scholarly journals Genetic Profile and Associated Characteristics of 150 Korean Patients with Retinitis Pigmentosa

2021 ◽  
Vol 2021 ◽  
pp. 1-15
Author(s):  
You Na Kim ◽  
Yoon Jeon Kim ◽  
Chang Ahn Seol ◽  
Eul-Ju Seo ◽  
Joo Yong Lee ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Genetic Profile ◽  
Epiretinal Membranes ◽  
Korean Patients ◽  
Targeted Next Generation Sequencing ◽  
Nonlinear Mixed Models ◽  
Targeted Ngs ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Purpose. Retinitis pigmentosa (RP) shows great diversity between genotypes and phenotypes, and it is important to identify the causative genes. This study aimed to analyze the molecular profiles, associated ocular characteristics, and progression of RP in Korean patients. Methods. All the genetic variants in patients with RP, identified using targeted next-generation sequencing (NGS) with a panel of 88 RP-related genes between November 2018 and November 2019, were retrospectively reviewed. All the patients underwent comprehensive ophthalmological evaluations, and their clinical and family histories were recorded. The best-corrected visual acuity (BCVA) deterioration and photoreceptor disruption progression rates were determined based on the major causative mutational genes using nonlinear mixed models, and the differences among them were investigated using the interaction effect. Results. Among the 144 probands, 82 variants in 24 causative genes were identified in 77 families (53.5%). Most of the RP cases were associated with autosomal recessive variants (N = 64 (44.4%)), followed by autosomal dominant (N = 10 (6.9%)) and X-linked variants (N = 3 (2.1%)). The four most frequently affected genes were EYS (N = 15 (10.4%)), USH2A (N = 12 (8.3%)), PDE6B (N = 9 (6.3%)), and RP1 (N = 8 (5.6%)). Epiretinal membranes and cystoid macular edema were frequently noted in the patients with USH2A (75.0%) and PDE6B (50.0%) variants, respectively. During the follow-up period, the BCVA and photoreceptor disruption changes were significantly different among the patients carrying the four common causative genes ( P = 0.014 and 0.034, resp.). Patients with PDE6B variants showed faster BCVA changes (0.2 LogMAR/10 years), and those with USH2A variants showed the fastest ellipsoid zone disruptions (−170.4 µm/year). Conclusion. In conclusion, our genetic analysis using targeted NGS provides information about the prevalence of RP-associated mutations in Korean patients. Delineating clinical characteristics according to genetic variations may help clinicians identify subtype features and predict the clinical course of RP.

scholarly journals The ICR96 exon CNV validation series: a resource for orthogonal assessment of exon CNV calling in NGS data

2017 ◽  
Vol 2 ◽  
pp. 35 ◽  
Author(s):  
Shazia Mahamdallie ◽  
Elise Ruark ◽  
Shawn Yost ◽  
Emma Ramsay ◽  
Imran Uddin ◽  
...  
Keyword(s):  
Sequencing Data ◽  
Targeted Next Generation Sequencing ◽  
Negative Results ◽  
Targeted Ngs ◽  
Predisposition Genes ◽  
Next Generation Sequencing Ngs ◽  
Ngs Data ◽  
Validation Series ◽  
Generation Sequencing ◽  
Dependent Probe

Detection of deletions and duplications of whole exons (exon CNVs) is a key requirement of genetic testing. Accurate detection of this variant type has proved very challenging in targeted next-generation sequencing (NGS) data, particularly if only a single exon is involved. Many different NGS exon CNV calling methods have been developed over the last five years. Such methods are usually evaluated using simulated and/or in-house data due to a lack of publicly-available datasets with orthogonally generated results. This hinders tool comparisons, transparency and reproducibility. To provide a community resource for assessment of exon CNV calling methods in targeted NGS data, we here present the ICR96 exon CNV validation series. The dataset includes high-quality sequencing data from a targeted NGS assay (the TruSight Cancer Panel) together with Multiplex Ligation-dependent Probe Amplification (MLPA) results for 96 independent samples. 66 samples contain at least one validated exon CNV and 30 samples have validated negative results for exon CNVs in 26 genes. The dataset includes 46 exon CNVs in BRCA1, BRCA2, TP53, MLH1, MSH2, MSH6, PMS2, EPCAM or PTEN, giving excellent representation of the cancer predisposition genes most frequently tested in clinical practice. Moreover, the validated exon CNVs include 25 single exon CNVs, the most difficult type of exon CNV to detect. The FASTQ files for the ICR96 exon CNV validation series can be accessed through the European-Genome phenome Archive (EGA) under the accession number EGAS00001002428.

scholarly journals Genetic Variants Detected Using Cell-Free DNA from Blood and Tumor Samples in Patients with Inflammatory Breast Cancer

2020 ◽  
Vol 21 (4) ◽  
pp. 1290
Author(s):  
Jennifer S. Winn ◽  
Zachary Hasse ◽  
Michael Slifker ◽  
Jianming Pei ◽  
Sebastian M. Arisi-Fernandez ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Inflammatory Breast Cancer ◽  
Triple Negative ◽  
Genetic Profile ◽  
Cell Free Dna ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Free Dna ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

We studied genomic alterations in 19 inflammatory breast cancer (IBC) patients with advanced disease using samples of tissue and paired blood serum or plasma (cell-free DNA, cfDNA) by targeted next generation sequencing (NGS). At diagnosis, the disease was triple negative (TN) in eleven patients (57.8%), ER+ Her2- IBC in six patients (31.6%), ER+ Her2+ IBC in one patient (5.3%), and ER- Her2+ IBC in one other patient (5.3%). Pathogenic or likely pathogenic variants were frequently detected in TP53 (47.3%), PMS2 (26.3%), MRE11 (26.3%), RB1 (10.5%), BRCA1 (10.5%), PTEN (10.5%) and AR (10.5%); other affected genes included PMS1, KMT2C, BRCA2, PALB2, MUTYH, MEN1, MSH2, CHEK2, NCOR1, PIK3CA, ESR1 and MAP2K4. In 15 of the 19 patients in which tissue and paired blood were collected at the same time point, 80% of the variants detected in tissue were also detected in the paired cfDNA. Higher concordance between tissue and cfDNA was found for variants with higher allele fraction in tissue (AFtissue ≥ 5%). Furthermore, 86% of the variants detected in cfDNA were also detected in paired tissue. Our study suggests that the genetic profile measured in blood cfDNA is complementary to that of tumor tissue in IBC patients.

scholarly journals New Challenges in Tumor Mutation Heterogeneity in Advanced Ovarian Cancer by a Targeted Next-Generation Sequencing (NGS) Approach

Cells ◽  
2019 ◽  
Vol 8 (6) ◽  
pp. 584 ◽  
Author(s):  
Marica Garziera ◽  
Rossana Roncato ◽  
Marcella Montico ◽  
Elena De Mattia ◽  
Sara Gagno ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Next Generation Sequencing ◽  
Residual Disease ◽  
Advanced Ovarian Cancer ◽  
Genetic Profile ◽  
Next Generation ◽  
Platinum Based Chemotherapy ◽  
Targeted Ngs ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Next-generation sequencing (NGS) technology has advanced knowledge of the genomic landscape of ovarian cancer, leading to an innovative molecular classification of the disease. However, patient survival and response to platinum-based treatments are still not predictable based on the tumor genetic profile. This retrospective study characterized the repertoire of somatic mutations in advanced ovarian cancer to identify tumor genetic markers predictive of platinum chemo-resistance and prognosis. Using targeted NGS, 79 primary advanced (III–IV stage, tumor grade G2-3) ovarian cancer tumors, including 64 high-grade serous ovarian cancers (HGSOCs), were screened with a 26 cancer-genes panel. Patients, enrolled between 1995 and 2011, underwent primary debulking surgery (PDS) with optimal residual disease (RD < 1 cm) and platinum-based chemotherapy as first-line treatment. We found a heterogeneous mutational landscape in some uncommon ovarian histotypes and in HGSOC tumor samples with relevance in predicting platinum sensitivity. In particular, we identified a poor prognostic signature in patients with HGSOC harboring concurrent mutations in two driver actionable genes of the panel. The tumor heterogeneity described, sheds light on the translational potential of targeted NGS approach for the identification of subgroups of patients with distinct therapeutic vulnerabilities, that are modulated by the specific mutational profile expressed by the ovarian tumor.

scholarly journals Differential Mutation Detection Capability Through Capture-Based Targeted Sequencing in Plasma Samples in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Jian Gao ◽  
Lei Xi ◽  
Rentao Yu ◽  
Huailong Xu ◽  
Min Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Circulating Tumor Dna ◽  
Tumor Burden ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Tumor Protein P53 ◽  
Next Generation Sequencing Ngs ◽  
Coding Variants ◽  
G Protein Coupled ◽  
Generation Sequencing

Circulating tumor DNA (ctDNA) is a promising biomarker for accurate monitoring and less invasive assessment of tumor burden and treatment response. Here, targeted next-generation sequencing (NGS) with a designed gene panel of 176 cancer-relevant genes was used to assess mutations in 90 ctDNA samples from 90 patients with multiple types of liver disease and 10 healthy donor samples for control. Using our ctDNA detection panel, we identified mutations in 98.89% (89/90) of patient plasma biopsy samples, and 19 coding variants located in 10 cancer-related genes [ACVR2A, PCLO, TBCK, adhesion G protein-coupled receptor (ADGRV1), COL1A1, GABBR1, MUC16, MAGEC1, FASLG, and JAK1] were identified in 96.7% of patients (87/90). The 10 top mutated genes were tumor protein p53 (TP53), ACVR2A, ADGRV1, MUC16, TBCK, PCLO, COL11A1, titin (TTN), DNAH9, and GABBR1. TTN and TP53 and TTN and DNAH9 mutations tended to occur together in hepatocellular carcinoma samples. Most importantly, we found that most of those variants were insertions (frameshift insertions) and deletions (frameshift deletions and in-frame deletions), such as insertion variants in ACVR2A, PCLO, and TBCK; such mutations were detected in almost 95% of patients. Our study demonstrated that the targeted NGS-based ctDNA mutation profiling was a useful tool for hepatocellular carcinoma (HCC) monitoring and could potentially be used to guide treatment decisions in HCC.

scholarly journals Characterizing the pharmacogenome using molecular inversion probes for targeted next-generation sequencing

2019 ◽  
Vol 20 (14) ◽  
pp. 1005-1020 ◽  
Author(s):  
Oscar Suzuki ◽  
Olivia M Dong ◽  
Rachel M Howard ◽  
Tim Wiltshire
Keyword(s):  
Next Generation Sequencing ◽  
Control Cell ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Technical Performance ◽  
Targeted Ngs ◽  
Molecular Inversion Probes ◽  
Next Generation Sequencing Ngs ◽  
Molecular Inversion Probe ◽  
Generation Sequencing

Aim: This study assesses the technical performance and cost of a targeted next-generation sequencing (NGS) multigene pharmacogenetic (PGx) test. Materials & methods: A genetic test was developed for 21 PGx genes using molecular inversion probes to generate library fragments for NGS. Performance of this test was assessed using 53 unique reference control cell lines from the Genetic Testing Reference Materials Coordination Program (GeT-RM). Results: 93.7% of variants were successfully called and the repeatability rate was 99.9%. Reference calls were available for 78.4% of diplotype calls resulting from PGx testing, and concordance for the test was 85.7%. Cost per sample was $32–$56. Conclusion: A targeted NGS assay using molecular inversion probe technology is able to characterize the pharmacogenome efficiently.

Identification of a Disease-Causing Mutation in a Chinese Patient with Retinitis Pigmentosa by Targeted Next-Generation Sequencing

2017 ◽  
Vol 27 (6) ◽  
pp. 791-796 ◽  
Author(s):  
Jianping Xiao ◽  
Xueqin Guo ◽  
Yong Wang ◽  
Mingkun Shao ◽  
Xiaoming Wei ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinitis Pigmentosa ◽  
Sanger Sequencing ◽  
Bioinformatics Analysis ◽  
Family Members ◽  
Chinese Patient ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Generation Sequencing

Purpose To identify disease-causing mutations in a Chinese patient with retinitis pigmentosa (RP). Methods A detailed clinical examination was performed on the proband. Targeted next-generation sequencing (NGS) combined with bioinformatics analysis was performed on the proband to detect candidate disease-causing mutations. Sanger sequencing was performed on all subjects to confirm the candidate mutations and assess cosegregation within the family. Results Clinical examinations of the proband showed typical characteristics of RP. Three candidate heterozygous mutations in 3 genes associated with RP were detected in the proband by targeted NGS. The 3 mutations were confirmed by Sanger sequencing and the deletion (c.357_358delAA) in PRPF31 was shown to cosegregate with RP phenotype in 7 affected family members, but not in 3 unaffected family members. Conclusions The deletion (c.357_358delAA) in PRPF31 was the disease-causing mutation for the proband and his affected family members with RP. To our knowledge, this is the second report of the deletion and the first report of the other 2 mutations in the Chinese population. Targeted NGS combined with bioinformatics analysis proved to be an effective molecular diagnostic tool for RP.

scholarly journals A Novel p.G141R Mutation in ILDR1 Leads to Recessive Nonsyndromic Deafness DFNB42 in Two Chinese Han Families

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Xueling Wang ◽  
Longhao Wang ◽  
Hu Peng ◽  
Tao Yang ◽  
Hao Wu
Keyword(s):  
Sanger Sequencing ◽  
Pcr Amplification ◽  
Homozygous Mutation ◽  
Frequent Mutation ◽  
Nonsyndromic Deafness ◽  
Chinese Han ◽  
Targeted Next Generation Sequencing ◽  
Targeted Ngs ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Genetic hearing impairment is highly heterogeneous. In this study, targeted next-generation sequencing (NGS) in two Chinese Han families identified a novel p.G141R homozygous mutation in ILDR1 as the genetic cause of the deafness. Consistent with the recessive inheritance, cosegregation of the p.G141R variant with the hearing loss was confirmed in members of both families by PCR amplification and Sanger sequencing. SNP genotyping analysis suggested that those two families were not closely related. Our study showed that targeted NGS is an effective tool for diagnosis of genetic deafness and that p.G141R in ILDR1 may be a relatively frequent mutation for DFNB42 in Chinese Hans.

scholarly journals Improving the Management of Patients with Hearing Loss by the Implementation of an NGS Panel in Clinical Practice

Genes ◽  
2020 ◽  
Vol 11 (12) ◽  
pp. 1467
Author(s):  
Gema García-García ◽  
Alba Berzal-Serrano ◽  
Piedad García-Díaz ◽  
Rebeca Villanova-Aparisi ◽  
Sara Juárez-Rodríguez ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Autosomal Recessive ◽  
Targeted Next Generation Sequencing ◽  
Pathogenic Variants ◽  
Targeted Ngs ◽  
Syndromic Hearing Loss ◽  
Genetics And Genomics ◽  
Custom Panel ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

A cohort of 128 patients from 118 families diagnosed with non-syndromic or syndromic hearing loss (HL) underwent an exhaustive clinical evaluation. Molecular analysis was performed using targeted next-generation sequencing (NGS) with a custom panel that included 59 genes associated with non-syndromic HL or syndromic HL. Variants were prioritized according to the minimum allele frequency and classified according to the American College of Medical Genetics and Genomics guidelines. Variant(s) responsible for the disease were detected in a 40% of families including autosomal recessive (AR), autosomal dominant (AD) and X-linked patterns of inheritance. We identified pathogenic or likely pathogenic variants in 26 different genes, 15 with AR inheritance pattern, 9 with AD and 2 that are X-linked. Fourteen of the found variants are novel. This study highlights the clinical utility of targeted NGS for sensorineural hearing loss. The optimal panel for HL must be designed according to the spectrum of the most represented genes in a given population and the laboratory capabilities considering the pressure on healthcare.

scholarly journals CACNA1B gene variants in adult-onset isolated focal dystonia

2020 ◽  
Author(s):  
Relu Cocoș ◽  
Florina Raicu ◽  
Ovidiu Lucian Băjenaru ◽  
Iulia Olaru ◽  
Laura Dumitrescu ◽  
...  
Keyword(s):  
Frameshift Mutation ◽  
Age At Onset ◽  
Focal Dystonia ◽  
Adult Onset ◽  
Targeted Next Generation Sequencing ◽  
Voltage Gated Calcium Channels ◽  
Targeted Ngs ◽  
Genetic And Environmental Factors ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background Isolated focal dystonia (IFD) is a heterogeneous group of potentially invalidating movement disorders. The etiopathogenesis is complex, both genetic and environmental factors playing a role, but remains elusive. The CACNA1B gene codes for the N-type neuronal voltage-gated calcium channels CaV2.2, which may play a role in the development of some IFD. Methods We analyzed samples from the GENDYS cohort for mutations in CACNA1B gene, using targeted next-generation sequencing (NGS). Results The GENDYS cohort consists of 120 people with adult-onset IFD (cervical dystonia 47.5%, blepharospasm 47.2%, others 8.3%). Of these, 35% had subsequent topographical extension. Average age at onset was 42 and average disease durations 8 years. Targeted NGS revealed a novel frameshift mutation c.2291AGG > A, in exon 19, and a previously reported variant, c.6834T > G, in exon 47. Conclusion Our findings suggest that disease-causing mutations in CACNA1B gene may be involved in the development of some adult-onset IFD. To our knowledge, this is the first study that identified a disease-causing CACNA1B gene mutation in association with adult-onset IFD.

scholarly journals Phenocopy of a heterozygous carrier of X-linked retinitis pigmentosa due to mosaicism for a RHO variant

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ine Strubbe ◽  
Caroline Van Cauwenbergh ◽  
Julie De Zaeytijd ◽  
Sarah De Jaegere ◽  
Marieke De Bruyne ◽  
...  
Keyword(s):  
Retinitis Pigmentosa ◽  
Somatic Mosaicism ◽  
Retinal Disease ◽  
Hair Follicles ◽  
Disease Genes ◽  
Female Carrier ◽  
Autofluorescence Imaging ◽  
Targeted Next Generation Sequencing ◽  
Whole Exome ◽  
Next Generation Sequencing Ngs

AbstractWe describe both phenotype and pathogenesis in two male siblings with typical retinitis pigmentosa (RP) and the potentially X-linked RP (XLRP) carrier phenotype in their mother. Two affected sons, two unaffected daughters, and their mother underwent detailed ophthalmological assessments including Goldmann perimetry, color vision testing, multimodal imaging and ISCEV-standard electroretinography. Genetic testing consisted of targeted next-generation sequencing (NGS) of known XLRP genes and whole exome sequencing (WES) of known inherited retinal disease genes (RetNet-WES). Variant validation and segregation analysis were performed by Sanger sequencing. The mutational load of the RHO variant in the mother was assessed in DNA from leucocytes, buccal cells and hair follicles using targeted NGS. Both affected sons showed signs of classical RP, while the mother displayed patches of hyperautofluorescence on blue light autofluorescence imaging and regional, intraretinal, spicular pigmentation, reminiscent of a carrier phenotype of XLRP. XLRP testing was negative. RetNet-WES testing revealed RHO variant c.404G > C p.(Arg135Pro) in a mosaic state (21% of the reads) in the mother and in a heterozygous state in both sons. Targeted NGQSS of the RHO variant in different maternal tissues showed a mutation load between 25.06% and 41.72%. We report for the first time that somatic mosaicism of RHO variant c.404G > C p.(Arg135Pro) mimics the phenotype of a female carrier of XLRP, in combination with heterozygosity for the variant in the two affected sons.

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