 with an autosomal recessive (AR) inheritance pattern and 12 with an autosomal dominant (AD) pattern. Candidate variants in 19 different genes were identified in the study cohort, 11 with AR inheritance pattern and 8 with AD pattern. 14 of the variants identified in the study were novel. Compared with CES, the custom-designed HL panel has comparatively higher diagnostic yield (61.5% vs. 29.1%), less expensive price, similar turn-around time, and can be used as an efficient diagnostic tool for hearing loss in the clinical practice. Conclusions: Next-generation sequencing facilitates genetic diagnosis and improves the management of patients with hearing loss in the clinical practice.

scholarly journals Next generation sequencing (NGS) to improve the diagnosis and management of patients with disorders of sex development (DSD)

2019 ◽  
Vol 8 (2) ◽  
pp. 100-110 ◽  
Author(s):  
L A Hughes ◽  
K McKay-Bounford ◽  
E A Webb ◽  
P Dasani ◽  
S Clokie ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Patient Management ◽  
Diagnostic Yield ◽  
Management Strategies ◽  
Genetic Diagnosis ◽  
Disorders Of Sex Development ◽  
Next Generation ◽  
Sex Development ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Disorders of sex development (DSDs) are a diverse group of conditions where the chromosomal, gonadal or anatomical sex can be atypical. The highly heterogeneous nature of this group of conditions often makes determining a genetic diagnosis challenging. Prior to next generation sequencing (NGS) technologies, genetic diagnostic tests were only available for a few of the many DSD-associated genes, which consequently had to be tested sequentially. Genetic testing is key in establishing the diagnosis, allowing for personalised management of these patients. Pinpointing the molecular cause of a patient’s DSD can significantly impact patient management by informing future development needs, altering management strategies and identifying correct inheritance pattern when counselling family members. We have developed a 30-gene NGS panel, designed to be used as a frontline test for all suspected cases of DSD (both 46,XX and 46,XY cases). We have confirmed a diagnosis in 25 of the 80 patients tested to date. Confirmed diagnoses were linked to mutations in AMH, AMHR2, AR, HSD17B3, HSD3B2, MAMLD1, NR5A1, SRD5A2 and WT1 which have resulted in changes to patient management. The minimum diagnostic yield for patients with 46,XY DSD is 25/73. In 34/80 patients, only benign or likely benign variants were identified, and in 21/80 patients only variants of uncertain significance (VOUS) were identified, resulting in a diagnosis not being confirmed in these individuals. Our data support previous studies that an NGS panel approach is a clinically useful and cost-effective frontline test for patients with DSDs.

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