scholarly journals Novel TTLL5 Variants Associated with Cone-Rod Dystrophy and Early-Onset Severe Retinal Dystrophy

2021 ◽  
Vol 22 (12) ◽  
pp. 6410
Author(s):  
Vasily Smirnov ◽  
Olivier Grunewald ◽  
Jean Muller ◽  
Christina Zeitz ◽  
Carolin D. Obermaier ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Copy Number Variants ◽  
Cone Dystrophy ◽  
The Novel ◽  
Targeted Next Generation Sequencing ◽  
Large Deletions ◽  
Gene Panels ◽  
Generation Sequencing

Variants of the TTLL5 gene, which encodes tubulin tyrosine ligase-like family member five, are a rare cause of cone dystrophy (COD) or cone-rod dystrophy (CORD). To date, only a few TTLL5 patients have been clinically and genetically described. In this study, we report five patients harbouring biallelic variants of TTLL5. Four adult patients presented either COD or CORD with onset in the late teenage years. The youngest patient had a phenotype of early onset severe retinal dystrophy (EOSRD). Genetic analysis was performed by targeted next generation sequencing of gene panels and assessment of copy number variants (CNV). We identified eight variants, of which six were novel, including two large multiexon deletions in patients with COD or CORD, while the EOSRD patient harboured the novel homozygous p.(Trp640*) variant and three distinct USH2A variants, which might explain the observed rod involvement. Our study highlights the role of TTLL5 in COD/CORD and the importance of large deletions. These findings suggest that COD or CORD patients lacking variants in known genes may harbour CNVs to be discovered in TTLL5, previously undetected by classical sequencing methods. In addition, variable phenotypes in TTLL5-associated patients might be due to the presence of additional gene defects.

Genetic and clinical findings in a Chinese cohort with Leber congenital amaurosis and early onset severe retinal dystrophy

2019 ◽  
Vol 104 (7) ◽  
pp. 932-937 ◽  
Author(s):  
Ke Xu ◽  
Yue Xie ◽  
Tengyang Sun ◽  
Xiaohui Zhang ◽  
Chunjie Chen ◽  
...  
Keyword(s):  
Early Onset ◽  
Retinal Dystrophy ◽  
Case Series ◽  
Clinical Findings ◽  
Chinese Patients ◽  
Pcr Analysis ◽  
Common Mutation ◽  
Essential Information ◽  
Leber Congenital Amaurosis ◽  
Targeted Next Generation Sequencing

BackgroundLeber congenital amaurosis (LCA) and early onset severe retinal dystrophy (EOSRD) are clinically and genetically heterogeneous inherited retinal disorders that cause severe visual impairment in children. The objective of this study was to describe the mutation profile and phenotypic characteristics in Chinese patients with LCA or EOSRD.MethodsRetrospective consecutive case series (2010–2017) study was performed in 148 probands (91 with LCA and 57 with EOSRD). All patients underwent ophthalmic evaluation. Mutations were revealed using targeted next-generation sequencing, followed by Sanger DNA-sequencing and real-time quantitative PCR analysis.ResultsWe identified two diseasing-causing mutations in 88 unrelated patients, heterozygous autosomal dominant mutations in 11 probands and X-linked hemizygous mutations in 11 patients, for an overall mutation detection rate of 74.3% (110/148). We detected 158 different disease-causing mutations involving 14 LCA genes, 16 retinitis pigmentosa or cone-rod dystrophy genes and 3 syndromic retinal dystrophy genes. Of these 158 mutations, 98 were novel. The most common mutation was p.Q141X of AIPL1, with a gene-specific allele frequency of 60%. The first five most frequently mutated genes were AIPL1 (11.0%), RPGRIP1 (8.8%) and CEP290, GUCY2D and RPE65 (each 7.7%) in the patients with LCA and RPGR (12.3%), CRB1 (10.5%), RPE65 (10.5%), RDH12 (7.0%) and RP2 (5.3%) in the patients with EOSRD.ConclusionsOur results revealed that the mutation spectrum of patients with LCA differs from that of the patients with EOSRD and established the configuration of the mutation frequencies for each LCA gene in Chinese patients, thereby providing essential information for future genetic counselling and gene therapy.

scholarly journals Benchmark of tools for CNV detection from NGS panel data in a genetic diagnostics context

2019 ◽  
Author(s):  
José Marcos Moreno-Cabrera ◽  
Jesús del Valle ◽  
Elisabeth Castellanos ◽  
Lidia Feliubadaló ◽  
Marta Pineda ◽  
...  
Keyword(s):  
Copy Number Variants ◽  
Hereditary Diseases ◽  
Next Generation Sequencing Data ◽  
Genetic Diagnostics ◽  
Screening Methods ◽  
Sequencing Data ◽  
Targeted Next Generation Sequencing ◽  
Highly Sensitive ◽  
Ngs Data ◽  
Generation Sequencing

ABSTRACTMotivationAlthough germline copy number variants (CNVs) are the genetic cause of multiple hereditary diseases, detecting them from targeted next-generation sequencing data (NGS) remains a challenge. Existing tools perform well for large CNVs but struggle with single and multi-exon alterations. The aim of this work is to evaluate CNV calling tools working on gene panel NGS data with CNVs up to single-exon resolution and their suitability as a screening step before orthogonal confirmation in genetic diagnostics strategies.ResultsFive tools (DECoN, CoNVaDING, panelcn.MOPS, ExomeDepth and CODEX2) were tested against four genetic diagnostics datasets (495 samples, 231 CNVs), using the default and sensitivity-optimized parameters. Most tools were highly sensitive and specific, but the performance was dataset-dependant. In our in-house datasets, DECoN and panelcn.MOPS with optimized parameters showed enough sensitivity to be used as screening methods in genetic diagnostics.AvailabilityBenchmarking-optimization code is freely available at https://github.com/TranslationalBioinformaticsIGTP/CNVbenchmarkeR.

scholarly journals Next-Generation Sequencing Improves Diagnosis, Prognosis and Clinical Management of Myeloid Neoplasms

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1364 ◽  
Author(s):  
Diego Carbonell ◽  
Julia Suárez-González ◽  
María Chicano ◽  
Cristina Andrés-Zayas ◽  
Juan Carlos Triviño ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number Variants ◽  
Genetic Alterations ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Myeloid Neoplasms ◽  
Diagnostic Samples ◽  
Gene Panels ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Molecular diagnosis of myeloid neoplasms (MN) is based on the detection of multiple genetic alterations using various techniques. Next-generation sequencing (NGS) has been proved as a useful method for analyzing many genes simultaneously. In this context, we analyzed diagnostic samples from 121 patients affected by MN and ten relapse samples from a subset of acute myeloid leukemia patients using two enrichment-capture NGS gene panels. Pathogenicity classification of variants was enhanced by the development and application of a custom onco-hematology score. A total of 278 pathogenic variants were detected in 84% of patients. For structural alterations, 82% of those identified by cytogenetics were detected by NGS, 25 of 31 copy number variants and three out of three translocations. The detection of variants using NGS changed the diagnosis of seven patients and the prognosis of 15 patients and enabled us to identify 44 suitable candidates for clinical trials. Regarding AML, six of the ten relapsed patients lost or gained variants, comparing with diagnostic samples. In conclusion, the use of NGS panels in MN improves genetic characterization of the disease compared with conventional methods, thus demonstrating its potential clinical utility in routine clinical testing. This approach leads to better-adjusted treatments for each patient.

scholarly journals A comprehensive analysis of dominant and recessive parkinsonism genes in REM sleep behavior disorder

2020 ◽  
Author(s):  
Kheireddin Mufti ◽  
Uladzislau Rudakou ◽  
Eric Yu ◽  
Jennifer A. Ruskey ◽  
Farnaz Asayesh ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Copy Number Variants ◽  
Rem Sleep Behavior Disorder ◽  
Behavior Disorder ◽  
European Ancestry ◽  
Compound Heterozygous ◽  
Sleep Behavior ◽  
Targeted Next Generation Sequencing ◽  
Variants Of Unknown Significance

AbstractObjectiveTo examine the role of autosomal dominant (AD) and recessive (AR) Parkinsonism genes in the risk of isolated rapid-eye-movement (REM) sleep behavior disorder (iRBD).MethodsTen genes implicated in AD and AR Parkinsonism were fully sequenced using targeted next-generation sequencing in 1,039 iRBD patients and 1,852 controls of European ancestry. These include the AR genes PRKN, DJ-1 (PARK7), PINK1, VPS13C, ATP13A2, FBXO7 and PLA2G6, and the AD genes LRRK2, GCH1 and VPS35. To examine the role of rare heterozygous variants in these genes, burden test and SKAT-O analyses were performed. The contribution of homozygous and compound heterozygous variants was further examined in the AR genes. Copy number variants (CNVs) in PRKN were tested in a subset of samples (n=374) using multiplex ligation-dependent probe amplification followed by analysis of all samples using ExomeDepth.ResultsWe found no association between rare heterozygous variants in the tested genes and risk for iRBD. Several homozygous and compound heterozygous carriers were identified with variants of unknown significance, yet there was no overrepresentation in iRBD patients versus controls.ConclusionOur results do not support a major role for variants in PRKN, PARK7, PINK1, VPS13C, ATP13A2, FBXO7, PLA2G6, LRRK2, GCH1 and VPS35 in the risk of iRBD.

scholarly journals Germline Pathogenic Variants Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma

2021 ◽  
Vol 8 (1) ◽  
pp. 19-24
Author(s):  
Sinem Yalcintepe ◽  
Hakan Gurkan ◽  
Fatma Nur Korkmaz ◽  
Selma Demir ◽  
Engin Atli ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Susceptibility Genes ◽  
Next Generation ◽  
Clinical Genetic ◽  
Targeted Next Generation Sequencing ◽  
Clinical Genetic Testing ◽  
Pathogenic Variants ◽  
Diagnosis Rate ◽  
Gene Panels ◽  
Generation Sequencing

The aim of this study was to evaluate germline variant frequencies of pheochromocytoma and paraganglioma targeted susceptibility genes with next-generation sequencing method. Germline DNA from 75 cases were evaluated with targeted next-generation sequencing on an Illumina NextSeq550 instrument. KIF1B, RET, SDHB, SDHD, TMEM127, and VHL genes were included in the study, and Sanger sequencing was used for verifying the variants. The pathogenic/likely pathogenic variants were in the VHL, RET, SDHB, and SDHD genes, and the diagnosis rate was 24% in this study. Three different novel pathogenic variants were determined in five cases. This is the first study from Turkey, evaluating germline susceptibility genes of pheochromocytoma and paraganglioma with a detection rate of 24% and three novel variants. All patients with pheochromocytoma and paraganglioma need clinical genetic testing with expanded targeted gene panels for higher diagnosis rates.

scholarly journals A novel variant in PAX6  as the cause of aniridia in a Chinese family

2020 ◽  
Author(s):  
Xin Jin ◽  
Wei Liu ◽  
HouBin Huang ◽  
Linghui Qv ◽  
Wenqin Xv
Keyword(s):  
Autosomal Dominant ◽  
Novel Mutation ◽  
Causative Mutation ◽  
Chinese Family ◽  
The Novel ◽  
Slit Lamp ◽  
Targeted Next Generation Sequencing ◽  
Novel Variant ◽  
Foveal Hypoplasia ◽  
Generation Sequencing

Abstract Background: Aniridia is a kind of congenital human pan-ocular anomaly, which is related to PAX6 commonly.Methods: The ophthalmic examinations including visual acuity, slit lamp and fundoscopy examination were performed in a Chinese aniridia pedigree. The targeted next-generation sequencing of aniridia genes was used to identify the causative mutation.Results: A novel heterozygous PAX6 nonsense mutation c.619A>T (p.K207*) was identified in the Chinese autosomal dominant family with aniridia. Phenotype related to the novel mutation included nystagmus, keratopathy, absence of iris, cataract and foveal hypoplasia.Conclusion: The novel nonsense variation in PAX6 was the cause of aniridia in this family, which expanded the spectrum of the PAX6 mutation.

scholarly journals Deep sequencing of small RNA facilitates tissue and sex specific microRNA discovery in zebrafish

2015 ◽  
Author(s):  
Candida Vaz ◽  
Choon Wei Wee ◽  
Serene Gek Ping Lee ◽  
Philip W Ingham ◽  
Vivek Tanavde ◽  
...  
Keyword(s):  
The Novel ◽  
Sequencing Technology ◽  
Next Generation Sequencing Technology ◽  
Mirna Expression Data ◽  
Mrna Gene ◽  
Gene Regulatory ◽  
Genomic Resource ◽  
The Brain ◽  
Generation Sequencing

Role of microRNAs in gene regulation has been well established. Though the number of genes appear to be equal between human and zebrafish, miRNAs detected in zebrafish (~247) is significantly low compared to human (~2000; miRBase Release 19). It appears that most of the miRNAs in zebrafish are yet to be discovered. Using next generation sequencing technology, we sequenced small RNAs from brain, gut, liver, ovary, testis, eye, heart and embryo of zebrafish. In few tissues (brain, gut, liver) sequencing was done sex specifically. About 16-62% of the sequenced reads mapped to known miRNAs of zebrafish, with the exceptions of ovary (5.7%) and testis (7.8%). We used miRDeep2, the miRNA predication tool, to discover the novel miRNAs using the un-annotated reads that ranged from 7.6 to 23.0%, with exceptions of ovary (51.4%) and testis (55.2%) that had the largest pool of un-annotated reads. The prediction tool identified a total of 459 novel pre-miRNAs. Comparison of miRNA expression data of the tissues showed the presence of tissue and sex specific miRNAs that could serve as biomarkers. The brain and liver had highest number of tissue specific (36) and sex specific (34) miRNAs, respectively. Taken together, we have made a comprehensive approach to identify tissue and sex specific miRNAs from zebrafish. Further, we have discovered 459 novel pre-miRNAs (~30% homology to human miRNA) as additional genomic resource for zebrafish. This resource can facilitate further investigations to understand miRNA-mRNA gene regulatory network in zebrafish which will have implications to understand human miRNA function.

Abstract LB-412: TargetRich™ cancer gene panels: targeted next generation sequencing in cancer samples

2012 ◽  
Author(s):  
Katherine J. Spayd ◽  
Irina Vasenkova ◽  
Tatiana Shvetsova ◽  
Randall C. Bachmeyer ◽  
Richard M. Myers ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Cancer Gene ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Gene Panels ◽  
Generation Sequencing
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