Genome Canada

Our study assesses the Horizon model, a novel CNV classification tool developed in line with American College of Medical Genetics (ACMG) guidelines, to enhance the classification of pathogenicity in CNVs. Horizon utilizes a ranking-based algorithm, incorporating multiple proprietary databases and variant inheritance models as per ACMG standards. The model’s effectiveness was verified through Area Under the Curve (AUC) analyses on three datasets comprising 635 pathogenic inherited or de novo variants, as classified by clinical geneticists and several established tools. Horizon achieved an AUC of 0.96 (accuracy: 0.9611) in the discovery cohort, demonstrating high accuracy in CNV interpretation and proficiency in predicting pathogenicity. We observed an AUC of 0.96 (accuracy: 0.8776) in the de novo variant cohort and an overall AUC of 0.93 across all cohorts, surpassing tools like ClassifyCNV (AUC: 0.81),AnnotSV (AUC: 0.85), and ISV-CNV (AUC: 0.84). It showed particular effectiveness in interpreting duplication CNVs and the highest performance for CNVs sized 3–5 Mb. The Horizon model offers robust and accurate CNV interpretation, outperforming existing tools and aligning closely with clinical evaluations. Its comprehensive approach, integrating a range of genomic features and following ACMG guidelines, makes it a crucial tool in the genomic interpretation landscape, facilitating the rapid and accurate diagnosis of genetic disorders.

This study presents and discusses evidence on the value of biomarker testing and precision medicine in Latin America through a health equity lens. It is essential to explore how to harness the benefits of precision medicine to narrow the health equity gap, ensuring all patients have access to the best cancer treatment. The methodology employed to develop this document consists of a non-systematic literature review, followed by a process of validation and feedback with a group of experts in relevant fields. Precision medicine could help reduce health inequities in Latin America by providing better diagnosis and treatment for everyone with cancer. However, its success in achieving this depends on the implementation of policies that promote equitable access. Findings indicate that the current policy landscape in the Latin American region is not conducive to improving access, reach, quality, or outcome-related problems in cancer care, nor to realizing the full potential of precision medicine. The study explores how precision medicine can advance health equity, concluding with an analysis of the challenges and recommendations for overcoming them.

Biobanking plays a crucial role in promptly generating effective solutions to combat emerging infectious diseases. In direct response to the COVID-19 crisis, Quebec established the “Biobanque québécoise de la COVID-19” (BQC19) in March 2020. BQC19 swiftly amassed comprehensive demographic and clinical data and biosamples, from individuals across the province seeking care at participating hospitals and outpatient clinics. This article underscores the transformative potential of BQC19, which has thousands of digitized demographics and clinical records, biosamples from various stages of the pandemic, and provides digital access to the results of numerous multi-omic analyses. By advanced handling and analytical approaches to large sets of genomic, transcriptomic, metabolomic and proteomic data, BQC19 provides a platform to investigate diagnostic and prognostic biomarkers and explore patient stratification for a more personalized approach. Through BQC19, we examine the pivotal role of biobanks in deciphering the complexities of COVID-19 and their capacity to enhance readiness for future infectious threats. BQC19’s dynamic framework, encompassing participating hospitals, clinics, research institutions, core analysis laboratory data, and a network of Canadian and international medical professionals and researchers, exemplifies its versatility. With standardized protocols, secure data management, ethical guidelines and community engagement, BQC19 stands as a beacon for proactive research on emerging diseases.

Rett syndrome (RTT) is a neurological disorder marked by the loss of developmental milestones. Classic RTT involves variants in the methyl-CpG-binding protein 2 (MECP2) gene. Our study examines the genetic basis of typical and atypical RTT, along with RTT-like phenotypes, using MECP2-targeted sequencing (TS) and exome sequencing (ES). MECP2 sequencing was conducted on 27 Bangladeshi female participants with RTT features. ES was subsequently conducted on the 13 participants who tested negative for MECP2 variants. Data were processed using the Genome Analysis Toolkit and American College of Medical Genetics and Genomics-guided pathogenicity analysis was conducted with ANNOVAR and GenomeArc Horizon. Copy-number variation analysis was performed using CNVkit, and variants were classified according to the American College of Medical Genetics and Genomics guidelines. Of the 27 participants, 51.9% (14/27) had pathogenic MECP2 variants, all exhibiting the classic RTT phenotype, yielding an 87.5% (14/16) diagnostic rate for classic RTT through TS. The identified variants included 3 missense, 3 nonsense, and 3 frameshift deletions. Among the 13 MECP2-negative participants who underwent ES, 69.2% (9/13) harbored pathogenic variants, whereas 23.1% (3/13) carried a variant of uncertain significance, and 7.7% (1/13) had no clinically relevant variants. ES analysis identified 6 candidate genes were associated with atypical RTT (CACNA1E) and RTT-like phenotypes (ARHGEF9, KMT2C, TBC1D23, PGAP3, and LEO1). The overall diagnostic yield for TS and ES was 85.2% (23/27). This genetic study of clinically diagnosed Bangladeshi RTT participants identifies new genes involved in the etiology of RTT-like phenotypes and expands the phenotypic spectrum of known genes linked to neurodevelopmental disorders.

IntroductionIn Canada, care for individuals with hereditary cancer is fragmented across the provinces and territories, with carriers of pathogenic variants in cancer-susceptibility genes seeing multiple doctors and often advocating for their own management plans. The need for a national registry of carriers has been well established. While other cancer consortia exist, barriers in clinical and genomic data sharing limit the utility of the information gathered.Methods and analysisWithin the province of Ontario, the Ontario Hereditary Cancer Research Network (OHCRN), funded by and located at the Ontario Institute for Cancer Research, is being developed to fill this gap. The registry will hold clinical, genomic and self-reported data from consented carriers and will make this data available to qualified researchers in anonymised and aggregated form. Individuals must agree to certain components to participate in OHCRN; there are also optional consents participants can agree to without impacting their involvement in OHCRN. We plan to open the registry for participant enrolment in mid-2025.Ethics and disseminationEthics approval for registry creation was obtained from the Ontario Cancer Research Ethics Board, a centralised body that streamlines reviews for cancer research studies in Ontario. Registry data will be disseminated to participants and researchers as aggregate data through the OHCRN website and presented at scientific conferences, made available to Ontario Health (Cancer Care Ontario) to inform policy and evidence-based practice, as well as be available to the scientific community for further analysis and answering relevant questions.

Multiple system atrophy (MSA) is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated α-synuclein (α-syn) in oligodendrocytes. The origin of α-syn accumulation in GCIs is unclear, in particular whether abnormal α-syn aggregates result from the abnormal elevation of endogenous α-syn expression in MSA or ingested from the neuronal source. Tubulin polymerization promoting protein (TPPP) has been reported to play a crucial role in developing GCI pathology. Here, the total cell body, nucleus, and cytoplasmic area density of SNCA and TPPP transcripts in neurons and oligodendrocytes with and without various α-syn pathologies in the pontine base in autopsy cases of MSA (n = 4) and controls (n = 2) were evaluated using RNAscope with immunofluorescence. Single-nucleus RNA-sequencing data for TPPP was evaluated using control frontal cortex (n = 3). SNCA and TPPP transcripts were present in the nucleus and cytoplasm of oligodendrocytes in both controls and diseased, with higher area density in GCIs and glial nuclear inclusions in MSA. Area densities of SNCA and TPPP transcripts were lower in neurons showing cytoplasmic inclusions in MSA. Indeed, TPPP transcripts were unexpectedly found in neurons, while the anti-TPPP antibody failed to detect immunoreactivity. Single-nucleus RNA-sequencing revealed significant TPPP transcript expression predominantly in oligodendrocytes, but also in excitatory and inhibitory neurons. This study addressed the unclear origin of accumulated α-syn in GCIs, proposing that the elevation of SNCA transcripts may supply templates for misfolded α-syn. In addition, the parallel behavior of TPPP and SNCA transcripts in GCI development highlights their potential synergistic contribution to inclusion formation. In conclusion, this study advances our understanding of MSA pathogenesis, offers insights into the dynamics of SNCA and TPPP transcripts in inclusion formation, and proposes regulating their transcripts for future molecular therapy to MSA.

Y chromosomes are thought to undergo progressive degeneration due to stepwise loss of recombination and subsequent reduction in selection efficiency. However, the timescales and evolutionary forces driving degeneration remain unclear. To investigate the evolution of sex chromosomes on multiple timescales, we generated a high-quality phased genome assembly of the massive older (<10 MYA) and neo (<200,000 yr) sex chromosomes in the XYY cytotype of the dioecious plant Rumex hastatulus and a hermaphroditic outgroup Rumex salicifolius. Our assemblies, supported by fluorescence in situ hybridization, confirmed that the neo-sex chromosomes were formed by two key events: an X-autosome fusion and a reciprocal translocation between the homologous autosome and the Y chromosome. The enormous sex-linked regions of the X (296 Mb) and two Y chromosomes (503 Mb) both evolved from large repeat-rich genomic regions with low recombination; however, the complete loss of recombination on the Y still led to over 30% gene loss and major rearrangements. In the older sex-linked region, there has been a significant increase in transposable element abundance, even into and near genes. In the neo-sex-linked regions, we observed evidence of extensive rearrangements without gene degeneration and loss. Overall, we inferred significant degeneration during the first 10 million years of Y chromosome evolution but not on very short timescales. Our results indicate that even when sex chromosomes emerge from repetitive regions of already-low recombination, the complete loss of recombination on the Y chromosome still leads to a substantial increase in repetitive element content and gene degeneration.

Introduction: Copy number variations (CNVs) play a critical role in the pathogenesis of neurodevelopmental disorders (NDD) among children. In this study, we aim to identify clinically relevant CNVs, genes and their phenotypic characteristics in an ethnically underrepresented homogenous population of Bangladesh.Methods: We have conducted chromosomal microarray analysis (CMA) for 212 NDD patients with male to female ratio of 2.2:1.0 to identify rare CNVs. To identify candidate genes within the rare CNVs, gene constraint metrics [i.e., “Critical-Exon Genes (CEGs)”] were applied to the population data. Autism Diagnostic Observation Schedule-Second Edition (ADOS-2) was followed in a subset of 95 NDD patients to assess the severity of autism and all statistical tests were performed using the R package.Results: Of all the samples assayed, 12.26% (26/212) and 57.08% (121/212) patients carried pathogenic and variant of uncertain significance (VOUS) CNVs, respectively. While 2.83% (6/212) patients’ pathogenic CNVs were found to be located in the subtelomeric regions. Further burden test identified females are significant carriers of pathogenic CNVs compared to males (OR = 4.2; p = 0.0007). We have observed an increased number of Loss of heterozygosity (LOH) within cases with 23.85% (26/109) consanguineous parents. Our analyses on imprinting genes show, 36 LOH variants disrupting 69 unique imprinted genes and classified these variants as VOUS. ADOS-2 subset shows severe social communication deficit (p = 0.014) and overall ASD symptoms severity (p = 0.026) among the patients carrying duplication CNV compared to the CNV negative group. Candidate gene analysis identified 153 unique CEGs in pathogenic CNVs and 31 in VOUS. Of the unique genes, 18 genes were found to be in smaller (<1 MB) focal CNVs in our NDD cohort and we identified PSMC3 gene as a strong candidate gene for Autism Spectrum Disorder (ASD). Moreover, we hypothesized that KMT2B gene duplication might be associated with intellectual disability.Conclusion: Our results show the utility of CMA for precise genetic diagnosis and its integration into the diagnosis, therapy and management of NDD patients.