Long Reads Can Make Short Work of Rare Disease Diagnostics: Recent success stories bring hope that long read sequencing may make diagnosing rare genetic disease more successful

2021 ◽  
Vol 8 (4) ◽  
pp. 16-17, 20, 21
Author(s):  
Julianna LeMieux
Keyword(s):  
Rare Disease ◽  
Genetic Disease ◽  
Rare Genetic Disease ◽  
Success Stories ◽  
Recent Success ◽  
Long Reads ◽  
Disease Diagnostics ◽  
Long Read

scholarly journals Presence of the topic Xeroderma Pigmentoso in scientific articles published between 2003 and 2018

2020 ◽  
pp. 127-134
Author(s):  
Danilo José Silva Moreira ◽  
Juliana Brito da Fonseca ◽  
Karoline Rossi ◽  
Suzana dos Santos Vasconcelos ◽  
Vinicius Faustino Lima de Oliveira ◽  
...  
Keyword(s):  
Rare Disease ◽  
21St Century ◽  
Genetic Disease ◽  
Xeroderma Pigmentosum ◽  
Recessive Character ◽  
Rare Genetic Disease ◽  
Publication Rates ◽  
Selection Of

Xeroderma pigmentosum (XP) is a rare genetic disease, of autosomal and recessive character, and may affect both sexes, regardless of race, and often one case per 250,000 people. This disease has several other symptoms that present themselves heterogeneously over its carriers. The aim of this article was to quantitatively analyze the presence of the topic Xeroderma pigmentoso in scientific articles published between 2003 and 2018. In the identification, a total of 674 results were obtained. The follow-up of the following steps allowed, in the end, the selection of 24 papers. Regarding the language, most of the selected papers were written in Portuguese (around 58.33%), the rest in English (around 41.67%). The highest publication rates occurred between 2015 and 2017 (13%). The years 2007, 2007, 2011, 2014 and 2018 presented intermediate rates (9%) and the lowest rates (4%) occurred in 2003, 2008, 2010 and 2012, and 75% papers were published/presented in the 2nd decade of the 21st century, while the others (25%) were in the 1st decade of the 21st century. The findings of this study showed that there are few scientific studies on XP because it is a rare disease, which possibly leads to few investments in this area, especially with regard to treatment and medications.

scholarly journals Health and the Value of Inheritance: The meanings surrounding a rare genetic disease

2015 ◽  
Vol 12 (1) ◽  
pp. 109-140
Author(s):  
Waleska de Araújo Aureliano
Keyword(s):  
Rare Disease ◽  
Genetic Disease ◽  
Rio De Janeiro ◽  
Genetic Inheritance ◽  
Medical Progress ◽  
Rare Genetic Disease ◽  
The Family ◽  
Machado Joseph Disease

In this article I explore the meanings acquired by the notion of 'genetic inheritance' for families in Rio de Janeiro affected by a rare hereditary disorder, Machado-Joseph disease. My analysis examines three points: 1) how experience of the disease was thematized in the family prior to knowledge of its genetic and hereditary origin; 2) how knowledge of genetics affected the family's perception of their health and reproduction through the notion of risk contained in medical explanations; 3) finally, I problematize the meanings of 'hope,' a sentiment frequently cited by people with the disease and their descendants. Notably, despite the high value attributed to science and 'medical progress,' the use of certain biotechnologies is not always seen as positive or capable of enabling choices and actions in response to a rare disease. Notions of risk, responsibility and hope thus acquire singular contours for managing life and the continuity of the family.

scholarly journals Client Service Receipt Inventory as a standardised tool for measurement of socio-economic costs in the rare genetic disease population (CSRI-Ra)

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Claudia C. Y. Chung ◽  
Jasmine L. F. Fung ◽  
Adrian C. Y. Lui ◽  
Marcus C. Y. Chan ◽  
Yvette N. C. Ng ◽  
...  
Keyword(s):  
Focus Group ◽  
Rare Disease ◽  
Genetic Disease ◽  
Genetic Diseases ◽  
Face Validity ◽  
Economic Evaluations ◽  
Semantic Equivalence ◽  
Client Service Receipt Inventory ◽  
Rare Genetic Disease ◽  
Near Term

AbstractThe measurement of costs is fundamental in healthcare decision-making, but it is often challenging. In particular, standardised methods have not been developed in the rare genetic disease population. A reliable and valid tool is critical for research to be locally meaningful yet internationally comparable. Herein, we sought to develop, contextualise, translate, and validate the Client Service Receipt Inventory for the RAre disease population (CSRI-Ra) to be used in cost-of-illness studies and economic evaluations for healthcare planning. Through expert panel discussions and focus group meetings involving 17 rare disease patients, carers, and healthcare and social care professionals from Hong Kong, we have developed the CSRI-Ra. Rounds of forward and backward translations were performed by bilingual researchers, and face validity and semantic equivalence were achieved through interviews and telephone communications with focus group participants and an additional of 13 healthcare professional and university students. Intra-class correlation coefficient (ICC) was used to assess criterion validity between CSRI-Ra and electronic patient record in a sample of 94 rare disease patients and carers, with overall ICC being 0.69 (95% CI 0.56–0.78), indicating moderate to good agreement. Following rounds of revision in the development, contextualisation, translation, and validation stages, the CSRI-Ra is ready for use in empirical research. The CSRI-Ra provides a sufficiently standardised yet adaptable method for collecting socio-economic data related to rare genetic diseases. This is important for near-term and long-term monitoring of the resource consequences of rare diseases, and it provides a tool for use in economic evaluations in the future, thereby helping to inform planning for efficient and effective healthcare. Adaptation of the CSRI-Ra to other populations would facilitate international research.

scholarly journals Ultra-accurate microbial amplicon sequencing with synthetic long reads

Microbiome ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Benjamin J. Callahan ◽  
Dmitry Grinevich ◽  
Siddhartha Thakur ◽  
Michael A. Balamotis ◽  
Tuval Ben Yehezkel
Keyword(s):  
Microbial Community ◽  
16S Rrna ◽  
Amplicon Sequencing ◽  
Species Level ◽  
Full Length ◽  
16S Rrna Genes ◽  
Rrna Genes ◽  
Strain Identification ◽  
Long Reads ◽  
Long Read

Abstract Background Out of the many pathogenic bacterial species that are known, only a fraction are readily identifiable directly from a complex microbial community using standard next generation DNA sequencing. Long-read sequencing offers the potential to identify a wider range of species and to differentiate between strains within a species, but attaining sufficient accuracy in complex metagenomes remains a challenge. Methods Here, we describe and analytically validate LoopSeq, a commercially available synthetic long-read (SLR) sequencing technology that generates highly accurate long reads from standard short reads. Results LoopSeq reads are sufficiently long and accurate to identify microbial genes and species directly from complex samples. LoopSeq perfectly recovered the full diversity of 16S rRNA genes from known strains in a synthetic microbial community. Full-length LoopSeq reads had a per-base error rate of 0.005%, which exceeds the accuracy reported for other long-read sequencing technologies. 18S-ITS and genomic sequencing of fungal and bacterial isolates confirmed that LoopSeq sequencing maintains that accuracy for reads up to 6 kb in length. LoopSeq full-length 16S rRNA reads could accurately classify organisms down to the species level in rinsate from retail meat samples, and could differentiate strains within species identified by the CDC as potential foodborne pathogens. Conclusions The order-of-magnitude improvement in length and accuracy over standard Illumina amplicon sequencing achieved with LoopSeq enables accurate species-level and strain identification from complex- to low-biomass microbiome samples. The ability to generate accurate and long microbiome sequencing reads using standard short read sequencers will accelerate the building of quality microbial sequence databases and removes a significant hurdle on the path to precision microbial genomics.

scholarly journals Evaluating the accuracy of Listeria monocytogenes assemblies from quasimetagenomic samples using long and short reads

BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Seth Commichaux ◽  
Kiran Javkar ◽  
Padmini Ramachandran ◽  
Niranjan Nagarajan ◽  
Denis Bertrand ◽  
...  
Keyword(s):  
Public Health ◽  
Public Health Response ◽  
High Quality ◽  
Short Read ◽  
Short Reads ◽  
The Core ◽  
Long Reads ◽  
Health Response ◽  
Long Read ◽  
Core Genes

Abstract Background Whole genome sequencing of cultured pathogens is the state of the art public health response for the bioinformatic source tracking of illness outbreaks. Quasimetagenomics can substantially reduce the amount of culturing needed before a high quality genome can be recovered. Highly accurate short read data is analyzed for single nucleotide polymorphisms and multi-locus sequence types to differentiate strains but cannot span many genomic repeats, resulting in highly fragmented assemblies. Long reads can span repeats, resulting in much more contiguous assemblies, but have lower accuracy than short reads. Results We evaluated the accuracy of Listeria monocytogenes assemblies from enrichments (quasimetagenomes) of naturally-contaminated ice cream using long read (Oxford Nanopore) and short read (Illumina) sequencing data. Accuracy of ten assembly approaches, over a range of sequencing depths, was evaluated by comparing sequence similarity of genes in assemblies to a complete reference genome. Long read assemblies reconstructed a circularized genome as well as a 71 kbp plasmid after 24 h of enrichment; however, high error rates prevented high fidelity gene assembly, even at 150X depth of coverage. Short read assemblies accurately reconstructed the core genes after 28 h of enrichment but produced highly fragmented genomes. Hybrid approaches demonstrated promising results but had biases based upon the initial assembly strategy. Short read assemblies scaffolded with long reads accurately assembled the core genes after just 24 h of enrichment, but were highly fragmented. Long read assemblies polished with short reads reconstructed a circularized genome and plasmid and assembled all the genes after 24 h enrichment but with less fidelity for the core genes than the short read assemblies. Conclusion The integration of long and short read sequencing of quasimetagenomes expedited the reconstruction of a high quality pathogen genome compared to either platform alone. A new and more complete level of information about genome structure, gene order and mobile elements can be added to the public health response by incorporating long read analyses with the standard short read WGS outbreak response.

scholarly journals Hapo-G, haplotype-aware polishing of genome assemblies with accurate reads

2021 ◽  
Vol 3 (2) ◽  
Author(s):  
Jean-Marc Aury ◽  
Benjamin Istace
Keyword(s):  
Single Molecule ◽  
Direct Consequence ◽  
High Quality ◽  
Sequencing Errors ◽  
Coding Regions ◽  
Sequencing Technologies ◽  
Long Reads ◽  
Oxford Nanopore ◽  
Long Read ◽  
Genome Assemblies

Abstract Single-molecule sequencing technologies have recently been commercialized by Pacific Biosciences and Oxford Nanopore with the promise of sequencing long DNA fragments (kilobases to megabases order) and then, using efficient algorithms, provide high quality assemblies in terms of contiguity and completeness of repetitive regions. However, the error rate of long-read technologies is higher than that of short-read technologies. This has a direct consequence on the base quality of genome assemblies, particularly in coding regions where sequencing errors can disrupt the coding frame of genes. In the case of diploid genomes, the consensus of a given gene can be a mixture between the two haplotypes and can lead to premature stop codons. Several methods have been developed to polish genome assemblies using short reads and generally, they inspect the nucleotide one by one, and provide a correction for each nucleotide of the input assembly. As a result, these algorithms are not able to properly process diploid genomes and they typically switch from one haplotype to another. Herein we proposed Hapo-G (Haplotype-Aware Polishing Of Genomes), a new algorithm capable of incorporating phasing information from high-quality reads (short or long-reads) to polish genome assemblies and in particular assemblies of diploid and heterozygous genomes.

scholarly journals Short and long-read genome sequencing methodologies for somatic variant detection; genomic analysis of a patient with diffuse large B-cell lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hannah E. Roberts ◽  
Maria Lopopolo ◽  
Alistair T. Pagnamenta ◽  
Eshita Sharma ◽  
Duncan Parkes ◽  
...  
Keyword(s):  
B Cell ◽  
Genome Sequencing ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Somatic Variation ◽  
Single Nucleotide Variants ◽  
Germline Variants ◽  
Specificity And Sensitivity ◽  
Long Reads ◽  
Long Read

AbstractRecent advances in throughput and accuracy mean that the Oxford Nanopore Technologies PromethION platform is a now a viable solution for genome sequencing. Much of the validation of bioinformatic tools for this long-read data has focussed on calling germline variants (including structural variants). Somatic variants are outnumbered many-fold by germline variants and their detection is further complicated by the effects of tumour purity/subclonality. Here, we evaluate the extent to which Nanopore sequencing enables detection and analysis of somatic variation. We do this through sequencing tumour and germline genomes for a patient with diffuse B-cell lymphoma and comparing results with 150 bp short-read sequencing of the same samples. Calling germline single nucleotide variants (SNVs) from specific chromosomes of the long-read data achieved good specificity and sensitivity. However, results of somatic SNV calling highlight the need for the development of specialised joint calling algorithms. We find the comparative genome-wide performance of different tools varies significantly between structural variant types, and suggest long reads are especially advantageous for calling large somatic deletions and duplications. Finally, we highlight the utility of long reads for phasing clinically relevant variants, confirming that a somatic 1.6 Mb deletion and a p.(Arg249Met) mutation involving TP53 are oriented in trans.

EP165 Significant renal arteriovenous malformation in the context of a rare genetic disease: The Bannayan Riley Ruvalcaba syndrome

2014 ◽  
Vol 13 (5) ◽  
pp. 175
Author(s):  
A.D. Urbina Lima ◽  
A.B. Albano Del Pozo ◽  
J.J. Colombo Stenstrom ◽  
J. Murillo Mirat ◽  
A. Pijierro Amador ◽  
...  
Keyword(s):  
Arteriovenous Malformation ◽  
Genetic Disease ◽  
Rare Genetic Disease ◽  
Renal Arteriovenous Malformation

Long read sequencing reveals sequential complex rearrangements driven by Hepatitis B virus integration

2021 ◽  
Author(s):  
Songbo Wang ◽  
Jiadong Lin ◽  
Xiaofei Yang ◽  
Zihang Li ◽  
Tun Xu ◽  
...  
Keyword(s):  
Hepatitis B ◽  
Clinical Samples ◽  
Metabolic Dysfunction ◽  
Cellular Functions ◽  
Human Genomes ◽  
Long Reads ◽  
B Virus ◽  
Long Read ◽  
Genetic Structures ◽  
Virus Integration

Integration of Hepatitis B (HBV) virus into human genome disrupts genetic structures and cellular functions. Here, we conducted multiplatform long read sequencing on two cell lines and five clinical samples of HBV-induced hepatocellular carcinomas (HCC). We resolved two types of complex viral integration induced genome rearrangements and established a Time-phased Integration and Rearrangement Model (TIRM) to depict their formation progress by differentiating inserted HBV copies with HiFi long reads. We showed that the two complex types were initialized from focal replacements and the fragile virus-human junctions triggered subsequent rearrangements. We further revealed that these rearrangements promoted a prevalent loss-of-heterozygosity at chr4q, accounting for 19.5% of HCC samples in ICGC cohort and contributing to immune and metabolic dysfunction. Overall, our long read based analysis reveals a novel sequential rearrangement progress driven by HBV integration, hinting the structural and functional implications on human genomes.

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