scholarly journals Crowdfunded whole-genome sequencing of the celebrity cat Lil BUB identifies causal mutations for her osteopetrosis and polydactyly

2019 ◽  
Author(s):  
Mike Bridavsky ◽  
Heiner Kuhl ◽  
Arthur Woodruff ◽  
Uwe Kornak ◽  
Bernd Timmermann ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genomic Analysis ◽  
Heterozygous Mutation ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Genetic Literacy ◽  
Alternative Funding ◽  
Diagnosis And Prognosis ◽  
Frameshift Deletion

AbstractRare diseases and their underlying molecular causes are often poorly studied, posing challenges for patient diagnosis and prognosis. The development of next-generation sequencing and its decreasing costs promises to alleviate such issues by supplying personal genomic information at a moderate price. Here, we used crowdfunding as an alternative funding source to sequence the genome of Lil BUB, a celebrity cat affected by rare disease phenotypes characterized by supernumerary digits, osteopetrosis and dwarfism, all phenotypic traits that also occur in human patients. We discovered that Lil BUB is affected by two distinct mutations: a heterozygous mutation in the limb enhancer of the Sonic hedgehog gene, previously associated with polydactyly in Hemingway cats; and a novel homozygous frameshift deletion affecting the TNFRSF11A (RANK) gene, which has been linked to osteopetrosis in humans. We communicated the progress of this project to a large online audience, detailing the ‘inner workings’ of personalized whole genome sequencing with the aim of improving genetic literacy. Our results highlight the importance of genomic analysis in the identification of disease-causing mutations and support crowdfunding as a means to fund low-budget projects and as a platform for scientific communication.

scholarly journals Identification of Pathogenic Structural Variants in Rare Disease Patients through Genome Sequencing

2019 ◽  
Author(s):  
James M. Holt ◽  
Camille L. Birch ◽  
Donna M. Brown ◽  
Manavalan Gajapathy ◽  
Nadiya Sosonkina ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Rare Disease ◽  
Genome Sequencing ◽  
Genomic Analysis ◽  
Whole Genome ◽  
Structural Variants ◽  
Single Nucleotide Variants ◽  
Standard Clinical Practice ◽  
Wide Range ◽  
Genetic Features

AbstractPurposeClinical whole genome sequencing is becoming more common for determining the molecular diagnosis of rare disease. However, standard clinical practice often focuses on small variants such as single nucleotide variants and small insertions/deletions. This leaves a wide range of larger “structural variants” that are not commonly analyzed in patients.MethodsWe developed a pipeline for processing structural variants for patients who received whole genome sequencing through the Undiagnosed Diseases Network (UDN). This pipeline called structural variants, stored them in an internal database, and filtered the variants based on internal frequencies and external annotations. The remaining variants were manually inspected and then interesting findings were reported as research variants to clinical sites in the UDN.ResultsOf 477 analyzed UDN cases, 286 cases (≈ 60%) received at least one structural variant as a research finding. The variants in 16 cases (≈ 4%) are considered “Certain” or “Highly likely” molecularly diagnosed and another 4 cases are currently in review. Of those 20 cases, at least 13 were identified originally through our pipeline with one finding leading to identification of a new disease. As part of this paper, we have also released the collection of variant calls identified in our cohort along with heterozygous and homozygous call counts. This data is available at https://github.com/HudsonAlpha/UDN_SV_export.ConclusionStructural variants are key genetic features that should be analyzed during routine clinical genomic analysis. For our UDN patients, structural variants helped solve ≈ 4% of the total number of cases (≈ 13% of all genome sequencing solves), a success rate we expect to improve with better tools and greater understanding of the human genome.

scholarly journals Application of combined genomic and transfer analyses to identify factors mediating regional spread of antibiotic resistant bacterial lineages

2020 ◽  
Author(s):  
Joyce Wang ◽  
Betsy Foxman ◽  
Ali Pirani ◽  
Zena Lapp ◽  
Lona Mody ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Genomic Analysis ◽  
Patient Characteristics ◽  
Patient Transfer ◽  
Whole Genome ◽  
Nursing Facilities ◽  
Antibiotic Resistant ◽  
Patient Level ◽  
Healthcare Associated

ABSTRACTBackgroundPatients entering nursing facilities (NFs) are frequently colonized with antibiotic resistant organisms (AROs). To understand the determinants of ARO colonization on NF admission we applied whole-genome sequencing to track the spread of four ARO species across regional NFs and evaluated patient-level characteristics and transfer acute-care hospitals (ACHs) as risk factors for colonization.Methods584 patients from six NFs were surveyed for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis/faecium (VREfc/VREfm) and ciprofloxacin-resistant Escherichia coli (CipREc) colonization. Genomic analysis was performed to quantify ARO spread between NFs and compared to patient-transfer networks. The association between admission colonization and patient-level variables and recent ACH exposures was examined using multivariable regression models.ResultsThe majority of ARO isolates across study sites belonged to major healthcare-associated lineages: MRSA (ST5;N=89/117); VREfc (ST6;N=68/75); CipREc (ST131; N=58/64), and VREfm (clade A; N=129/129). While the genomic similarity of strains between NF pairs was associated with overlap in their feeder ACHs (Spearman’s rho=0.44-0.75, p<0.05 for MRSA, VREfc and CipREc), limited phylogenetic clustering by either ACH or NF supported regional endemicity. Significant predictors for ARO colonization on NF admission included lower functional status (adjusted odds ratio [aOR]>1 for all four AROs) and recent exposure to glycopeptides (aOR>2 for VREfm, VREfc and MRSA) or 3rd/4th-generation cephalosporins (aOR>2 for MRSA and VREfm). Transfer from specific ACHs was an independent risk factor for only one ARO/ACH pair (VREfm/ACH19, aOR=2.48[1.06-5.83]).ConclusionIn this region, healthcare-associated ARO lineages are endemic among connected NFs and ACHs, making patient characteristics more informative of NF admission colonization risk than exposure to specific ACHs.SummaryUsing a combination of whole-genome sequencing, patient transfer and clinical data, we discerned the dissemination of four high-priority antibiotic-resistant organisms (ARO) in the regional healthcare network, and epidemiolocal drivers underlying the high ARO importation rate into regional nursing facilities.

scholarly journals Diagnostic utility of whole-genome sequencing for nephronophthisis

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Romain Larrue ◽  
Paul Chamley ◽  
Thomas Bardyn ◽  
Arnaud Lionet ◽  
Viviane Gnemmi ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Molecular Diagnosis ◽  
Kidney Diseases ◽  
Single Gene ◽  
Whole Genome ◽  
Autosomal Recessive Disorders ◽  
Monogenic Disorders ◽  
Diagnosis And Prognosis ◽  
End Stage

Abstract Next-generation sequencing has revolutionized the molecular diagnosis of individuals affected by genetic kidney diseases. Indeed, rapid genetic testing in individuals with suspected inherited nephropathy has not only important implications for diagnosis and prognosis but also for genetic counseling. Nephronophthisis (NPHP) and related syndromes, a leading cause of end-stage renal failure, are autosomal recessive disorders characterized by the variable presentation and considerable locus heterogeneity with more than 90 genes described as single-gene causes. In this case report, we demonstrate the utility of whole-genome sequencing (WGS) for the molecular diagnosis of NPHP by identifying two putative disease-causing intronic mutations in the NPHP3 gene, including one deep intronic variant. We further show that both intronic variants, by affecting splicing, result in a truncated nephrocystin-3 protein. This study provides a framework for applying WGS as a first-line diagnostic tool for highly heterogeneous disease such as NPHP and further suggests that deep intronic variations are an important underestimated cause of monogenic disorders.

scholarly journals Symptomatic SARS-CoV-2 Reinfection in a Healthy Healthcare Worker in Italy Confirmed by Whole-Genome Sequencing

Viruses ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 899
Author(s):  
Daniela Loconsole ◽  
Anna Sallustio ◽  
Marisa Accogli ◽  
Francesca Centrone ◽  
Daniele Casulli ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Healthcare Worker ◽  
Genome Sequencing ◽  
Genomic Analysis ◽  
Nucleic Acid Amplification ◽  
Whole Genome ◽  
Serological Tests ◽  
Routine Surveillance ◽  
Two Samples ◽  
Genomic Analyses

This study describes a case of SARS-CoV-2 reinfection confirmed by whole-genome sequencing in a healthy physician who had been working in a COVID-19 hospital in Italy since the beginning of the pandemic. Nasopharyngeal swabs were obtained from the patient at each presentation as part of routine surveillance. Nucleic acid amplification testing was performed on the two samples to confirm SARS-CoV-2 infection, and serological tests were used to detect SARS-CoV-2 IgG antibodies. Comparative genome analysis with whole-genome sequencing was performed on nasopharyngeal swabs collected during the two episodes of COVID-19. The first COVID-19 episode was in March 2020, and the second was in January 2021. Both SARS-CoV-2 infections presented with mild symptoms, and seroconversion for SARS-CoV-2 IgG was documented. Genomic analysis showed that the viral genome from the first infection belonged to the lineage B.1.1.74, while that from the second infection to the lineage B.1.177. Epidemiological, clinical, serological, and genomic analyses confirmed that the second episode of SARS-CoV-2 infection in the healthcare worker met the qualifications for “best evidence” for reinfection. Further studies are urgently needed to assess the frequency of such a worrisome occurrence, particularly in the light of the recent diffusion of SARS-CoV-2 variants of concern.

scholarly journals One substance to rule them all and in the darkness bind them: whole-genome sequencing illuminates multifaceted targets of humic adaptation in Eurasian perch

2021 ◽  
Author(s):  
Mikhail Ozerov ◽  
Kristina Noreikiene ◽  
Siim Kahar ◽  
Magnus Huss ◽  
Ari Huusko ◽  
...  
Keyword(s):  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Extreme Environments ◽  
Gene Families ◽  
Regulatory Elements ◽  
Phenotypic Traits ◽  
Whole Genome ◽  
Humic Lakes ◽  
Whole Genome Analysis ◽  
Eurasian Perch

Extreme environments are inhospitable to the majority of species, but some organisms are able to survive in such hostile conditions due to evolutionary adaptations. For example, modern bony fishes have colonized various aquatic environments, including perpetually dark, hypoxic, hypersaline and toxic habitats. Eurasian perch (Perca fluviatilis) is among the few fish species of northern latitudes that is able to live in extremely acidic humic lakes. Such lakes represent almost “nocturnal” environments; they contain high levels of dissolved organic matter, which in addition to creating a challenging visual environment, also affects a large number of other habitat parameters and biotic interactions. To reveal the genomic targets of humic-associated selection, we performed whole-genome sequencing of perch originating from 16 humic and 16 clear-water lakes in northern Europe. We identified over 800,000 SNPs, of which >10,000 were identified as potential candidates under selection (associated with >3,000 genes) using multiple outlier approaches. Our findings suggest that adaptation to the humic environment involves hundreds of regions scattered across the genome. Putative signals of adaptation were detected in genes and gene families with diverse functions, including organism development and ion transportation. The observed excess of variants under selection in regulatory regions highlights the importance of adaptive evolution via regulatory elements, rather than via protein sequence modification. Our study demonstrates the power of whole-genome analysis to illuminate multifaceted nature of humic adaptation and highlights the next challenge moving from high-throughput outlier identification towards functional validation of causal mutations underlying phenotypic traits of ecological and evolutionary importance.

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