Prevalence of Low-Frequency, Antiviral Resistance Variants in SARS-CoV-2 Isolates in Ontario, Canada, 2020-2023.

Importance: Nirmatrelvir-ritonavir is an oral antiviral medication that improves outcomes in SARS-CoV-2 infections. However, there is concern that antiviral resistance will develop and that these viruses could be selected for after treatment.

Objective: To determine the prevalence of low-frequency SARS-CoV-2 variants in patient samples that could be selected for by nirmatrelvir-ritonavir.

Utility of SARS-CoV-2 Genomic Sequencing for Understanding Transmission and School Outbreaks.

Objective: An understanding of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) transmission in schools is important. It is often difficult, using epidemiological information alone, to determine whether cases associated with schools represent multiple introductions from the community or transmission within the school. We describe the use of whole genome sequencing (WGS) in multiple schools to investigate outbreaks of SARS-CoV-2 in the pre-Omicron period.

The DataHarmonizer: a tool for faster data harmonization, validation, aggregation and analysis of pathogen genomics contextual information.

Pathogen genomics is a critical tool for public health surveillance, infection control, outbreak investigations as well as research. In order to make use of pathogen genomics data, they must be interpreted using contextual data (metadata). Contextual data include sample metadata, laboratory methods, patient demographics, clinical outcomes and epidemiological information.

Genome-Wide Sequencing Identified Rare Genetic Variants for Childhood-Onset Monogenic Lupus.

Objective: Genetics play an important role in systemic lupus erythematosus (SLE) pathogenesis. We calculated the prevalence of rare variants in known monogenic lupus genes among children suspected of monogenic lupus.

Methods: We completed paired-end genome-wide sequencing (whole genome sequencing [WGS] or whole exome sequencing) in patients suspected of monogenic lupus, and focused on 36 monogenic lupus genes.

Comparing genome sequencing technologies to improve rare disease diagnostics: a protocol for the evaluation of a pilot project, Genome-wide Sequencing Ontario.

Background: Genome-wide sequencing has emerged as a promising strategy for the timely diagnosis of rare diseases, but it is not yet available as a clinical test performed in Canadian diagnostic laboratories. We describe the protocol for evaluating a 2-year pilot project, Genome-wide Sequencing Ontario, to offer high-quality clinical genome-wide sequencing in Ontario, Canada.

Methods: The Genome-wide Sequencing Ontario protocol was codesigned by the Ontario Ministry of Health, the Hospital for Sick Children in Toronto and the Children's Hospital of Eastern Ontario in Ottawa.

A National Research Agenda for the Transition of Youth With Autism.

In this article, we outline a national research agenda to improve the transition to adulthood among youth with autism. We synthesized the results from 5 interconnected sets of activities: (1) a scoping review of published autism research and research priority statements, (2) a series of key informant interviews with stakeholders, (3) a 2-day National Research Agenda meeting, (4) a modified Delphi survey of stakeholders, and (5) 2 formal reviews of published literature on autism and transition. We identified 2 overarching priorities to advance research about autism and transition: (1) increased focus on community- and systems-level factors that influence outcomes with population-level approaches to measuring outcomes and (2) greater involvement of people with autism in establishing research priorities, designing research studies, and producing study findings and recommendations.

Stakeholder Perspectives on Research and Practice in Autism and Transition.

Objectives: Individuals with autism spectrum disorder (ASD) are reported to experience significant challenges during the transition to adulthood. Although recent evidence indicates that individuals with ASD experience poor outcomes in adulthood, little is understood about the contributing factors. In this qualitative study, we investigated the barriers to and needs in research and practice in the transition to adulthood among individuals with ASD.

The Diagnostic Odyssey of Autism Spectrum Disorder.

Objectives: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by challenges in social communication and interaction and restricted or repetitive behavior, interests, or activities. Although ASD symptoms generally manifest in early childhood, many individuals experience delays accessing an autism diagnosis and related services. In this study, we identify the individual, social, and structural factors that influence parents' experiences of children's ASD diagnosis.

Introduction to Transitions in the Life Course of Autism and Other Developmental Disabilities.

The Health Care Transitions Research Network for Autism Spectrum Disorder and other Developmental Disabilities and the Life Course Research Network, both funded by the Maternal and Child Health Bureau, invited articles for this Supplement. Our goal in this Supplement is to highlight and explore developmental and transition-related challenges over the life course of individuals on the autism spectrum and other neurodevelopmental disabilities, discuss the clinical and practice implications of these issues, highlight gaps in knowledge, and identify directions for future research.

Molecular Diagnostic Yield of Chromosomal Microarray Analysis and Whole-Exome Sequencing in Children With Autism Spectrum Disorder.

Importance: The use of genome-wide tests to provide molecular diagnosis for individuals with autism spectrum disorder (ASD) requires more study.

Objective: To perform chromosomal microarray analysis (CMA) and whole-exome sequencing (WES) in a heterogeneous group of children with ASD to determine the molecular diagnostic yield of these tests in a sample typical of a developmental pediatric clinic.

Design, Setting, And Participants: The sample consisted of 258 consecutively ascertained unrelated children with ASD who underwent detailed assessments to define morphology scores based on the presence of major congenital abnormalities and minor physical anomalies.

Whole-Exome Sequencing and Targeted Copy Number Analysis in Primary Ciliary Dyskinesia.

Primary ciliary dyskinesia (PCD) is an autosomal-recessive disorder resulting from loss of normal ciliary function. Symptoms include neonatal respiratory distress, chronic sinusitis, bronchiectasis, situs inversus, and infertility. Clinical features may be subtle and highly variable, making the diagnosis of PCD challenging.

Whole-exome analysis of foetal autopsy tissue reveals a frameshift mutation in OBSL1, consistent with a diagnosis of 3-M Syndrome.

Background: We report a consanguineous couple that has experienced three consecutive pregnancy losses following the foetal ultrasound finding of short limbs. Post-termination examination revealed no skeletal dysplasia, but some subtle proximal limb shortening in two foetuses, and a spectrum of mildly dysmorphic features. Karyotype was normal in all three foetuses (46, XX) and comparative genomic hybridization microarray analysis detected no pathogenic copy number variants.

Identification of a novel MSH6 germline variant in a family with multiple gastro-intestinal malignancies by next generation sequencing.

The identification of germline variants that predispose to cancer is important to further our understanding of tumorigenesis, guide patient management, prevent disease in unaffected relatives, and inform best practice for health care. We describe a kindred with multiple gastrointestinal malignancies where a novel MSH6 germline susceptibility variant was identified by exome sequencing after eluding serial routine testing in multiple affected members. This case fosters discussion of our current understanding of DNA mismatch repair deficiency, the management of Lynch Syndrome, and the emerging role of next generation sequencing in laboratory medicine to identify rare pathogenic germline variants in a comprehensive, unbiased fashion.

Brain-expressed exons under purifying selection are enriched for de novo mutations in autism spectrum disorder.

A universal challenge in genetic studies of autism spectrum disorders (ASDs) is determining whether a given DNA sequence alteration will manifest as disease. Among different population controls, we observed, for specific exons, an inverse correlation between exon expression level in brain and burden of rare missense mutations. For genes that harbor de novo mutations predicted to be deleterious, we found that specific critical exons were significantly enriched in individuals with ASD relative to their siblings without ASD (P < 1.

Detection of clinically relevant genetic variants in autism spectrum disorder by whole-genome sequencing.

Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations).

Intra- and interindividual epigenetic variation in human germ cells.

Epigenetics represents a secondary inheritance system that has been poorly investigated in human biology. The objective of this study was to perform a comprehensive analysis of DNA methylation variation between and within the germlines of normal males. First, methylated cytosines were mapped using bisulphite modification-based sequencing in the promoter regions of the following disease genes: presenilins (PSEN1 and PSEN2), breast cancer (BRCA1 and BRCA2), myotonic dystrophy (DM1), and Huntington disease (HD).