Recent Advances in the Clinical Application of Next-Generation Sequencing

Ki, Chang‐Seok

doi:10.5223/pghn.2021.24.1.1

Cited by 11 publications

(8 citation statements)

References 25 publications

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“…The overall diagnostic yield of genetic variants identi ed by WES in cohorts of different pathologies varies in the literature from 5% [67], 25,2% [68] to 40 -50% [69, 70], even considering patients with immunological impairment [16,17,71]. From a genetic point of view, these yield variations can be explained, for example, by possible repeated expansion variants, somatic variants and deep intron variants with indeterminate splicing effects [70].…”

Section: Discussionmentioning

confidence: 99%

Genetic Profile of Inborn Errors of Immunity Using Whole Exome Sequencing in Individuals With BCG Localized Adverse Events

Monteiro

Martin

Filippelli-Silva

et al. 2021

Preprint

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Purpose: In Mycobacterium tuberculosis endemic regions, BCG vaccine is administered early after birth to confer protection against severe form of tuberculosis disease. Previous reports suggest that BCG adverse events, even localized ones (BCGitis), can be the first manifestation of immunodeficiency. We investigated children with a history of BCGitis who needed drug treatment looking for possibly pathogenic variants in inborn errors of immunity genes (IEI-genes). Methods: Forty-four probands were evaluated. The exome sequences obtained by Next-Generation Sequencing were filtered for variants in the 344 IEI-genes described by the International Union of Immunological Societies (IUIS) and classified according to the recommendations of the American College of Medical Genetics. The identified candidate variants were validated by Sanger sequencing. Results: Out of the 44 probands, 36 were sporadic cases and 8 were familial cases. Thirty-one in 44 (70.5%) presented immunoallergic or other infectious clinical conditions besides BCGitis; 19 in 44 (43.2%) presented variants classified as pathogenic or likely pathogenic in 17 different IEI-genes, of which 35.3% were genes related to defects in intrinsic and innate immunity, including Mendelian Susceptibility to Mycobacterial Disease (MSMD) genes (IRF8, IFNGR1, JAK1, STAT1, TLR3 and TBK1). Remaining genes were distributed in another five IUIS classifications groups (CARD14, CFH, CHD7, FOXN1, NFAT5, NLRP3, NOD2, PMS2, STAT3, TNFRSF13B and TNFSF12). Conclusion: The high prevalence of pathogenic or likely pathogenic variants found in IEI-genes may be associated with BCGitis, which should be considered a sign of an inborn error of immunity.

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Section: Discussionmentioning

confidence: 99%

Genetic Profile of Inborn Errors of Immunity Using Whole Exome Sequencing in Individuals With BCG Localized Adverse Events

Monteiro

Martin

Filippelli-Silva

et al. 2021

Preprint

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“…2 As of 2016, some papers showed that over 700 genes were reported in syndromic and non-syndromic ID. 1 Ghandil et al reported a novel homozygous variant in an Iranian family with syndromic ID. 3 Therefore, NGS has increased the number of causative genes liked to ID facilitating in the diagnosis of the patients.…”

Section: Introductionmentioning

confidence: 99%

“…These methods have accelerated the identification of causative genes and variants involved in the ethology of disease. 1 ID is a heterogeneous neurodevelopmental disorder characterized by significant impairment in intellectual and adaptive functioning with onset during the developmental period. By a total prevalence of 1%–3%, the disease has extensive phenotypic variability and genetic heterogeneity worldwide.…”

Section: Introductionmentioning

confidence: 99%

Novel variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability in Iranian consanguineous families

Moudi

Mehrjardi

Hozhabri

et al. 2022

Clinical Laboratory Analysis

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Background: Intellectual disability (ID) is a heterogeneous group of neurodevelopmental disorders that is characterized by significant impairment in intellectual and adaptive functioning with onset during the developmental period. Whole-exome sequencing (WES)-based studies in the consanguineous families with individuals affected with ID have shown a high burden of relevant variants. So far, over 700 genes have been reported in syndromic and non-syndromic ID. However, genetic causes in more than 50% of ID patients still remain unclear.Methods: Whole-exome sequencing was applied for investigation of various variants of ID, then Sanger sequencing and in silico analysis in ten patients from five Iranian consanguineous families diagnosed with autosomal recessive neurodevelopmental disorders, intellectual disability, performed for confirming the causative mutation within the probands. The most patients presented moderate-to-severe intellectual disability, developmental delay, seizure, speech problem, high level of lactate, and onset before 10 years. Results:Filtering the data identified by WES, two novel homozygous missense variants in FBXO31 and TIMM50 genes and one previously reported mutation in the CEP290 gene in the probands were found. Sanger sequencing confirmed the homozygote variant's presence of TIMM50 and FBXO31 genes in six patients and two affected siblings in their respective families. Our computational results predicted that the variants are located in the conserved regions across different species and have the impacts on the protein stability. Conclusion:Hence, we provide evidence for the pathogenicity of two novel variants in the patients which will expand our knowledge about potential mutation involved in the heterogeneous disease.

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“…The searching of genetic causative variants is mainly entrusted to Sanger sequencing or qPCR systems, where the exon-by-exon or variant-by-variant approach slows down diagnostic times. Fortunately, the advent of next-generation sequencing (NGS) is revolutionizing the field of both diagnosis and screening, playing a relevant role as a genetic support tool in the diagnosis of LSDs always in combination with biochemical and clinical data [ 11 ]. With NGS, the simultaneous analysis of large numbers of genetic loci and samples can drive down costs and turnaround time; laboratory processes can largely be automated, and a single assay can be used to screen a set of disorders (regardless of whether a biochemical marker is available) [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Design and Validation of a Custom NGS Panel Targeting a Set of Lysosomal Storage Diseases Candidate for NBS Applications

Cognata

Guarnaccia

Morello

et al. 2021

IJMS

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Lysosomal storage diseases (LSDs) are a heterogeneous group of approximately 70 monogenic metabolic disorders whose diagnosis represents an arduous challenge for clinicians due to their variability in phenotype penetrance, clinical manifestations, and high allelic heterogeneity. In recent years, the approval of disease-specific therapies and the rapid emergence of novel rapid diagnostic methods has opened, for a set of selected LSDs, the possibility for inclusion in extensive national newborn screening (NBS) programs. Herein, we evaluated the clinical utility and diagnostic validity of a targeted next-generation sequencing (tNGS) panel (called NBS_LSDs), designed ad hoc to scan the coding regions of six genes (GBA, GAA, SMPD1, IDUA1, GLA, GALC) relevant for a group of LSDs candidate for inclusion in national NBS programs (MPSI, Pompe, Fabry, Krabbe, Niemann Pick A-B and Gaucher diseases). A standard group of 15 samples with previously known genetic mutations was used to test and validate the entire flowchart. Analytical accuracy, sensitivity, and specificity, as well as turnaround time and costs, were assessed. Results showed that the Ion AmpliSeq and Ion Chef System-based high-throughput NBS_LSDs tNGS panel is a fast, accurate, and cost-effective process. The introduction of this technology into routine NBS procedures as a second-tier test along with primary biochemical assays will allow facilitating the identification and management of selected LSDs and reducing diagnostic delay.

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Recent Advances in the Clinical Application of Next-Generation Sequencing

Cited by 11 publications

References 25 publications

Genetic Profile of Inborn Errors of Immunity Using Whole Exome Sequencing in Individuals With BCG Localized Adverse Events

Genetic Profile of Inborn Errors of Immunity Using Whole Exome Sequencing in Individuals With BCG Localized Adverse Events

Novel variants underlying autosomal recessive neurodevelopmental disorders with intellectual disability in Iranian consanguineous families

Design and Validation of a Custom NGS Panel Targeting a Set of Lysosomal Storage Diseases Candidate for NBS Applications

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