Exome and Genome Sequencing to Diagnose the Genetic Basis of Neonatal Hypotonia: An International Consortium Study.

Background And Objectives: Hypotonia is a relatively common finding among infants in the neonatal intensive care unit (NICU). Consideration of genetic testing is recommended early in the care of infants with unexplained hypotonia. We aimed to assess the diagnostic yield and overall impact of exome and genome sequencing (ES and GS).

Gain-of-function and loss-of-function variants in GRIA3 lead to distinct neurodevelopmental phenotypes.

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) mediate fast excitatory neurotransmission in the brain. AMPARs form by homo- or heteromeric assembly of subunits encoded by the GRIA1-GRIA4 genes, of which only GRIA3 is X-chromosomal. Increasing numbers of GRIA3 missense variants are reported in patients with neurodevelopmental disorders (NDD), but only a few have been examined functionally.

Evaluation of the diagnostic accuracy of exome sequencing and its impact on diagnostic thinking for patients with rare disease in a publicly funded health care system: A prospective cohort study.

Purpose: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases.

Methods: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests.

Protocol for a Prospective, Observational Cost-effectiveness Analysis of Returning Secondary Findings of Genome Sequencing for Unexplained Suspected Genetic Conditions.

Purpose: Although costly, genome-wide sequencing (GWS) detects an extensive range of variants, enhancing our ability to diagnose and assess risk for an increasing number of diseases. In addition to detecting variants related to the indication for testing, GWS can detect secondary variants in BRCA1, BRCA2, and other genes for which early intervention may improve health. As the list of secondary findings grows, there is increased demand for surveillance and management by multiple specialists, adding pressure to constrained health care budgets.

Bridging clinical care and research in Ontario, Canada: Maximizing diagnoses from reanalysis of clinical exome sequencing data.

We examined the utility of clinical and research processes in the reanalysis of publicly-funded clinical exome sequencing data in Ontario, Canada. In partnership with eight sites, we recruited 287 families with suspected rare genetic diseases tested between 2014 and 2020. Data from seven laboratories was reanalyzed with the referring clinicians.

Rapid Genetic Testing in Pediatric and Neonatal Critical Care: A Scoping Review of Emerging Ethical Issues.

Background: Rapid genome-wide sequencing (rGWS) is being increasingly used to aid in prognostication and decision-making for critically ill newborns and children. Although its feasibility in this fast-paced setting has been described, this new paradigm of inpatient genetic care raises new ethical challenges.

Objective: A scoping review was performed to (1) identify salient ethical issues in this area of practice; and (2) bring attention to gaps and ethical tensions that warrant more deliberate exploration.

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.

Multicenter Consensus Approach to Evaluation of Neonatal Hypotonia in the Genomic Era: A Review.

Importance: Infants with hypotonia can present with a variety of potentially severe clinical signs and symptoms and often require invasive testing and multiple procedures. The wide range of clinical presentations and potential etiologies leaves diagnosis and prognosis uncertain, underscoring the need for rapid elucidation of the underlying genetic cause of disease.

Observations: The clinical application of exome sequencing or genome sequencing has dramatically improved the timely yield of diagnostic testing for neonatal hypotonia, with diagnostic rates of greater than 50% in academic neonatal intensive care units (NICUs) across Australia, Canada, the UK, and the US, which compose the International Precision Child Health Partnership (IPCHiP).

Monogenic variants in dystonia: an exome-wide sequencing study.

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia.

Clinical and genetic study of hereditary spastic paraplegia in Canada.

Objective: To describe the clinical, genetic, and epidemiologic features of hereditary spastic paraplegia (HSP) in Canada and to determine which clinical, radiologic, and genetic factors determine functional outcomes for patients with HSP.

Methods: We conducted a multicenter observational study of patients who met clinical criteria for the diagnosis of HSP in the provinces of Alberta, Ontario, and Quebec from 2012 to 2015. Characteristics of the participants were analyzed using descriptive statistics.

A 23 years follow-up study identifies GLUT1 deficiency syndrome initially diagnosed as complicated hereditary spastic paraplegia.

Glucose transporter 1 (GLUT1) deficiency syndrome (GLUT1DS) was initially described in the early 90s as a sporadic clinical condition, characterized by seizures, motor and intellectual impairment with variable clinical presentation, and without a known genetic cause. Although causative mutations in SLC2A1 were later identified and much more is known about the disease, it still remains largely underdiagnosed. In the current study, a previously described Italian family was re-analyzed using whole exome sequencing and clinically re-evaluated.

Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner.

Replication study of MATR3 in familial and sporadic amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by an extensive loss of motor neurons in the primary motor cortex, brainstem, and spinal cord. Genetic studies report a high heritability of ALS. Recently, whole-exome sequencing analysis of familial ALS (FALS) patients allowed the identification of missense variations within the MATR3 gene.

Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum.

Agenesis of the corpus callosum (ACC) is a common brain malformation which can be observed either as an isolated condition or as part of numerous congenital syndromes. Therefore, cognitive and neurological involvements in patients with ACC are variable, from mild linguistic and behavioral impairments to more severe neurological deficits. To date, the underlying genetic causes of isolated ACC remains elusive and causative genes have yet to be identified.

Deleterious mutations in the essential mRNA metabolism factor, hGle1, in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons. Causative mutations in the global RNA-processing proteins TDP-43 and FUS among others, as well as their aggregation in ALS patients, have identified defects in RNA metabolism as an important feature in this disease. Lethal congenital contracture syndrome 1 and lethal arthrogryposis with anterior horn cell disease are autosomal recessive fetal motor neuron diseases that are caused by mutations in another global RNA-processing protein, hGle1.

SYNE1 mutations in autosomal recessive cerebellar ataxia.

Importance: Autosomal recessive cerebellar ataxia type I, also known as recessive ataxia of Beauce, is a slowly progressive ataxia that leads to moderate disability with gait ataxia, dysarthria, dysmetria, mild oculomotor abnormalities, and diffuse cerebellar atrophy on brain imaging. Mutations in the synaptic nuclear envelope protein 1 (SYNE1) gene, located on chromosome 6p25, were first reported in patients who originated from a region known as "Beauce" in the province of Quebec, Canada.

Objective: To better evaluate the prevalence of SYNE1 mutations in individuals with mild pure cerebellar ataxia and cerebellar atrophy, we screened the gene in additional French-Canadian (FC) families and individuals from other populations.

C9orf72 hexanucleotide repeat expansions as the causative mutation for chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia.

Objective: To further assess the presence of a large hexanucleotide repeat expansion in the first intron of the C9orf72 gene identified as the genetic cause of chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) in 4 unrelated families with a conclusive linkage to c9ALS/FTD.

Design: A repeat-primed polymerase chain reaction assay.

Setting: Academic research.

Exome sequencing identifies FUS mutations as a cause of essential tremor.

Essential tremor (ET) is a common neurodegenerative disorder that is characterized by a postural or motion tremor. Despite a strong genetic basis, a gene with rare pathogenic mutations that cause ET has not yet been reported. We used exome sequencing to implement a simple approach to control for misdiagnosis of ET, as well as phenocopies involving sporadic and senile ET cases.

UBQLN2 mutations are rare in French and French-Canadian amyotrophic lateral sclerosis.

Mutations in the UBQLN2 gene, which encodes a member of the ubiquitin-like protein family (ubiquilin-2), have been recently identified in patients with dominant X-linked amyotrophic lateral sclerosis (ALS) and ALS with dementia. We report here the sequencing of the UBQLN2 gene in 590 ALS patients of French and French-Canadian ancestry. We identified two novel missense mutations (p.

Chromosomal position effects are linked to sir2-mediated variation in transcriptional burst size.

Gene expression noise varies with genomic position and is a driving force in the evolution of chromosome organization. Nevertheless, position effects remain poorly characterized. Here, we present a systematic analysis of chromosomal position effects by characterizing single-cell gene expression from euchromatic positions spanning the length of a eukaryotic chromosome.