ACMG/AMP variant classification framework in arginase 1 deficiency: Implications for birth prevalence estimates and diagnostics.

Purpose: Arginase 1 (ARG1) deficiency manifests with hyperargininemia and progressive neurological impairment. Recent estimates of birth prevalence using allele frequencies of variants do not sufficiently distinguish benign from pathogenic variants. Additionally, ongoing discussions of reproductive carrier screening for diseases such as ARG1 creates a need for improved understanding of variant classification.

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.

repeat expansion creates the unstable folate-sensitive fragile site FRA9A.

The hyper-unstable Chr9p21 locus, harbouring the interferon gene cluster, oncogenes and , is linked to multiple diseases. (GGGGCC)n expansions (Exp) are associated with incompletely penetrant amyotrophic lateral sclerosis, frontotemporal dementia and autoimmune disorders. Exp patients display hyperactive cGAS-STING-linked interferon immune and DNA damage responses, but the source of immunostimulatory or damaged DNA is unknown.

Impacts of the COVID-19 pandemic on access to sexual and reproductive health services for women and transgender people with disabilities in Canada: a qualitative study.

The COVID-19 pandemic has had a detrimental impact on sexual and reproductive health (SRH) and rights globally. However, little is known about the experiences of people with disabilities accessing SRH services during the COVID-19 pandemic. In this community-engaged qualitative study, we examined COVID-related impacts on access to SRH services for people with disabilities.

A Bayesian latent class approach to causal inference with longitudinal data.

Bayesian methods are becoming increasingly in demand in clinical and public health comparative effectiveness research. Limited literature has explored parametric Bayesian causal approaches to handle time-dependent treatment and time-dependent covariates. In this article, building on to the work on Bayesian g-computation, we propose a fully Bayesian causal approach, implemented using latent confounder classes which represent the patient's disease and health status.

Further delineation of the SCAF4-associated neurodevelopmental disorder.

While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant SCAF4-associated neurodevelopmental disorder.

BAY 81-8973 Demonstrates Long-Term Safety and Efficacy in Children With Severe Haemophilia A: Results From the LEOPOLD Kids Extension Study.

Objectives: To report the long-term safety and efficacy of BAY 81-8973 in the LEOPOLD Kids extension phase.

Methods: Patients received BAY 81-8973 (25-50 IU/kg) at least twice weekly. The primary endpoint was safety, assessed in all patients who entered the extension phase (n = 82).

Effects of gene dosage on cognitive ability: A function-based association study across brain and non-brain processes.

Copy-number variants (CNVs) that increase the risk for neurodevelopmental disorders also affect cognitive ability. However, such CNVs remain challenging to study due to their scarcity, limiting our understanding of gene-dosage-sensitive biological processes linked to cognitive ability. We performed a genome-wide association study (GWAS) in 258,292 individuals, which identified-for the first time-a duplication at 2q12.

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.

Neuroligin 1 Regulates Autistic-Like Repetitive Behavior through Modulating the Activity of Striatal D2 Receptor-Expressing Medium Spiny Neurons.

Restricted and repetitive behavior (RRB) is a primary symptom of autism spectrum disorder (ASD), which poses a significant risk to individuals' health and is becoming increasingly prevalent. However, the specific cellular and neural circuit mechanisms underlying the generation of RRB remain unclear. In this study, it is reported that the absence of the ASD-related protein Neuroligin 1 (NLGN1) in dopamine receptor D2-expressing medium spiny neurons (D2-MSNs) in the dorsal striatum is associated with the duration and frequency of self-grooming and digging behaviors.

Mesencephalosynapsis and aqueductal stenosis.

Mesencephalosynapsis is characterized by a failure of the dorsal brainstem colliculi to separate into distinct lateral masses (non-cleavage, a.k.a.

Factors Associated With Early Computed Tomography Imaging in Children Hospitalized With Severe Orbital Infections.

Objective: We identified factors associated with computed tomographic (CT) imaging within 24 hours of emergency department (ED) presentation in hospitalized children with severe orbital infections.

Patients And Methods: A multicenter retrospective cohort study was conducted that included children aged 2 months to 18 years between 2009 and 2018 who were admitted to the hospital with severe orbital infections, including periorbital and orbital cellulitis. Multivariable modified Poisson regression was used to identify possible factors associated with receiving a CT scan within 24 hours of ED presentation.

Treatments for RYR1-related disorders.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: Primary objective To analyse the benefits and harms of pharmacological or other interventions (e.g.

Irx3/5 Null Deletion in Mice Blocks Cochlea-Saccule Segregation and Disrupts the Auditory Tonotopic Map.

A gene cadre orchestrates the normal development of sensory and non-sensory cells in the inner ear, segregating the cochlea with a distinct tonotopic sound frequency map, similar brain projection, and five vestibular end-organs. However, the role of genes driving the ear development is largely unknown. Here, we show double deletion of the Iroquois homeobox 3 and 5 transcription factors (Irx3/5 DKO) leads to the fusion of the saccule and the cochlear base.

Extracellular vesicles in sputum of children with cystic fibrosis pulmonary exacerbations.

Background: The aim of this study was to quantify mediators of neutrophilic inflammation within airway extracellular vesicles (EVs) of children treated for a cystic fibrosis (CF) pulmonary exacerbation (PEx).

Methods: EVs were isolated from stored sputum samples collected before and after antibiotic therapy for PEx between 2011 and 2013, and characterised by nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM). Western blot analysis of EV protein extracts was used for EV canonical protein markers CD63, CD9 and flotillin-1 (FLOT1), as well as neutrophil elastase (NE), myeloperoxidase (MPO) and interleukin-8.

Phenotypic Spectrum of GNA11 R183C Mosaicism.

Background: Many vascular anomalies harbor postzygotic somatic variants in GNAQ and GNA11; however, the phenotype of specific G-protein variants has not been well described. We report the clinical characteristics of 17 patients with a GNA11 R183C variant.

Methods: This case series is derived from a multinational cohort of vascular anomaly patients whose pathogenic mutations were identified using high-depth next generation sequencing.