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 Assessment of the incorporation of CNV surveillance into gene panel next-generation sequencing testing for inherited retinal diseases

2017 ◽  
Vol 55 (2) ◽  
pp. 114-121 ◽  
Author(s):  
Jamie M Ellingford ◽  
Bradley Horn ◽  
Christopher Campbell ◽  
Gavin Arno ◽  
Stephanie Barton ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Diagnostic Yield ◽  
Diagnostic Testing ◽  
Read Depth ◽  
Gene Panel ◽  
Genomic Variation ◽  
Next Generation ◽  
Diagnostic Laboratory ◽  
Inherited Retinal Dystrophies ◽  
Generation Sequencing

BackgroundDiagnostic use of gene panel next-generation sequencing (NGS) techniques is commonplace for individuals with inherited retinal dystrophies (IRDs), a highly genetically heterogeneous group of disorders. However, these techniques have often failed to capture the complete spectrum of genomic variation causing IRD, including CNVs. This study assessed the applicability of introducing CNV surveillance into first-tier diagnostic gene panel NGS services for IRD.MethodsThree read-depth algorithms were applied to gene panel NGS data sets for 550 referred individuals, and informatics strategies used for quality assurance and CNV filtering. CNV events were confirmed and reported to referring clinicians through an accredited diagnostic laboratory.ResultsWe confirmed the presence of 33 deletions and 11 duplications, determining these findings to contribute to the confirmed or provisional molecular diagnosis of IRD for 25 individuals. We show that at least 7% of individuals referred for diagnostic testing for IRD have a CNV within genes relevant to their clinical diagnosis, and determined a positive predictive value of 79% for the employed CNV filtering techniques.ConclusionIncorporation of CNV analysis increases diagnostic yield of gene panel NGS diagnostic tests for IRD, increases clarity in diagnostic reporting and expands the spectrum of known disease-causing mutations.

scholarly journals Designing Myeloid Gene Panels

2021 ◽  
Author(s):  
Fang Zhao ◽  
David S. Bosler ◽  
James R. Cook
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Pathology ◽  
Diagnostic Yield ◽  
Gene Panel ◽  
Next Generation ◽  
Gene Set ◽  
Variants Of Unknown Significance ◽  
The Core ◽  
Unknown Significance ◽  
Generation Sequencing

Context.— Next-generation sequencing studies are increasingly used in the evaluation of suspected chronic myeloid neoplasms (CMNs), but there is wide variability among laboratories in the genes analyzed for this purpose. Recently, the Association for Molecular Pathology CMN working group recommended a core 34-gene set as a minimum target list for evaluation of CMNs. This list was recommended based on literature review, and its diagnostic yield in clinical practice is unknown. Objective.— To determine the diagnostic yield of the core 34 genes and assess the potential impact of including selected additional genes. Design.— We retrospectively reviewed 185 patients with known or suspected CMNs tested using a 62-gene next-generation sequencing panel that included all 34 core genes. Results.— The Association for Molecular Pathology's core 34 genes had a diagnostic yield of 158 of 185 (85.4%) to detect at least 1 variant with strong/potential clinical significance and 107 of 185 (57.8%) to detect at least 2 such variants. The 62-gene panel had a diagnostic yield of 160 of 185 (86.5%) and 112 of 185 (60.5%), respectively. Variants of unknown significance were identified in 49 of 185 (26.5%) using the core 34 genes versus 76 of 185 (41.1%) using the 62-gene panel. Conclusions.— This study demonstrates that the Association for Molecular Pathology–recommended core 34-gene set has a high diagnostic yield in CMNs. Inclusion of selected additional genes slightly increases the rate of abnormal results, while also increasing the detection of variants of unknown significance. We recommend inclusion of CUX1, DDX41, ETNK1, RIT1, and SUZ12 in addition to the Association for Molecular Pathology's 34-gene core set for routine evaluation of CMNs.

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 Diagnostic Utility of Next-Generation Sequencing-Based Panel Testing in 543 Patients with Suspected Skeletal Dysplasia

2021 ◽  
Author(s):  
Alicia Scocchia ◽  
Tiia Kangas-Kontio ◽  
Melita Irving ◽  
Matti Hero ◽  
Inka Saarinen ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Skeletal Dysplasia ◽  
Diagnostic Yield ◽  
Diagnostic Utility ◽  
Next Generation ◽  
Patient Reports ◽  
Panel Testing ◽  
Generation Sequencing ◽  
Growth Disorder

Abstract Background: Skeletal dysplasia is typically diagnosed using a combination of radiographic imaging, clinical examinations, and molecular testing. Identifying a molecular diagnosis for an individual with a skeletal dysplasia can lead to improved clinical care, guide future medical management and treatment, and inform assessment of risk for familial recurrence. The molecular diagnostic utility of multi-gene panel testing using next-generation sequencing (NGS) has not yet been characterized for an unselected population of individuals with suspected skeletal dysplasia. In this study, we retrospectively reviewed patient reports to assess the diagnostic yield, reported variant characteristics, impact of copy number variation, and performance in prenatal diagnostics of panel tests for variants in genes associated with skeletal dysplasia and growth disorders. Results: Clinical reports of consecutive patients with a clinical indication of suspected skeletal dysplasia who underwent panel testing were examined. The 543 patients included in the study submitted samples for diagnostic genetic testing with an indication of suspected skeletal dysplasia or growth disorder and received one of three nested panel tests. A molecular diagnosis was established in 42.0% of patients (n=228/543). Diagnostic variants were identified in 71 genes, nearly half of which (n=35, 49.3%) contributed uniquely to a molecular diagnosis for a single patient in this cohort. Diagnostic yield was significantly higher among fetal samples (58.0%, n=51/88) than postnatal samples (38.9%, n=177/455; z=3.32, p<0.0009). Diagnostic variants in fetal cases were identified across 18 genes. Thirteen diagnostic CNVs were reported, representing 5.7% of diagnostic findings and ranging in size from 241-bp to whole chromosome aneuploidy. Additionally, 11.4% (36/315) of non-diagnostic patient reports had suspicious variants of unknown significance (VUS), in which additional family studies that provide segregation data and/or functional characterization may result in reclassification to likely pathogenic. Conclusions: These findings demonstrate the utility of panel testing for individuals with a suspected skeletal dysplasia or growth disorder, with a particularly high diagnostic yield seen in prenatal cases. Pursuing comprehensive panel testing with high-resolution CNV analysis can provide a diagnostic benefit, given the considerable phenotype overlap amongst skeletal dysplasia conditions.

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 Diagnostic utility of next-generation sequencing-based panel testing in 543 patients with suspected skeletal dysplasia

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Alicia Scocchia ◽  
Tiia Kangas-Kontio ◽  
Melita Irving ◽  
Matti Hero ◽  
Inka Saarinen ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Skeletal Dysplasia ◽  
Diagnostic Yield ◽  
Diagnostic Utility ◽  
Next Generation ◽  
Patient Reports ◽  
Panel Testing ◽  
Generation Sequencing ◽  
Growth Disorder

Abstract Background Skeletal dysplasia is typically diagnosed using a combination of radiographic imaging, clinical examinations, and molecular testing. Identifying a molecular diagnosis for an individual with a skeletal dysplasia can lead to improved clinical care, guide future medical management and treatment, and inform assessment of risk for familial recurrence. The molecular diagnostic utility of multi-gene panel testing using next-generation sequencing (NGS) has not yet been characterized for an unselected population of individuals with suspected skeletal dysplasia. In this study, we retrospectively reviewed patient reports to assess the diagnostic yield, reported variant characteristics, impact of copy number variation, and performance in prenatal diagnostics of panel tests for variants in genes associated with skeletal dysplasia and growth disorders. Results Clinical reports of consecutive patients with a clinical indication of suspected skeletal dysplasia who underwent panel testing were examined. The 543 patients included in the study submitted samples for diagnostic genetic testing with an indication of suspected skeletal dysplasia or growth disorder and received one of three nested panel tests. A molecular diagnosis was established in 42.0% of patients (n = 228/543). Diagnostic variants were identified in 71 genes, nearly half of which (n = 35, 49.3%) contributed uniquely to a molecular diagnosis for a single patient in this cohort. Diagnostic yield was significantly higher among fetal samples (58.0%, n = 51/88) than postnatal samples (38.9%, n = 177/455; z = 3.32, p < 0.0009). Diagnostic variants in fetal cases were identified across 18 genes. Thirteen diagnostic CNVs were reported, representing 5.7% of diagnostic findings and ranging in size from 241-bp to whole chromosome aneuploidy. Additionally, 11.4% (36/315) of non-diagnostic patient reports had suspicious variants of unknown significance (VUS), in which additional family studies that provide segregation data and/or functional characterization may result in reclassification to likely pathogenic. Conclusions These findings demonstrate the utility of panel testing for individuals with a suspected skeletal dysplasia or growth disorder, with a particularly high diagnostic yield seen in prenatal cases. Pursuing comprehensive panel testing with high-resolution CNV analysis can provide a diagnostic benefit, given the considerable phenotype overlap amongst skeletal dysplasia conditions.

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.

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