scholarly journals A Multi-Strategy Sequencing Workflow in Inherited Retinal Dystrophies: Routine Diagnosis, Addressing Unsolved Cases and Candidate Genes Identification

2020 ◽  
Vol 21 (24) ◽  
pp. 9355
Author(s):  
Marta Martín-Sánchez ◽  
Nereida Bravo-Gil ◽  
María González-del Pozo ◽  
Cristina Méndez-Vidal ◽  
Elena Fernández-Suárez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Diagnostic Yield ◽  
Diagnostic Algorithm ◽  
Clinical Genetics ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Causal Variants ◽  
Simultaneous Study ◽  
Candidate Loci

The management of unsolved inherited retinal dystrophies (IRD) cases is challenging since no standard pipelines have been established. This study aimed to define a diagnostic algorithm useful for the diagnostic routine and to address unsolved cases. Here, we applied a Next-Generation Sequencing-based workflow, including a first step of panel sequencing (PS) followed by clinical-exome sequencing (CES) and whole-exome sequencing (WES), in 46 IRD patients belonging to 42 families. Twenty-six likely causal variants in retinal genes were found by PS and CES. CES and WES allowed proposing two novel candidate loci (WDFY3 and a X-linked region including CITED1), both abundantly expressed in human retina according to RT-PCR and immunohistochemistry. After comparison studies, PS showed the best quality and cost values, CES and WES involved similar analytical efforts and WES presented the highest diagnostic yield. These results reinforce the relevance of panels as a first step in the diagnostic routine and suggest WES as the next strategy for unsolved cases, reserving CES for the simultaneous study of multiple conditions. Standardizing this algorithm would enhance the efficiency and equity of clinical genetics practice. Furthermore, the identified candidate genes could contribute to increase the diagnostic yield and expand the mutational spectrum in these disorders.

scholarly journals Novel Candidate Genes and a Wide Spectrum of Structural and Point Mutations Responsible for Inherited Retinal Dystrophies Revealed by Exome Sequencing

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0168966 ◽  
Author(s):  
Marta de Castro-Miró ◽  
Raul Tonda ◽  
Paula Escudero-Ferruz ◽  
Rosa Andrés ◽  
Andrés Mayor-Lorenzo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Wide Spectrum ◽  
Point Mutations ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies

scholarly journals High Diagnostic Yield of Whole Exome Sequencing in Participants With Retinal Dystrophies in a Clinical Ophthalmology Setting

2015 ◽  
Vol 160 (2) ◽  
pp. 354-363.e9 ◽  
Author(s):  
Kristy Lee ◽  
Jonathan S. Berg ◽  
Laura Milko ◽  
Kristy Crooks ◽  
Mei Lu ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
High Diagnostic Yield ◽  
Retinal Dystrophies ◽  
Whole Exome

scholarly journals Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Francisco Martinez-Granero ◽  
Fiona Blanco-Kelly ◽  
Carolina Sanchez-Jimeno ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Yield ◽  
Genetic Diagnosis ◽  
Diagnostic Algorithm ◽  
Signs And Symptoms ◽  
Autism Spectrum ◽  
Global Developmental Delay ◽  
Comparative Genomic ◽  
Clinical Exome Sequencing

AbstractMost consensus recommendations for the genetic diagnosis of neurodevelopmental disorders (NDDs) do not include the use of next generation sequencing (NGS) and are still based on chromosomal microarrays, such as comparative genomic hybridization array (aCGH). This study compares the diagnostic yield obtained by aCGH and clinical exome sequencing in NDD globally and its spectrum of disorders. To that end, 1412 patients clinically diagnosed with NDDs and studied with aCGH were classified into phenotype categories: global developmental delay/intellectual disability (GDD/ID); autism spectrum disorder (ASD); and other NDDs. These categories were further subclassified based on the most frequent accompanying signs and symptoms into isolated forms, forms with epilepsy; forms with micro/macrocephaly and syndromic forms. Two hundred and forty-five patients of the 1412 were subjected to clinical exome sequencing. Diagnostic yield of aCGH and clinical exome sequencing, expressed as the number of solved cases, was compared for each phenotype category and subcategory. Clinical exome sequencing was superior than aCGH for all cases except for isolated ASD, with no additional cases solved by NGS. Globally, clinical exome sequencing solved 20% of cases (versus 5.7% by aCGH) and the diagnostic yield was highest for all forms of GDD/ID and lowest for Other NDDs (7.1% versus 1.4% by aCGH) and ASD (6.1% versus 3% by aCGH). In the majority of cases, diagnostic yield was higher in the phenotype subcategories than in the mother category. These results suggest that NGS could be used as a first-tier test in the diagnostic algorithm of all NDDs followed by aCGH when necessary.

Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders

2017 ◽  
Vol 74 (3) ◽  
pp. 293 ◽  
Author(s):  
Miriam S. Reuter ◽  
Hasan Tawamie ◽  
Rebecca Buchert ◽  
Ola Hosny Gebril ◽  
Tawfiq Froukh ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Candidate Genes ◽  
Neurodevelopmental Disorders ◽  
Diagnostic Yield

scholarly journals Prioritizing variants of uncertain significance for reclassification using a rule-based algorithm in inherited retinal dystrophies

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Ionut-Florin Iancu ◽  
Almudena Avila-Fernandez ◽  
Ana Arteche ◽  
Maria Jose Trujillo-Tiebas ◽  
Rosa Riveiro-Alvarez ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Rare Diseases ◽  
Molecular Diagnostic ◽  
Rule Based ◽  
Variants Of Uncertain Significance ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Clinical Exome Sequencing ◽  
Uncertain Significance

AbstractInherited retinal dystrophies (IRD) are a highly heterogeneous group of rare diseases with a molecular diagnostic rate of >50%. Reclassification of variants of uncertain significance (VUS) poses a challenge for IRD diagnosis. We collected 668 IRD cases analyzed by our geneticists using two different clinical exome-sequencing tests. We identified 114 unsolved cases pending reclassification of 125 VUS and studied their genomic, functional, and laboratory-specific features, comparing them to pathogenic and likely pathogenic variants from the same cohort (N = 390). While the clinical exome used did not show differences in diagnostic rate, the more IRD-experienced geneticist reported more VUS (p = 4.07e-04). Significantly fewer VUS were reported in recessive cases (p = 2.14e-04) compared to other inheritance patterns, and of all the genes analyzed, ABCA4 and IMPG2 had the lowest and highest VUS frequencies, respectively (p = 3.89e-04, p = 6.93e-03). Moreover, few frameshift and stop-gain variants were found to be informed VUS (p = 6.73e-08 and p = 2.93e-06). Last, we applied five pathogenicity predictors and found there is a significant proof of deleteriousness when all score for pathogenicity in missense variants. Altogether, these results provided input for a set of rules that correctly reclassified ~70% of VUS as pathogenic in validation datasets. Disease- and setting-specific features influence VUS reporting. Comparison with pathogenic and likely pathogenic variants can prioritize VUS more likely to be reclassified as causal.

scholarly journals New Insights on Genetic Diagnostics in Cardiomyopathy and Arrhythmia Patients Gained by Stepwise Exome Data Analysis

2020 ◽  
Vol 9 (7) ◽  
pp. 2168
Author(s):  
Konstantinos Kolokotronis ◽  
Natalie Pluta ◽  
Eva Klopocki ◽  
Erdmute Kunstmann ◽  
Daniel Messroghli ◽  
...  
Keyword(s):  
Data Analysis ◽  
Exome Sequencing ◽  
Candidate Genes ◽  
Genetic Heterogeneity ◽  
Diagnostic Yield ◽  
Genetic Diagnostics ◽  
Routine Diagnostics ◽  
Exome Data ◽  
Gene Panels ◽  
Diagnostic Benefit

Inherited cardiomyopathies are characterized by clinical and genetic heterogeneity that challenge genetic diagnostics. In this study, we examined the diagnostic benefit of exome data compared to targeted gene panel analyses, and we propose new candidate genes. We performed exome sequencing in a cohort of 61 consecutive patients with a diagnosis of cardiomyopathy or primary arrhythmia, and we analyzed the data following a stepwise approach. Overall, in 64% of patients, a variant of interest (VOI) was detected. The detection rate in the main sub-cohort consisting of patients with dilated cardiomyopathy (DCM) was much higher than previously reported (25/36; 69%). The majority of VOIs were found in disease-specific panels, while a further analysis of an extended panel and exome data led to an additional diagnostic yield of 13% and 5%, respectively. Exome data analysis also detected variants in candidate genes whose functional profile suggested a probable pathogenetic role, the strongest candidate being a truncating variant in STK38. In conclusion, although the diagnostic yield of gene panels is acceptable for routine diagnostics, the genetic heterogeneity of cardiomyopathies and the presence of still-unknown causes favor exome sequencing, which enables the detection of interesting phenotype–genotype correlations, as well as the identification of novel candidate genes.

scholarly journals Whole exome sequencing and homozygosity mapping reveals genetic defects in consanguineous Iranian families with inherited retinal dystrophies

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Arash Salmaninejad ◽  
Nicola Bedoni ◽  
Zeinab Ravesh ◽  
Mathieu Quinodoz ◽  
Nasser Shoeibi ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Snp Array ◽  
Homozygosity Mapping ◽  
Retinal Cell ◽  
Additional Information ◽  
Inherited Retinal Dystrophies ◽  
Pathogenic Variants ◽  
Retinal Dystrophies ◽  
Whole Exome

Abstract Inherited retinal dystrophies (IRDs), displaying pronounced genetic and clinical heterogeneity, comprise of a broad range of diseases characterized by progressive retinal cell death and gradual loss of vision. By the combined use of whole exome sequencing (WES), SNP-array and WES-based homozygosity mapping, as well as directed DNA sequencing (Sanger), we have identified nine pathogenic variants in six genes (ABCA4, RPE65, MERTK, USH2A, SPATA7, TULP1) in 10 consanguineous Iranian families. Six of the nine identified variants were novel, including a putative founder mutation in ABCA4 (c.3260A>G, p.Glu1087Gly), detected in two families from Northeastern Iran. Our findings provide additional information to the molecular pathology of IRDs in Iran, hopefully contributing to better genetic counselling and patient management in the respective families from this country.

scholarly journals Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Marina Riera ◽  
Rafael Navarro ◽  
Sheila Ruiz-Nogales ◽  
Pilar Méndez ◽  
Anniken Burés-Jelstrup ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Genetic Diagnosis ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Whole Exome ◽  
Ion Proton

scholarly journals Exome Sequencing Reveals Novel and Recurrent Mutations with Clinical Significance in Inherited Retinal Dystrophies

PLoS ONE ◽  
2014 ◽  
Vol 9 (12) ◽  
pp. e116176 ◽  
Author(s):  
María González-del Pozo ◽  
Cristina Méndez-Vidal ◽  
Nereida Bravo-Gil ◽  
Alicia Vela-Boza ◽  
Joaquin Dopazo ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Clinical Significance ◽  
Inherited Retinal Dystrophies ◽  
Retinal Dystrophies ◽  
Recurrent Mutations
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