scholarly journals Use of Next-Generation Sequencing for the Molecular Diagnosis of 1,102 Patients With a Autosomal Optic Neuropathy

2021 ◽  
Vol 12 ◽  
Author(s):  
Majida Charif ◽  
Céline Bris ◽  
David Goudenège ◽  
Valérie Desquiret-Dumas ◽  
Estelle Colin ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Retinal Ganglion Cells ◽  
Molecular Diagnosis ◽  
Optic Neuropathy ◽  
Ganglion Cells ◽  
Genetic Disorders ◽  
Retinal Ganglion ◽  
Next Generation ◽  
Pathogenic Variants ◽  
Generation Sequencing

Advances in next-generation sequencing (NGS) facilitate the diagnosis of genetic disorders. To evaluate its use for the molecular diagnosis of inherited optic neuropathy (ION), a blinding disease caused by the degeneration of retinal ganglion cells, we performed genetic analysis using targeted NGS of 22 already known and candidate genes in a cohort of 1,102 affected individuals. The panel design, library preparation, and sequencing reactions were performed using the Ion AmpliSeq technology. Pathogenic variants were detected in 16 genes in 245 patients (22%), including 186 (17%) and 59 (5%) dominant and recessive cases, respectively. Results confirmed that OPA1 variants are responsible for the majority of dominant IONs, whereas ACO2 and WFS1 variants are also frequently involved in both dominant and recessive forms of ION. All pathogenic variants were found in genes encoding proteins involved in the mitochondrial function, highlighting the importance of mitochondria in the survival of retinal ganglion cells.

scholarly journals Next-Generation Sequencing for Molecular Diagnosis of Cystic Fibrosis in a Brazilian Cohort

2021 ◽  
Vol 2021 ◽  
pp. 1-8
Author(s):  
Amanda Cambraia ◽  
Mario Campos Junior ◽  
Verônica Marques Zembrzuski ◽  
Ricardo Magrani Junqueira ◽  
Pedro Hernán Cabello ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Specific Treatment ◽  
Epidemiological Data ◽  
Next Generation ◽  
Gene Encoding ◽  
Access To Treatment ◽  
Pathogenic Variants ◽  
Generation Sequencing

Cystic fibrosis (CF), an autosomal recessive genetic disease, is recognized as one of the most prevalent diseases in Caucasian populations. Epidemiological data show that the incidence of CF varies between countries and ethnic groups in the same region. CF occurs due to pathogenic variants in the gene encoding cystic fibrosis transmembrane conductance regulator (CFTR), located on chromosome 7q31.2. To date, more than 2,000 variants have been registered in the CFTR database. The study of these variants leads to the diagnosis and the possibility of a specific treatment for each patient through precision medicine. In this study, complete screening of CFTR was performed through next-generation sequencing (NGS) to gain insight into the variants circulating in the population of Rio de Janeiro and to provide patient access to treatment through genotype-specific therapies. Samples from 93 patients with an inconclusive molecular diagnosis were subjected to full-length screening of CFTR using an Illumina NGS HiSeq platform. Among these patients, 46 had two pathogenic variants, whereas 12 had only one CFTR variant. Twenty-four variants were not part of our routine screening. Of these 24 variants, V938Gfs ∗ 37 had not been described in the CF databases previously. This research achieved a molecular diagnosis of the patients with CF and identification of possible molecular candidates for genotype-specific treatments.

scholarly journals Challenges in the diagnosis and discovery of rare genetic disorders using contemporary sequencing technologies

2020 ◽  
Vol 19 (4) ◽  
pp. 243-258 ◽  
Author(s):  
Eleanor G Seaby ◽  
Sarah Ennis
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Genetic Disorders ◽  
Next Generation Sequencing Data ◽  
Disease Genes ◽  
Incomplete Penetrance ◽  
Next Generation ◽  
Sequencing Data ◽  
New Gene ◽  
Generation Sequencing

Abstract Next generation sequencing (NGS) has revolutionised rare disease diagnostics. Concomitant with advancing technologies has been a rise in the number of new gene disorders discovered and diagnoses made for patients and their families. However, despite the trend towards whole exome and whole genome sequencing, diagnostic rates remain suboptimal. On average, only ~30% of patients receive a molecular diagnosis. National sequencing projects launched in the last 5 years are integrating clinical diagnostic testing with research avenues to widen the spectrum of known genetic disorders. Consequently, efforts to diagnose genetic disorders in a clinical setting are now often shared with efforts to prioritise candidate variants for the detection of new disease genes. Herein we discuss some of the biggest obstacles precluding molecular diagnosis and discovery of new gene disorders. We consider bioinformatic and analytical challenges faced when interpreting next generation sequencing data and showcase some of the newest tools available to mitigate these issues. We consider how incomplete penetrance, non-coding variation and structural variants are likely to impact diagnostic rates, and we further discuss methods for uplifting novel gene discovery by adopting a gene-to-patient-based approach.

scholarly journals NGS4THAL, a one-stop molecular diagnosis and carrier screening tool for thalassemia and other hemoglobinopathies by next-generation sequencing

2021 ◽  
Author(s):  
Yujie Cao ◽  
Shau Yin Ha ◽  
Chi-Chiu So ◽  
Tong Ming For ◽  
Clara Sze-Man Tang ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Carrier Screening ◽  
Detection Accuracy ◽  
Next Generation ◽  
Sequencing Data ◽  
Pathogenic Variants ◽  
Accurate Detection ◽  
Ngs Data ◽  
Generation Sequencing

Abstract Background Thalassemia is one of the most common genetic diseases and a major health threat worldwide. Accurate, efficient and scalable genetic testing methodology is much needed for its molecular diagnosis and carrier screening.Results We developed NGS4THAL, a bioinformatics analysis pipeline analyzing next generation sequencing (NGS) data to detect pathogenic variants for thalassemia and other hemoglobinopathies. NGS4THAL recovers and realigns ambiguously mapped NGS reads derived from the homologous hemoglobin gene clusters to achieve accurate detection of point mutations and small insertion/deletions (InDels). And it uses several structural variant (SV) detection tools with complementary algorithms, and an inhouse database with control data on a number of known SVs to achieve accurate detection of hemoglobin SVs. Detected variants are matched with those in HbVar, allowing recognition of known pathogenic variants, including disease modifiers. Tested on simulation data, NGS4THAL achieved high sensitivity and specificity. For targeted NGS sequencing data from samples with laboratory-confirmed pathogenic hemoglobin variants, it achieved 100% detection accuracy. Application of NGS4THAL on whole genome sequencing data from unrelated studies detected thalassemia mutation carrier rates for Hong Kong Chinese and Northern Vietnamese that were consistent with those from epidemiological studies.Conclusions NGS4THAL is a highly accurate and efficient molecular diagnosis tool for thalassemia and other hemoglobinopathies based on tailored analysis of NGS data, and is potentially scalable for carrier screening purposes.

scholarly journals Analysis of pathogenic variants from the ClinVar database in healthy people using next-generation sequencing

2017 ◽  
Vol 99 ◽  
Author(s):  
TAUTVYDAS RANČELIS ◽  
JUSTAS ARASIMAVIČIUS ◽  
LAIMA AMBROZAITYTĖ ◽  
INGRIDA KAVALIAUSKIENĖ ◽  
INGRIDA DOMARKIENĖ ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Genetic Disorders ◽  
Population Data ◽  
Healthy People ◽  
Next Generation ◽  
Single Nucleotide Variants ◽  
Genomic Variants ◽  
Pathogenic Variants ◽  
Generation Sequencing ◽  
Short Indels

SummaryNext-generation sequencing (NGS) became an effective approach for finding novel causative genomic variants of genetic disorders and is increasingly used for diagnostic purposes. Public variant databases that gather data of pathogenic variants are being relied upon as a source for clinical diagnosis. However, research of pathogenic variants using public databases data could be carried out not only in patients, but also in healthy people. This could provide insights into the most common recessive disorders in populations. The study aim was to use NGS and data from the ClinVar database for the identification of pathogenic variants in the exomes of healthy individuals from the Lithuanian population. To achieve this, 96 exomes were sequenced. An average of 42 139 single-nucleotide variants (SNVs) and 2306 short INDELs were found in each individual exome. Pooled data of study exomes provided a total of 243 192 unique SNVs and 31 623 unique short INDELs. Three hundred and twenty-one unique SNVs were classified as pathogenic. Comparison of the European data from the 1000 Genomes Project with our data revealed five pathogenic genomic variants that are inherited in an autosomal recessive pattern and that statistically significantly differ from the European population data.

scholarly journals A targeted next-generation sequencing assay for the molecular diagnosis of genetic disorders with orodental involvement

2015 ◽  
Vol 53 (2) ◽  
pp. 98-110 ◽  
Author(s):  
Megana K Prasad ◽  
Véronique Geoffroy ◽  
Serge Vicaire ◽  
Bernard Jost ◽  
Michael Dumas ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Molecular Diagnosis ◽  
Genetic Disorders ◽  
Next Generation ◽  
Targeted Next Generation Sequencing ◽  
Generation Sequencing

scholarly journals Protective Effects of Oroxylin A on Retinal Ganglion Cells in Experimental Model of Anterior Ischemic Optic Neuropathy

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 902
Author(s):  
Jia-Ying Chien ◽  
Shu-Fang Lin ◽  
Yu-Yau Chou ◽  
Chi-Ying F. Huang ◽  
Shun-Ping Huang
Keyword(s):  
Retinal Ganglion Cells ◽  
Optic Neuropathy ◽  
Ganglion Cells ◽  
Ischemic Injury ◽  
Anterior Ischemic Optic Neuropathy ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Ischemic Optic Neuropathy ◽  
Retinal Ganglion ◽  
Oroxylin A

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of acute vision loss in older people, and there is no effective therapy. The effect of the systemic or local application of steroids for NAION patients remains controversial. Oroxylin A (OA) (5,7-dihydroxy-6-methoxyflavone) is a bioactive flavonoid extracted from Scutellariae baicalensis Georgi. with various beneficial effects, including anti-inflammatory and neuroprotective effects. A previous study showed that OA promotes retinal ganglion cell (RGC) survival after optic nerve (ON) crush injury. The purpose of this research was to further explore the potential actions of OA in ischemic injury in an experimental anterior ischemic optic neuropathy (rAION) rat model induced by photothrombosis. Our results show that OA efficiently attenuated ischemic injury in rats by reducing optic disc edema, the apoptotic death of retinal ganglion cells, and the infiltration of inflammatory cells. Moreover, OA significantly ameliorated the pathologic changes of demyelination, modulated microglial polarization, and preserved visual function after rAION induction. OA activated nuclear factor E2 related factor (Nrf2) signaling and its downstream antioxidant enzymes NAD(P)H:quinone oxidoreductase (NQO-1) and heme oxygenase 1 (HO-1) in the retina. We demonstrated that OA activates Nrf2 signaling, protecting retinal ganglion cells from ischemic injury, in the rAION model and could potentially be used as a therapeutic approach in ischemic optic neuropathy.

scholarly journals Hereditary Optic Neuropathies: Induced Pluripotent Stem Cell-Based 2D/3D Approaches

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 112
Author(s):  
Marta García-López ◽  
Joaquín Arenas ◽  
M. Esther Gallardo
Keyword(s):  
Stem Cell ◽  
Retinal Ganglion Cells ◽  
Pluripotent Stem Cell ◽  
Ganglion Cells ◽  
Genetic Disorders ◽  
Three Dimensional ◽  
Induced Pluripotent Stem Cell ◽  
Underlying Mechanism ◽  
Retinal Ganglion ◽  
Induced Pluripotent

Inherited optic neuropathies share visual impairment due to the degeneration of retinal ganglion cells (RGCs) as the hallmark of the disease. This group of genetic disorders are caused by mutations in nuclear genes or in the mitochondrial DNA (mtDNA). An impaired mitochondrial function is the underlying mechanism of these diseases. Currently, optic neuropathies lack an effective treatment, and the implementation of induced pluripotent stem cell (iPSC) technology would entail a huge step forward. The generation of iPSC-derived RGCs would allow faithfully modeling these disorders, and these RGCs would represent an appealing platform for drug screening as well, paving the way for a proper therapy. Here, we review the ongoing two-dimensional (2D) and three-dimensional (3D) approaches based on iPSCs and their applications, taking into account the more innovative technologies, which include tissue engineering or microfluidics.

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