Biogeographical distribution of house dust mites: database from the literature

There has been a multitude of research into mite fauna with focus on the medical and economic implications of these species, but there is not a recent comprehensive report of all indoor house dust mite fauna worldwide. 347 articles from 1950 to the beginning of 2017 were collected through online searches using Web of Science, Google Scholar, EThOs, ProQuest Dissertations & Theses Global, Summon2.0, Interlibrary loans, and archives in the University of Reading collection, as well as the resources available at the University College of London library. Only mites which were collected from a location where people were living (i.e. sleeping and eating on a regular basis), as well as clothing, were included. Mites identified from other indoor locations, from human sputum after ingestion, or following an allergic reaction or anaphylactic shock were excluded. Specimens which were morphologically identified, as opposed to DNA identified, were incorporated. 531 species were collected from 63 countries worldwide, with the most diverse mite fauna in India (153 species), Japan (112 species), and Brazil (99 species). Dermatophagoides pteronyssinus, Dermatophagoides farinae, and Euroglyphus maynei were the three most common species, collected from 298, 235 and 155 publications respectively. There were some issues with creating this database, including the large discrepancy in the number of studies conducted within one region or country. Therefore the minimal number of studies may not be an accurate representation of all mite fauna in that country. There are many geographical and housing differences between regions within a country, as well as sampling variations. There may also be an issue with species misidentification, particularly pertinent with older publications before more accurate keys had been produced. Some publications also only searched for specific species, so many others may be excluded. Finally, there is a bias towards English-written publications. Research published in certain journals or different languages may have not been encompassed within the online searches. Some information or articles may also be overlooked due to poor translation, as often an English abstract or summary is provided but not the reminder of the publication. Therefore, although this database contains as many publications as possible, some mite fauna may still be missing. However, as this house dust mite fauna database notes specific locations and collection times, it assists with detecting the previously outlined issues of sampling bias and differences between locations

House dust mites and their genetic systems

Despite their medical implications and widespread distribution, there is limited knowledge of house dust mites. I assessed their biogeographical distribution, examined the genetic system of one of the most common species of house dust mite, Dermatophagoides farinae, and modelled different mating systems of mites, with the aim of improving understanding. This included assembling a database of house dust mite diversity, and identifying the most successful protocols for molecular work, which will save researchers time and provide a solid base for future studies. The creation of a house dust mite fauna database through published resources provided a worldwide distribution of all mites collected from homes. This may prove useful in future, particularly by allergists who are focusing on eradicating these mites for the benefit of human health. In addition, this identified the possibility of a latitudinal diversity gradient in house dust mites. Assessing D. farinae mitochondrial and nuclear genome regions through PCR and sequencing has illustrated dissimilarity between populations. This suggested that D. farinae may have been previously misidentified and the examined populations actually represent more than one species. This gives a basis for further analysis with an increased number of populations from a variety of locations. Finally, modelling and comparing different mating systems which may be found in mites, illustrate that despite the benefits of being haplodiploid, it is difficult to transition to this system from diploidy. This indicates that cytoplasmically inherited maternally-transmitted haplodiploidy is not favoured in diploid populations, forming part of the reason why many species are still in the ancestral diploid state

Incidental findings from cancer next generation sequencing panels

Next-generation sequencing (NGS) technologies have facilitated multi-gene panel (MGP) testing to detect germline DNA variants in hereditary cancer patients. This sensitive technique can uncover unexpected, non-germline incidental findings indicative of mosaicism, clonal hematopoiesis (CH), or hematologic malignancies. A retrospective chart review was conducted to identify cases of incidental findings from NGS-MGP testing. Inclusion criteria included: 1) multiple pathogenic variants in the same patient; 2) pathogenic variants at a low allele fraction; and/or 3) the presence of pathogenic variants not consistent with family history. Secondary tissue analysis, complete blood count (CBC) and medical record review were conducted to further delineate the etiology of the pathogenic variants. Of 6060 NGS-MGP tests, 24 cases fulfilling our inclusion criteria were identified. Pathogenic variants were detected in TP53, ATM, CHEK2, BRCA1 and APC. 18/24 (75.0%) patients were classified as CH, 3/24 (12.5%) as mosaic, 2/24 (8.3%) related to a hematologic malignancy, and 1/24 (4.2%) as true germline. We describe a case-specific workflow to identify and interpret the nature of incidental findings on NGS-MGP. This workflow will provide oncology and genetic clinics a practical guide for the management and counselling of patients with unexpected NGS-MGP findings

CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC’s functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications

LZTR1 molecular genetic overlap with clinical implications for Noonan syndrome and schwannomatosis

Abstract Background Noonan syndrome (NS) is a genetic disorder characterized by developmental delays, typical facial gestalt and cardiovascular defects. LZTR1 variants have been recently described in patients with NS and schwannomatosis, but the association, inheritance pattern and management strategy has not been fully elucidated. Here, we review the contribution of LZTR1 in NS and describe a patient with a novel, likely pathogenic variant in LZTR1. Case presentation A female patient was diagnosed with clinical NS at 8 months of age. She presented in adulthood when a brain and spine MRI identified plexiform neurofibromas; however, she did not meet the clinical criteria for Neurofibromatosis type 1. No pathogenic variants were identified through molecular genetic analysis of NF1, SPRED1 and a multigene NS panel. Whole exome sequencing at age 23 identified a novel de novo likely pathogenic heterozygous variant in the LZTR1 gene denoted as c.743G>A (p.Gly248Glu). Serial MRIs have shown stable imaging findings and the patient is being followed clinically by cardiology, neurology and medical genetics. Conclusions We identified a novel mutation in the LZTR1 gene, not previously reported in association with NS. This report provides additional evidence to support for the assessment of schwannomatosis in patients with LZTR1-NS and may have overlap with Neurofibromatosis type 1

GeneTerpret: a customizable multilayer approach to genomic variant prioritization and interpretation

Abstract Background Variant interpretation is the main bottleneck in medical genomic sequencing efforts. This usually involves genome analysts manually searching through a multitude of independent databases, often with the aid of several, mostly independent, computational tools. To streamline variant interpretation, we developed the GeneTerpret platform which collates data from current interpretation tools and databases, and applies a phenotype-driven query to categorize the variants identified in the genome(s). The platform assigns quantitative validity scores to genes by query and assembly of the genotype–phenotype data, sequence homology, molecular interactions, expression data, and animal models. It also uses the American College of Medical Genetics and Genomics (ACMG) criteria to categorize variants into five tiers of pathogenicity. The final output is a prioritized list of potentially causal variants/genes. Results We tested GeneTerpret by comparing its performance to expert-curated genes (ClinGen’s gene-validity database) and variant pathogenicity reports (DECIPHER database). Output from GeneTerpret was 97.2% and 83.5% concordant with the expert-curated sources, respectively. Additionally, similar concordance was observed when GeneTerpret’s performance was compared with our internal expert-interpreted clinical datasets. Conclusions GeneTerpret is a flexible platform designed to streamline the genome interpretation process, through a unique interface, with improved ease, speed and accuracy. This modular and customizable system allows the user to tailor the component-programs in the analysis process to their preference. GeneTerpret is available online at https://geneterpret.com

A community approach to the cancer-variant-interpretation bottleneck

As guidelines, therapies and literature on cancer variants expand, the lack of consensus variant interpretations impedes clinical applications. CIViC is a public-domain, crowd-sourced and adaptable knowledgebase of evidence for the clinical interpretation of variants in cancer, designed to reduce barriers to knowledge sharing and alleviate the variant-interpretation bottleneck