scholarly journals Case for genome sequencing in infants and children with rare, undiagnosed or genetic diseases

2019 ◽  
Vol 56 (12) ◽  
pp. 783-791 ◽  
Author(s):  
David Bick ◽  
Marilyn Jones ◽  
Stacie L Taylor ◽  
Ryan J Taft ◽  
John Belmont
Keyword(s):  
Genome Sequencing ◽  
Genetic Diseases ◽  
Diagnostic Testing ◽  
Disease Genes ◽  
Sequencing Technologies ◽  
Pathogenic Variants ◽  
Clinical Indications ◽  
And Performance ◽  
The Individual ◽  
Laboratory Workflow

Up to 350 million people worldwide suffer from a rare disease, and while the individual diseases are rare, in aggregate they represent a substantial challenge to global health systems. The majority of rare disorders are genetic in origin, with children under the age of five disproportionately affected. As these conditions are difficult to identify clinically, genetic and genomic testing have become the backbone of diagnostic testing in this population. In the last 10 years, next-generation sequencing technologies have enabled testing of multiple disease genes simultaneously, ranging from targeted gene panels to exome sequencing (ES) and genome sequencing (GS). GS is quickly becoming a practical first-tier test, as cost decreases and performance improves. A growing number of studies demonstrate that GS can detect an unparalleled range of pathogenic abnormalities in a single laboratory workflow. GS has the potential to deliver unbiased, rapid and accurate molecular diagnoses to patients across diverse clinical indications and complex presentations. In this paper, we discuss clinical indications for testing and historical testing paradigms. Evidence supporting GS as a diagnostic tool is supported by superior genomic coverage, types of pathogenic variants detected, simpler laboratory workflow enabling shorter turnaround times, diagnostic and reanalysis yield, and impact on healthcare.

scholarly journals Genome sequencing in families with congenital limb malformations

2021 ◽  
Author(s):  
Jonas Elsner ◽  
Martin A. Mensah ◽  
Manuel Holtgrewe ◽  
Jakob Hertzberg ◽  
Stefania Bigoni ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Disease Genes ◽  
Structural Variants ◽  
Clinical Genetic ◽  
Limb Malformation ◽  
Pathogenic Variants ◽  
Diagnostic Potential ◽  
Limb Malformations ◽  
Congenital Limb ◽  
Complex Structural

AbstractThe extensive clinical and genetic heterogeneity of congenital limb malformation calls for comprehensive genome-wide analysis of genetic variation. Genome sequencing (GS) has the potential to identify all genetic variants. Here we aim to determine the diagnostic potential of GS as a comprehensive one-test-for-all strategy in a cohort of undiagnosed patients with congenital limb malformations. We collected 69 cases (64 trios, 1 duo, 5 singletons) with congenital limb malformations with no molecular diagnosis after standard clinical genetic testing and performed genome sequencing. We also developed a framework to identify potential noncoding pathogenic variants. We identified likely pathogenic/disease-associated variants in 12 cases (17.4%) including four in known disease genes, and one repeat expansion in HOXD13. In three unrelated cases with ectrodactyly, we identified likely pathogenic variants in UBA2, establishing it as a novel disease gene. In addition, we found two complex structural variants (3%). We also identified likely causative variants in three novel high confidence candidate genes. We were not able to identify any noncoding variants. GS is a powerful strategy to identify all types of genomic variants associated with congenital limb malformation, including repeat expansions and complex structural variants missed by standard diagnostic approaches. In this cohort, no causative noncoding SNVs could be identified.

scholarly journals Genetic burden linked to founder effects in Saguenay-Lac-Saint-Jean illustrates the importance of genetic screening test availability

2021 ◽  
pp. jmedgenet-2021-107809
Author(s):  
Mbarka Bchetnia ◽  
Luigi Bouchard ◽  
Jean Mathieu ◽  
Philippe Campeau ◽  
Charles Morin ◽  
...  
Keyword(s):  
Genetic Diseases ◽  
Founder Mutations ◽  
Rare Disorders ◽  
Population Database ◽  
Inherited Disorders ◽  
Sequencing Technologies ◽  
Pathogenic Variants ◽  
Rare Genetic Diseases ◽  
Causal Genes ◽  
Region Data

The Saguenay–Lac-Saint-Jean (SLSJ) region located in the province of Quebec was settled in the 19th century by pioneers issued from successive migration waves starting in France in the 17th century and continuing within Quebec until the beginning of the 20th century. The genetic structure of the SLSJ population is considered to be the product a triple founder effect and is characterised by a higher prevalence of some rare genetic diseases. Several studies were performed to elucidate the historical, demographic and genetic background of current SLSJ inhabitants to assess the origins of these rare disorders and their distribution in the population. Thanks to the development of new sequencing technologies, the genes and the variants responsible for the most prevalent conditions were identified. Combined with other resources such as the BALSAC population database, identifying the causal genes and the pathogenic variants allowed to assess the impacts of some of these founder mutations on the population health and to design precision medicine public health strategies based on carrier testing. Furthermore, it stimulated the establishment of many public programmes.We report here a review and an update of a subset of inherited disorders and founder mutations in the SLSJ region. Data were collected from published scientific sources. This work expands the knowledge about the current frequencies of these rare disorders, the frequencies of other rare genetic diseases in this population, the relevance of the carrier tests offered to the population, as well as the current available treatments and research about future therapeutic avenues for these inherited disorders.

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 B.06 Whole exome sequencing in genetic ataxias associated with cerebellar atrophy: the Canadian experience

2019 ◽  
Vol 46 (s1) ◽  
pp. S11
Author(s):  
L Gauquelin ◽  
T Hartley ◽  
M Tarnopolsky ◽  
DA Dyment ◽  
B Brais ◽  
...  
Keyword(s):  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Diagnostic Yield ◽  
Genetic Diseases ◽  
Genetic Diagnosis ◽  
Cerebellar Atrophy ◽  
Clinical Findings ◽  
Disease Genes ◽  
Pathogenic Variants ◽  
Whole Exome

Background: Cerebellar atrophy is characterized by loss of cerebellar tissue, with evidence on brain imaging of enlarged interfolial spaces compared to the foliae. Genetic ataxias associated with cerebellar atrophy are a heterogeneous group of disorders. We investigated the prevalence in Canada and the diagnostic yield of whole exome sequencing (WES) for this group of conditions. Methods: Between 2011 and 2017, WES was performed in 91 participants with cerebellar atrophy as part of one of two national research programs, Finding of Rare Genetic Disease Genes (FORGE) or Enhanced Care for Rare Genetic Diseases in Canada (Care4Rare). Results: A genetic diagnosis was established in 58% of cases (53/91). Pathogenic variants were found in 24 known genes, providing a diagnosis for 46/53 participants (87%), and in four novel genes, accounting for 7/53 cases (13%). 38/91 cases (42%) remained unsolved. The most common diagnoses were channelopathies in 12/53 patients (23%) and mitochondrial disorders in 9/53 (17%). Inheritance was autosomal recessive in the majority of cases. Additional clinical findings provided useful clues to some of the diagnoses. Conclusions: This is the first report on the prevalence of genetic ataxias associated with cerebellar atrophy in Canada, and the utility of WES for this group of conditions.

scholarly journals WikiGenomes: an open Web application for community consumption and curation of gene annotation data in Wikidata

2017 ◽  
Author(s):  
Tim E. Putman ◽  
Sebastien Lelong ◽  
Sebastian Burgstaller-Muehlbacher ◽  
Andra Waagmeester ◽  
Colin Diesh ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Web Application ◽  
Scientific Community ◽  
Gene Annotation ◽  
Genomic Data ◽  
Knowledge Graph ◽  
Link Type ◽  
Sequencing Technologies ◽  
Annotation Data ◽  
The Individual

AbstractWith the advancement of genome sequencing technologies, new genomes are being sequenced daily. While these sequences are deposited in publicly available data warehouses, their functional and genomic annotations (beyond genes which are predicted automatically) mostly reside in the text of primary publications. Professional curators are hard at work extracting those annotations from the literature for the most studied organisms and depositing them in structured databases. However, the resources don’t exist to fund the comprehensive curation of the thousands of newly sequenced organisms in this manner. Here, we describe WikiGenomes (wikigenomes.org), a web application that facilitates the consumption and curation of genomic data by the entire scientific community. WikiGenomes is based on Wikidata, an openly editable knowledge graph with the goal of aggregating published knowledge into a free and open database. WikiGenomes empowers the individual genomic researcher to contribute their expertise to the curation effort and integrates the knowledge into Wikidata, enabling it to be accessed by anyone without restriction.

scholarly journals Heat Pump Bridge Analysis Using the Modified Energy Transfer Diagram

Energies ◽  
2020 ◽  
Vol 14 (1) ◽  
pp. 137
Author(s):  
Florian Schlosser ◽  
Heinrich Wiebe ◽  
Timothy G. Walmsley ◽  
Martin J. Atkins ◽  
Michael R. W. Walmsley ◽  
...  
Keyword(s):  
Energy Transfer ◽  
Heat Pump ◽  
Heat Recovery ◽  
Heat Pumps ◽  
Coefficient Of Performance ◽  
Combined Application ◽  
Recovery Potential ◽  
Composite Curve ◽  
And Performance ◽  
The Individual

Heat pumps are the key technology to decarbonise thermal processes by upgrading industrial surplus heat using renewable electricity. Existing insight-based integration methods refer to the idealised Grand Composite Curve requiring the full exploitation of heat recovery potential but leave the question of how to deal with technical or economic limitations unanswered. In this work, a novel Heat Pump Bridge Analysis (HPBA) is introduced for practically targeting technical and economic heat pump potential by applying Coefficient of Performance curves into the Modified Energy Transfer Diagram (METD). Removing cross-Pinch violations and operating heat exchangers at minimum approach temperatures by combined application of Bridge Analysis increases the heat recovery rate and reduce the temperature lift to be pumped at the same time. The insight-based METD allows the individual matching of heat surpluses and deficits of individual streams with the capabilities and performance of different market-available heat pump concepts. For an illustrative example, the presented modifications based on HPBA increase the economically viable share of the technical heat pump potential from 61% to 79%.

scholarly journals Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
William L. Macken ◽  
Annie Godwin ◽  
Gabrielle Wheway ◽  
Karen Stals ◽  
Liliya Nazlamova ◽  
...  
Keyword(s):  
Genome Sequencing ◽  
Donor Site ◽  
Xenopus Tropicalis ◽  
Splice Donor Site ◽  
Homologous Region ◽  
Disease Genes ◽  
Coat Proteins ◽  
Splice Donor ◽  
Severe Intellectual Disability

Abstract Background Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as “coatopathies”. Methods Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1’s splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2’s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2’s mutation. Results We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β’-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi. Conclusions This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

scholarly journals One4Two®: An Integrated Molecular Approach to Optimize Infertile Couples’ Journey

Genes ◽  
2021 ◽  
Vol 12 (1) ◽  
pp. 60
Author(s):  
Valeria D’Argenio ◽  
Federica Cariati ◽  
Rossella Tomaiuolo
Keyword(s):  
Disease Genes ◽  
Diagnostic Efficacy ◽  
Whole Process ◽  
Pathogenic Variants ◽  
Limiting Step ◽  
Number Of Genes ◽  
Infertile Couples ◽  
Next Generation Sequencing Ngs ◽  
And Diffusion ◽  
Generation Sequencing

The current diagnostic path of infertile couples is long lasting and often ineffective. Genetic tests, in particular, appear as a limiting step due to their jeopardized use on one side, and to the limited number of genes evaluated on the other. In this context, the development and diffusion, also in routine diagnostic settings, of next generation sequencing (NGS)-based methods for the analyses of several genes in multiple subjects at a time is improving the diagnostic sensitivity of molecular analyses. Thus, we developed One4Two®, a custom NGS panel to optimize the diagnostic journey of infertile couples. The panel validation was carried out in three steps analyzing a total of 83 subjects. Interestingly, all the previously identified variants were confirmed, assessing the analytic sensitivity of the method. Moreover, additional pathogenic variants have been identified underlying the diagnostic efficacy of the proposed method. One4Two® allows the simultaneous analysis of infertility-related genes, disease-genes of common inherited diseases, and of polymorphisms related to therapy outcome. Thus, One4Two® is able to improve the diagnostic journey of infertile couples by simplifying the whole process not only for patients, but also for laboratories and reproduction specialists moving toward an even more personalized medicine.

scholarly journals Analyzing Low-Level mtDNA Heteroplasmy—Pitfalls and Challenges from Bench to Benchmarking

2021 ◽  
Vol 22 (2) ◽  
pp. 935
Author(s):  
Federica Fazzini ◽  
Liane Fendt ◽  
Sebastian Schönherr ◽  
Lukas Forer ◽  
Bernd Schöpf ◽  
...  
Keyword(s):  
Variant Calling ◽  
Illumina Miseq ◽  
Bioinformatic Analysis ◽  
Low Level ◽  
Sequencing Technologies ◽  
Laboratory Setup ◽  
Dna Mixture ◽  
The Individual ◽  
Highly Sensitive Detection ◽  
Sensitivity Specificity

Massive parallel sequencing technologies are promising a highly sensitive detection of low-level mutations, especially in mitochondrial DNA (mtDNA) studies. However, processes from DNA extraction and library construction to bioinformatic analysis include several varying tasks. Further, there is no validated recommendation for the comprehensive procedure. In this study, we examined potential pitfalls on the sequencing results based on two-person mtDNA mixtures. Therefore, we compared three DNA polymerases, six different variant callers in five mixtures between 50% and 0.5% variant allele frequencies generated with two different amplification protocols. In total, 48 samples were sequenced on Illumina MiSeq. Low-level variant calling at the 1% variant level and below was performed by comparing trimming and PCR duplicate removal as well as six different variant callers. The results indicate that sensitivity, specificity, and precision highly depend on the investigated polymerase but also vary based on the analysis tools. Our data highlight the advantage of prior standardization and validation of the individual laboratory setup with a DNA mixture model. Finally, we provide an artificial heteroplasmy benchmark dataset that can help improve somatic variant callers or pipelines, which may be of great interest for research related to cancer and aging.

scholarly journals Genome-wide inferring gene–phenotype relationship by walking on the heterogeneous network

2010 ◽  
Vol 26 (9) ◽  
pp. 1219-1224 ◽  
Author(s):  
Yongjin Li ◽  
Jagdish C. Patra
Keyword(s):  
Heterogeneous Network ◽  
Gene Network ◽  
Genetic Diseases ◽  
Supplementary Information ◽  
Disease Genes ◽  
Phenotypic Data ◽  
Disease Associations ◽  
Improved Performance ◽  
Leave One Out ◽  
Phenotype Network

Abstract Motivation: Clinical diseases are characterized by distinct phenotypes. To identify disease genes is to elucidate the gene–phenotype relationships. Mutations in functionally related genes may result in similar phenotypes. It is reasonable to predict disease-causing genes by integrating phenotypic data and genomic data. Some genetic diseases are genetically or phenotypically similar. They may share the common pathogenetic mechanisms. Identifying the relationship between diseases will facilitate better understanding of the pathogenetic mechanism of diseases. Results: In this article, we constructed a heterogeneous network by connecting the gene network and phenotype network using the phenotype–gene relationship information from the OMIM database. We extended the random walk with restart algorithm to the heterogeneous network. The algorithm prioritizes the genes and phenotypes simultaneously. We use leave-one-out cross-validation to evaluate the ability of finding the gene–phenotype relationship. Results showed improved performance than previous works. We also used the algorithm to disclose hidden disease associations that cannot be found by gene network or phenotype network alone. We identified 18 hidden disease associations, most of which were supported by literature evidence. Availability: The MATLAB code of the program is available at http://www3.ntu.edu.sg/home/aspatra/research/Yongjin_BI2010.zip Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online.

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