Genetics Adviser: The development and usability testing of a new patient digital health application to support clinical genomic testing.

Purpose: Increasing demand for genomic testing coupled with genetics workforce shortages has placed unsustainable pressure on standard models of care. Digital tools can offer improved access, efficiency, and cost savings. We created a patient-facing digital health application to support genomic testing.

Clinical Utility of Genomic Sequencing for Hereditary Cancer Syndromes: An Observational Cohort Study.

Purpose: Genomic sequencing (GS) is increasingly used to improve diagnoses and inform targeted therapies. GS can also be used to identify the 10% of cancer patients with an underlying hereditary cancer syndrome (HCS), who can benefit from surveillance and preventive surgery that reduce morbidity/mortality. However, the evidence on clinical utility of GS for HCS is limited: we aimed to fill this gap by assessing yield of all cancer results and associated recommendations for patients undergoing GS for HCS.

Characterizing the SARS-CoV-2 antibody response and associations with patient factors: Serological profiling of participants enrolled in the GENCOV study.

Introduction: The GENCOV study sought to evaluate serological differences between individuals with differing COVID-19 severity and outcomes. We assessed the SARS-CoV-2 antibody response of GENCOV participants cross-sectionally 1-, 6-, and 12-months following COVID-19 diagnosis to identify patient factors associated with more robust and durable humoral immune responses.

Materials And Methods: COVID-19 patients and a control cohort of vaccinated infection-naïve participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada.

Opportunistic genomic screening has clinical utility: An interventional cohort study.

Background: Practice is shifting toward genome-first approaches, such as opportunistic screening for secondary findings (SFs). Analysis of SFs could be extended beyond medically actionable results to include non-medically actionable monogenic disease risks, carrier status, pharmacogenomic variants, and risk variants for common complex disease. However, evidence on the clinical utility of returning these results is lacking.

Variant classification changes over time in the clinical molecular diagnostic laboratory setting.

Background: Variant classification in the setting of germline genetic testing is necessary for patients and their families to receive proper care. Variants are classified as pathogenic (P), likely pathogenic (LP), uncertain significance (VUS), likely benign (LB) and benign (B) using the standards and guidelines recommended by the American College of Medical Genetics and the Association for Molecular Pathology, with modifications for specific genes. As the literature continues to rapidly expand, and evidence continues to accumulate, prior classifications can be updated accordingly.

COVID-19 vaccine reactogenicity among participants enrolled in the GENCOV study.

Background: GENCOV is a prospective, observational cohort study of COVID-19-positive adults. Here, we characterize and compare side effects between COVID-19 vaccines and determine whether reactogenicity is exacerbated by prior SARS-CoV-2 infection.

Methods: Participants were recruited across Ontario, Canada.

Canadian COVID-19 host genetics cohort replicates known severity associations.

The HostSeq initiative recruited 10,059 Canadians infected with SARS-CoV-2 between March 2020 and March 2023, obtained clinical information on their disease experience and whole genome sequenced (WGS) their DNA. We analyzed the WGS data for genetic contributors to severe COVID-19 (considering 3,499 hospitalized cases and 4,975 non-hospitalized after quality control). We investigated the evidence for replication of loci reported by the International Host Genetics Initiative (HGI); analyzed the X chromosome; conducted rare variant gene-based analysis and polygenic risk score testing.

Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis.

Background: Causal variants underlying rare disorders may remain elusive even after expansive gene panels or exome sequencing (ES). Clinicians and researchers may then turn to genome sequencing (GS), though the added value of this technique and its optimal use remain poorly defined. We therefore investigated the advantages of GS within a phenotypically diverse cohort.

Recontact to return new or updated genetic results in the clinical laboratory setting.

Objective: The purpose of this study was to recontact individuals with clinically actionable test results identified through a retrospective research study and to provide a framework for laboratories to recontact patients.

Methods: Genetic testing was conducted on 2977 individuals originally referred for and hereditary breast and ovarian cancer testing that had a negative genetic test result. A gene panel was used to identify pathogenic variants in known or newly discovered genes that could explain the underlying cause of disease; however, analysis was restricted to for the purposes of this study.

The Deceased, Public Health, and Research: Proposing Legal Reforms.

There is little guidance concerning biomedical research using tissues from deceased individuals. Unique ethical and legal challenges gained visibility during the coronavirus disease 2019 (COVID-19) pandemic, when important studies using genome sequencing required access to biological materials from deceased individuals. These studies proposed to determine whether specific genomic profiles were associated with important disease outcomes.

Applications of SARS-CoV-2 serological testing: impact of test performance, sample matrices, and patient characteristics.

Laboratory testing has been a key tool in managing the SARS-CoV-2 global pandemic. While rapid antigen and PCR testing has proven useful for diagnosing acute SARS-CoV-2 infections, additional testing methods are required to understand the long-term impact of SARS-CoV-2 infections on immune response. Serological testing, a well-documented laboratory practice, measures the presence of antibodies in a sample to uncover information about host immunity.

Characterizing Risk Factors for Hospitalization and Clinical Characteristics in a Cohort of COVID-19 Patients Enrolled in the GENCOV Study.

The GENCOV study aims to identify patient factors which affect COVID-19 severity and outcomes. Here, we aimed to evaluate patient characteristics, acute symptoms and their persistence, and associations with hospitalization. Participants were recruited at hospital sites across the Greater Toronto Area in Ontario, Canada.

Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease.

Autosomal dominant polycystic kidney disease (ADPKD) resulting from pathogenic variants in PKD1 and PKD2 is the most common form of PKD, but other genetic causes tied to primary cilia function have been identified. Biallelic pathogenic variants in the serine/threonine kinase NEK8 cause a syndromic ciliopathy with extra-kidney manifestations. Here we identify NEK8 as a disease gene for ADPKD in 12 families.

Germline whole genome sequencing in adults with multiple primary tumors.

Multiple primary tumors (MPTs) are a harbinger of hereditary cancer syndromes. Affected individuals often fit genetic testing criteria for a number of hereditary cancer genes and undergo multigene panel testing. Other genomic testing options, such as whole exome (WES) and whole genome sequencing (WGS) are available, but the utility of these genomic approaches as a second-tier test for those with uninformative multigene panel testing has not been explored.

Public knowledge of SARS-CoV-2 serological and viral lineage laboratory testing and result interpretation: A GENCOV study cross-sectional survey.

Objectives: Concepts related to SARS-CoV-2 laboratory testing and result interpretation can be challenging to understand. A cross-sectional survey of COVID-19 positive adults residing in Ontario, Canada was conducted to explore how well people understand SARS-CoV-2 laboratory tests and their associated results.

Design And Methods: Participants were recruited through fliers or by prospective recruitment of outpatients and hospitalized inpatients with COVID-19.

Loss-of-function variants in cause a syndromic neurodevelopmental disorder.

Purpose: variants in (Cullin-3 ubiquitin ligase) have been strongly associated with neurodevelopmental disorders (NDDs), but no large case series have been reported so far. Here we aimed to collect sporadic cases carrying rare variants in describe the genotype-phenotype correlation, and investigate the underlying pathogenic mechanism.

Methods: Genetic data and detailed clinical records were collected via multi-center collaboration.

A model for the return and referral of all clinically significant secondary findings of genomic sequencing.

Secondary findings (SFs) identified through genomic sequencing (GS) can offer a wide range of health benefits to patients. Resource and capacity constraints pose a challenge to their clinical management; therefore, clinical workflows are needed to optimise the health benefits of SFs. In this paper, we describe a model we created for the return and referral of all clinically significant SFs, beyond medically actionable results, from GS.

HLA Variation and SARS-CoV-2 Specific Antibody Response.

Differences in SARS-CoV-2-specific immune responses have been observed between individuals following natural infection or vaccination. In addition to already known factors, such as age, sex, COVID-19 severity, comorbidity, vaccination status, hybrid immunity, and duration of infection, inter-individual variations in SARS-CoV-2 immune responses may, in part, be explained by structural differences brought about by genetic variation in the human leukocyte antigen (HLA) molecules responsible for the presentation of SARS-CoV-2 antigens to T effector cells. While dendritic cells present peptides with HLA class I molecules to CD8+ T cells to induce cytotoxic T lymphocyte responses (CTLs), they present peptides with HLA class II molecules to T follicular helper cells to induce B cell differentiation followed by memory B cell and plasma cell maturation.