Whole-genome sequencing as a first-tier diagnostic framework for rare genetic diseases

2021 ◽  
pp. 153537022110400
Author(s):  
Haseeb Nisar ◽  
Bilal Wajid ◽  
Samiah Shahid ◽  
Faria Anwar ◽  
Imran Wajid ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Genetic Diseases ◽  
Correct Diagnosis ◽  
Clinical Settings ◽  
Whole Genome ◽  
Rare Genetic Diseases ◽  
Diagnostic Approaches ◽  
Diagnostic Framework

Rare diseases affect nearly 300 million people globally with most patients aged five or less. Traditional diagnostic approaches have provided much of the diagnosis; however, there are limitations. For instance, simply inadequate and untimely diagnosis adversely affects both the patient and their families. This review advocates the use of whole genome sequencing in clinical settings for diagnosis of rare genetic diseases by showcasing five case studies. These examples specifically describe the utilization of whole genome sequencing, which helped in providing relief to patients via correct diagnosis followed by use of precision medicine.

scholarly journals Continuing the sequence? Towards an economic evaluation of whole genome sequencing for the diagnosis of rare diseases in Scotland

2021 ◽  
Author(s):  
Michael Abbott ◽  
Lynda McKenzie ◽  
Blanca Viridiana Guizar Moran ◽  
Sebastian Heidenreich ◽  
Rodolfo Hernández ◽  
...  
Keyword(s):  
Economic Evaluation ◽  
Genetic Testing ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Genomic Medicine ◽  
Future Research ◽  
Clinical Genetics ◽  
Whole Genome ◽  
Peace Of Mind

AbstractNovel developments in genomic medicine may reduce the length of the diagnostic odyssey for patients with rare diseases. Health providers must thus decide whether to offer genome sequencing for the diagnosis of rare conditions in a routine clinical setting. We estimated the costs of singleton standard genetic testing and trio-based whole genome sequencing (WGS), in the context of the Scottish Genomes Partnership (SGP) study. We also explored what users value about genomic sequencing. Insights from the costing and value assessments will inform a subsequent economic evaluation of genomic medicine in Scotland. An average cost of £1,841 per singleton was estimated for the standard genetic testing pathway, with significant variability between phenotypes. WGS cost £6625 per family trio, but this estimate reflects the use of WGS during the SGP project and large cost savings may be realised if sequencing was scaled up. Patients and families valued (i) the chance of receiving a diagnosis (and the peace of mind and closure that brings); (ii) the information provided by WGS (including implications for family planning and secondary findings); and (iii) contributions to future research. Our costings will be updated to address limitations of the current study for incorporation in budget impact modelling and cost-effectiveness analysis (cost per diagnostic yield). Our insights into the benefits of WGS will guide the development of a discrete choice experiment valuation study. This will inform a user-perspective cost–benefit analysis of genome-wide sequencing, accounting for the broader non-health outcomes. Taken together, our research will inform the long-term strategic development of NHS Scotland clinical genetics testing services, and will be of benefit to others seeking to undertake similar evaluations in different contexts.

scholarly journals Practices and views of neurologists regarding the use of whole-genome sequencing in clinical settings: a web-based survey

2017 ◽  
Vol 25 (7) ◽  
pp. 801-808 ◽  
Author(s):  
Iris Jaitovich Groisman ◽  
Thierry Hurlimann ◽  
Amir Shoham ◽  
Béatrice Godard
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Clinical Settings ◽  
Whole Genome ◽  
Web Based

scholarly journals Whole-Genome Sequencing in Diagnostics of Selected Slovenian Undiagnosed Patients with Rare Disorders

Life ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 205
Author(s):  
Gaber Bergant ◽  
Aleš Maver ◽  
Borut Peterlin
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genetic Disorders ◽  
Genetic Diseases ◽  
Diagnostic Testing ◽  
Positive Family History ◽  
Clinical Diagnostics ◽  
Whole Genome ◽  
Exon Duplication ◽  
The Impact

Several patients with rare genetic disorders remain undiagnosed following comprehensive diagnostic testing using whole-exome sequencing (WES). In these patients, pathogenic genetic variants may reside in intronic or regulatory regions or they may emerge through mutational mechanisms not detected by WES. For this reason, we implemented whole-genome sequencing (WGS) in routine clinical diagnostics of patients with undiagnosed genetic disorders and report on the outcome in 30 patients. Criteria for consideration included (1) negative WES, (2) a high likelihood of a genetic cause for the disorders, (3) positive family history, (4) detection of large blocks of homozygosity or (5) detection of a single pathogenic variant in a gene associated with recessive conditions. We successfully discovered a causative genetic variant in 6 cases, a retrotranspositional event in the APC gene, non-coding variants in the intronic region of the OTC gene and the promotor region of the UFM1 gene, repeat expansion in the RFC1 gene and a single exon duplication in the CNGB3 gene. We also discovered one coding variant, an indel, which was missed by variant caller during WES data analysis. Our study demonstrates the impact of WGS in the group of patients with undiagnosed genetic diseases after WES in the clinical setting and the diversity of mutational mechanisms discovered, which would remain undetected using other methods.

scholarly journals The Brazilian Rare Genomes Project: validation of whole genome sequencing for rare diseases diagnosis

2021 ◽  
Author(s):  
Antonio Victor Campos Coelho ◽  
Bruna Mascaro Cordeiro de Azevedo ◽  
Danielle Ribeiro Lucon ◽  
Maria Soares Nobrega ◽  
Rodrigo de Souza Reis ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Clinical Laboratory ◽  
Genomic Medicine ◽  
Uniparental Disomy ◽  
Public Healthcare ◽  
Whole Genome ◽  
Single Nucleotide Variants ◽  
F Measure

Rare diseases affect 3.2 to 13.2 million individuals in Brazil. The Brazilian Rare Genomes Project is envisioned to further the implementation of genomic medicine into the Brazilian public healthcare system. Here we report the results of the validation of a whole genome sequencing (WGS) procedure for implementation in a clinical laboratory. In addition, we report data quality for the first 1,200 real world patients sequenced. For the validation, we sequenced a well characterized group of 76 samples, including seven gold standard genomes, using a PCR-free WGS protocol on Illumina Novaseq 6000 equipment. We compared the observed variant calls with their expected calls, observing good concordance for single nucleotide variants (SNVs; mean F-measure = 99.82%) and indels (mean F-measure = 99.57%). Copy number variants and structural variants events detection performances were as expected (F-measures 96.6% and 90.3%, respectively). Our protocol presented excellent intra- and inter-assay reproducibility, with coefficients of variation ranging between 0.03% and 0.20% and 0.02% and 0.09%, respectively. Limitations of the procedure include the inability to confidently detect variants such as uniparental disomy, balanced translocations, repeat expansion variants and low-level mosaicism. In summary, the observed performance of the test was in accordance with that seen in the best centers worldwide. The Rare Genomes Project is an important initiative to improve Brazil's general population access to the innovative WGS technology which has the potential to reduce the time until diagnosis of rare diseases, bringing pivotal improvements for the quality of life of the affected individuals.

scholarly journals Whole genome sequencing reveals a frameshift mutation and a large deletion in YY1AP1 in a girl with a panvascular artery disease

2021 ◽  
Vol 15 (1) ◽  
Author(s):  
Víctor Raggio ◽  
Nicolas Dell’Oca ◽  
Camila Simoes ◽  
Alejandra Tapié ◽  
Conrado Medici ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Molecular Diagnosis ◽  
Rare Diseases ◽  
High Throughput Sequencing ◽  
Heart Defects ◽  
Large Deletion ◽  
Compound Heterozygous ◽  
Whole Genome ◽  
Artery Disease

Abstract Background Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. Results We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. Conclusions In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.

scholarly journals Diagnostic and clinical utility of whole genome sequencing in a cohort of undiagnosed Chinese families with rare diseases

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Hong-Yan Liu ◽  
Liyuan Zhou ◽  
Meng-Yue Zheng ◽  
Jia Huang ◽  
Shu Wan ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Disease Status ◽  
Copy Number Variations ◽  
Initial Diagnosis ◽  
Deletion Syndrome ◽  
Whole Genome ◽  
Structural Variations ◽  
Promising Alternative

AbstractRare diseases are usually chronically debilitating or even life-threatening with diagnostic and therapeutic challenges in current clinical practice. It has been estimated that 80% of rare diseases are genetic in origin, and thus genome sequencing-based diagnosis offers a promising alternative for rare-disease management. In this study, 79 individuals from 16 independent families were performed for whole-genome sequencing (WGS) in an effort to identify the causative mutations for 16 distinct rare diseases that are largely clinically intractable. Comprehensive analysis of variations, including simple nucleotide variants (SNVs), copy-number variations (CNVs), and structural variations (SVs), was implemented using the WGS data. A flexible analysis pipeline that allowed a certain degree of misclassification of disease status was developed to facilitate the identification of causative variants. As a result, disease-causing variants were identified in 10 of the 16 investigated diseases, yielding a diagnostic rate of 62.5%. Additionally, new potentially pathogenic variants were discovered for two disorders, including IGF2/INS-IGF2 in mitochondrial disease and FBN3 in Klippel–Trenaunay–Weber syndrome. Our WGS analysis not only detected a CNV associated with 3p deletion syndrome but also captured a simple sequence repeat (SSR) variation associated with Machado–Joseph disease. To our knowledge, this is the first time the clinical WGS analysis of short-read sequences has been used successfully to identify a causative SSR variation that perfectly segregates with a repeat expansion disorder. After the WGS analysis, we confirmed the initial diagnosis for three of 10 established disorders and modified or corrected the initial diagnosis for the remaining seven disorders. In summary, clinical WGS is a powerful tool for the diagnosis of rare diseases, and its diagnostic clarity at molecular levels offers important benefits for the participating families.

scholarly journals Whole-genome sequencing of rare disease patients in a national healthcare system

2019 ◽  
Author(s):  
Willem H Ouwehand ◽  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Healthcare System ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Genetic Diagnosis ◽  
Whole Genome ◽  
Phenotypic Data ◽  
National Healthcare ◽  
National Healthcare System

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and mediating genes for more than half such disorders remain to be discovered. We implemented whole-genome sequencing (WGS) in a national healthcare system to streamline diagnosis and to discover unknown aetiological variants, in the coding and non-coding regions of the genome. In a pilot study for the 100,000 Genomes Project, we generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 patients with detailed phenotypic data. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed aetiological. Using WGS of UK Biobank1, we showed that rare alleles can explain the presence of some individuals in the tails of a quantitative red blood cell (RBC) trait. Finally, we reported 4 novel non-coding variants which cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

scholarly journals Meeting summary: ethical aspects of whole exome and whole genome sequencing studies (WES/WGS) in rare diseases, Tel Aviv, Israel, January 2013

2013 ◽  
Vol 95 (2-3) ◽  
pp. 53-56 ◽  
Author(s):  
LUBA FARBEROV ◽  
AVITAL GILAM ◽  
OFER ISAKOV ◽  
NOAM SHOMRON
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Rare Diseases ◽  
Genetic Basis ◽  
Diagnostic Tools ◽  
Whole Genome ◽  
Ethical Aspects ◽  
Genomic Technologies ◽  
Whole Exome ◽  
Sequencing Studies

SummaryA recent E-Rare workshop reviewed the ethical aspects of whole exome and whole genome-sequencing studies (WES and WGS, respectively) in rare diseases. Leveraging new genomic technologies, which output vast amounts of known and novel genetic variants, researchers are learning more about the genetic basis and mechanisms involved in rare diseases. In some cases, these findings are translated into diagnostic tools for the benefit of rare disease patients. Among the disclosed data, which can assist in treatment management, incidental findings await, bringing with them ethical concerns for the clinicians, researchers and patients.

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