A roadmap for navigating child health research data sharing across Canada and beyond - building on UCAN CAN-DU.

Background: Sharing health data within and across jurisdictions is important for research and improving healthcare quality; however, researchers, governments and funders must balance the benefits of data sharing with data privacy. Though frameworks exist to guide data sharing it can be difficult to translate these into practice. Therefore, our aim was to create a practical example of data sharing for researchers in pediatric rheumatology.

Exome Sequencing in the Diagnostic Pathway for Suspected Rare Genetic Diseases: Does the Order of Testing Affect its Cost-Effectiveness?

Background: Patients with suspected rare diseases often experience lengthy and uncertain diagnostic pathways. This study aimed to estimate the cost-effectiveness of exome sequencing (ES) in different positions in the diagnostic pathway for patients suspected of having a rare genetic disease.

Methods: Data collected retrospectively from 305 patients suspected of having a rare genetic disease (RGD), who received clinical-grade ES and participated in the Canadian multicentre Care4Rare-SOLVE study, informed a discrete event simulation of the diagnostic pathway.

An interactive atlas of three-dimensional syndromic facial morphology.

Craniofacial phenotyping is critical for both syndrome delineation and diagnosis because craniofacial abnormalities occur in 30% of characterized genetic syndromes. Clinical reports, textbooks, and available software tools typically provide two-dimensional, static images and illustrations of the characteristic phenotypes of genetic syndromes. In this work, we provide an interactive web application that provides three-dimensional, dynamic visualizations for the characteristic craniofacial effects of 95 syndromes.

Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

Purpose: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype.

Methods: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy.

Developing a Framework of Cost Elements of Socioeconomic Burden of Rare Disease: A Scoping Review.

Background And Objective: Rare diseases place a significant burden on patients, families, the healthcare system, and society. Evidence on the socioeconomic burden of rare disease is limited and mostly reflects diseases where treatments are available. We developed a framework encompassing recommended cost elements for studies of the socioeconomic burden of rare diseases.

Comparing 2D and 3D representations for face-based genetic syndrome diagnosis.

Human genetic syndromes are often challenging to diagnose clinically. Facial phenotype is a key diagnostic indicator for hundreds of genetic syndromes and computer-assisted facial phenotyping is a promising approach to assist diagnosis. Most previous approaches to automated face-based syndrome diagnosis have analyzed different datasets of either 2D images or surface mesh-based 3D facial representations, making direct comparisons of performance challenging.

Care4Rare Canada: Outcomes from a decade of network science for rare disease gene discovery.

The past decade has witnessed a rapid evolution in rare disease (RD) research, fueled by the availability of genome-wide (exome and genome) sequencing. In 2011, as this transformative technology was introduced to the research community, the Care4Rare Canada Consortium was launched: initially as FORGE, followed by Care4Rare, and Care4Rare SOLVE. Over what amounted to three eras of diagnosis and discovery, the Care4Rare Consortium used exome sequencing and, more recently, genome and other 'omic technologies to identify the molecular cause of unsolved RDs.

Hnrnpul1 controls transcription, splicing, and modulates skeletal and limb development in vivo.

Mutations in RNA-binding proteins can lead to pleiotropic phenotypes including craniofacial, skeletal, limb, and neurological symptoms. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are involved in nucleic acid binding, transcription, and splicing through direct binding to DNA and RNA, or through interaction with other proteins in the spliceosome. We show a developmental role for Hnrnpul1 in zebrafish, resulting in reduced body and fin growth and missing bones.

The complexity of diagnosing rare disease: An organizing framework for outcomes research and health economics based on real-world evidence.

Purpose: To facilitate robust economic analyses of clinical exome and genome sequencing, this study was taken up with the objective of establishing a framework for organizing diagnostic testing trajectories for patients with rare disease.

Methods: We collected diagnostic investigations-related data before exome sequencing from the medical records of 228 cases. Medical geneticist experts participated in a consensus building process to develop the SOLVE Framework for organizing the complex range of observed tests.

Early Death of 2 Siblings Related to Mutations in , a Recently Discovered Cause of Neonatal Dilated Cardiomyopathy.

We report a family with 2 neonatal deaths related to dilated cardiomyopathy (DCM) and compound heterozygous loss-of-function variants (c.1243_1244del, p.Leu415Valfs*108 and c.

IMPACT webinars: Improving Patient Access to genetic Counselling and Testing using webinars-the Alberta experience with hypertrophic cardiomyopathy.

Growing demand for genetic counselling and testing has created a need for innovative service delivery models to provide quality care in an efficient manner. The goal of this study was to develop and evaluate a patient-facing webinar providing pre-test genetic counselling to individuals with hypertrophic cardiomyopathy. A patient-facing webinar was developed and implemented between April 2019 and January 2021.

De novo variants in MPP5 cause global developmental delay and behavioral changes.

Membrane Protein Palmitoylated 5 (MPP5) is a highly conserved apical complex protein essential for cell polarity, fate and survival. Defects in cell polarity are associated with neurologic disorders including autism and microcephaly. MPP5 is essential for neurogenesis in animal models, but human variants leading to neurologic impairment have not been described.

(Un)standardized testing: the diagnostic odyssey of children with rare genetic disorders in Alberta, Canada.

Purpose: We provide a description of the diagnostic odyssey for a cohort of children seeking diagnosis of a rare genetic disorder in terms of the time from initial consultation to most recent visit or receipt of diagnosis, the number of tests per patient, and the types of tests received.

Methods: Retrospective chart review of 299 children seen at the Alberta Children's Hospital (ACH) Genetics Clinic (GC) for whom the result of at least one single-gene test, gene panel, or chromosome microarray analysis (CMA) was recorded.

Results: Of 299 patients, 90 (30%) received a diagnosis in the period of the review.

Effects of prenatal exposure and co-exposure to metallic or metalloid elements on early infant neurodevelopmental outcomes in areas with small-scale gold mining activities in Northern Tanzania.

Background: Artisanal and small-scale gold mining (ASGM) is associated with release of neurotoxic metallic or metalloid chemical elements including lead (Pb), mercury (Hg), cadmium (Cd) and arsenic (As).

Objective: To examine associations between prenatal exposure and co-exposure to total lead (T-Pb), total mercury (T-Hg), total cadmium (T-Cd) and total arsenic (T-As) and infant neurodevelopment at 6 to 12 months of age in areas with ASGM activities in Tanzania.

Methods: Women in their second trimester of pregnancy who resided in ASGM areas were enrolled from 2015 to 2017 (n = 883).

Prevalence rates study of selected isolated non-Mendelian congenital anomalies in the Hutterite population of Alberta, 1980-2016.

A study of the prevalence rates for selected isolated non-Mendelian congenital anomalies in the Hutterite Brethren of Alberta, Canada was undertaken to further examine longitudinal data in this isolated community that was last reported in 1985 (Lowry et al., 1985), although there are numerous publications on recessive disorders (Boycott et al., 2008; Triggs-Raine et al.

Automated syndrome diagnosis by three-dimensional facial imaging.

Purpose: Deep phenotyping is an emerging trend in precision medicine for genetic disease. The shape of the face is affected in 30-40% of known genetic syndromes. Here, we determine whether syndromes can be diagnosed from 3D images of human faces.

Maternal exposure to arsenic and mercury and associated risk of adverse birth outcomes in small-scale gold mining communities in Northern Tanzania.

Background: Exposure to arsenic and mercury in artisanal and small-scale gold mining (ASGM) communities is an issue that predominantly affects low and middle-income countries. Large epidemiology studies in these communities are rare, and the impact of such exposures on reproductive outcomes are not well understood.

Objective: To examine associations between prenatal maternal arsenic and mercury exposure and birth outcomes in both ASGM and non-ASGM communities in Northern Tanzania.

Correction: The value of diagnostic testing for parents of children with rare genetic diseases.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The value of diagnostic testing for parents of children with rare genetic diseases.

Purpose: Exome sequencing (ES) can rapidly identify disease-causing variants responsible for rare, single-gene diseases, and potentially reduce the duration of the diagnostic odyssey. Our study examines how parents and families value ES.

Methods: We developed a discrete choice experiment (DCE) survey that was administered to parents of children with rare diseases.

is a mitochondrial disease gene causing skeletal dysplasia, cataracts, and white matter changes.

Exome sequencing of two sisters with congenital cataracts, short stature, and white matter changes identified compound heterozygous variants in the gene, encoding the phosphatidylserine decarboxylase enzyme that converts phosphatidylserine to phosphatidylethanolamine (PE) in the inner mitochondrial membrane (IMM). Decreased conversion of phosphatidylserine to PE in patient fibroblasts is consistent with impaired phosphatidylserine decarboxylase (PISD) enzyme activity. Meanwhile, as evidence for mitochondrial dysfunction, patient fibroblasts exhibited more fragmented mitochondrial networks, enlarged lysosomes, decreased maximal oxygen consumption rates, and increased sensitivity to 2-deoxyglucose.

Next-Generation Sequencing Using a Cardiac Gene Panel in Prenatally Diagnosed Cardiac Anomalies.

Objective: Most prenatally identified congenital heart defects (CHDs) are the sole structural anomaly detected; however, there is a subgroup of cases where the specific genetic cause will impact prognosis, including chromosome abnormalities and single-gene causes. Next-generation sequencing of all the protein coding regions in the genome or targeted to genes involved in cardiac development is currently possible in the prenatal period, but there are minimal data on the clinical utility of such an approach. This study assessed the outcome of a CHD gene panel that included single-gene causes of syndromic and non-syndromic CHDs.

Is PNPT1-related hearing loss ever non-syndromic? Whole exome sequencing of adult siblings expands the natural history of PNPT1-related disorders.

PNPT1 is a mitochondrial RNA transport protein that has been linked to two discrete phenotypes, namely isolated sensorineural hearing loss (OMIM 614934) and combined oxidative phosphorylation deficiency (OMIM 614932). The latter has been described in multiple families presenting with complex neurologic manifestations in childhood. We describe adult siblings with biallelic PNPT1 variants identified through WES who presented with isolated severe congenital sensorineural hearing loss (SNHL).

Biallelic loss of function variants in COASY cause prenatal onset pontocerebellar hypoplasia, microcephaly, and arthrogryposis.

Pontocerebellar hypoplasia (PCH) is a heterogeneous neurodegenerative disorder with a prenatal onset. Using whole-exome sequencing, we identified variants in the gene Coenzyme A (CoA) synthase (COASY) gene, an enzyme essential in CoA synthesis, in four individuals from two families with PCH, prenatal onset microcephaly, and arthrogryposis. In family 1, compound heterozygous variants were identified in COASY: c.