scholarly journals Diagnostic Yield and Therapeutic Consequences of Targeted Next-Generation Sequencing in Sporadic Primary Immunodeficiency

2021 ◽  
pp. 1-13
Author(s):  
Georgios Sogkas ◽  
Natalia Dubrowinskaja ◽  
Katharina Schütz ◽  
Lars Steinbrück ◽  
Jasper Götting ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Primary Immunodeficiency ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Immune Dysregulation ◽  
Primary Immunodeficiencies ◽  
Target Enrichment ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

<b><i>Introduction:</i></b> Primary immunodeficiencies (PIDs) are a heterogeneous group of disorders characterized by increased susceptibility to infections, immune dysregulation, and/or malignancy. Genetic studies, especially during the last decade, led to a better understanding of the pathogenesis of primary immunodeficiencies and contributed to their classification into distinct monogenic disorders falling under one of the &#x3e;430 currently known inborn errors of immunity (IEI). The growing availability of molecular genetic testing resulted in the increasing identification of patients with IEI. Here, we evaluated the diagnostic yield and the clinical consequences of targeted next-generation sequencing (tNGS) in a cohort of 294 primary immunodeficiency patients, primarily consisting of cases with sporadic primary antibody deficiency. <b><i>Method:</i></b> We have custom designed a tNGS panel to sequence a cohort of PID patients. Agilent’s HaloPlex Target Enrichment System for Illumina was used for DNA target enrichment. <b><i>Results:</i></b> tNGS identified a definite or predicted pathogenic variant in 15.3% of patients. The highest diagnostic rate was observed among patients with combined immunodeficiency or immune dysregulation, for whom genetic diagnosis may affect therapeutic decision-making. <b><i>Conclusion:</i></b> Next-generation sequencing has changed diagnostic assignment and paved the way for targeted therapeutic intervention with agents directed at reverting the disease-causing molecular abnormality or its pathophysiological consequences. Therefore, such targeted therapies and identifying the genetic basis of PID can be essential for patients with manifested immune dysregulation as conventional immunomodulatory regimens may exert an immunosuppressive effect, aggravating their immunodeficiency or may only inadequately control autoimmune or lymphoproliferative manifestations.

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 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 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 Molekuláris genetikai vizsgálatok primer immundefektusokban

2018 ◽  
Vol 159 (49) ◽  
pp. 2095-2112
Author(s):  
Melinda Erdős
Keyword(s):  
Next Generation Sequencing ◽  
Primary Immunodeficiency ◽  
Molecular Genetic ◽  
Primary Immunodeficiencies ◽  
Genetic Diagnostics ◽  
Next Generation ◽  
Advantages And Disadvantages ◽  
Whole Exome ◽  
Molecular Genetic Diagnostics ◽  
Generation Sequencing

Abstract: Next generation sequencing methods represent the latest era of molecular genetic diagnostics. After a general introduction on primary immunodeficiencies, the author summarizes the importance of molecular genetic studies, especially next generation sequencing in the diagnosis of primary immunodeficiencies. Another purpose of the manuscript is to give a brief summary on the methodological basis of next generation sequencing. The author analyzes the advantages and disadvantages of primary immunodeficiency gene-panel sequencing and whole-exome and whole-genome sequencing. Primary immunodeficiency genes and diseases recognized by next generation sequencing is also summarized. Finally, the author emphasizes the indispensability of gene level diagnostics in primary immunodeficiencies and presents the results achieved in this field in Hungary. Orv Hetil. 2018; 159(49): 2095–2112.

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.

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