Author
Grace Yoon
Other affiliations: VU University Amsterdam, Hospital for Sick Children
Bio: Grace Yoon is an academic researcher from University of Toronto. The author has contributed to research in topics: Ataxia & Exome sequencing. The author has an hindex of 26, co-authored 114 publications receiving 2719 citations. Previous affiliations of Grace Yoon include VU University Amsterdam & Hospital for Sick Children.
Papers published on a yearly basis
Papers
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Children's Hospital of Eastern Ontario1, McGill University2, North York General Hospital3, McGill University Health Centre4, Alberta Children's Hospital5, Montreal Neurological Institute and Hospital6, Ottawa Hospital7, University of Toronto8, Université de Montréal9, Memorial University of Newfoundland10, University of Manitoba11, University of Calgary12, University of British Columbia13, University of Alberta14, Halifax15, University of Western Ontario16, McMaster University17
TL;DR: The analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases.
Abstract: An accurate diagnosis is an integral component of patient care for children with rare genetic disease. Recent advances in sequencing, in particular whole-exome sequencing (WES), are identifying the genetic basis of disease for 25-40% of patients. The diagnostic rate is probably influenced by when in the diagnostic process WES is used. The Finding Of Rare Disease GEnes (FORGE) Canada project was a nation-wide effort to identify mutations for childhood-onset disorders using WES. Most children enrolled in the FORGE project were toward the end of the diagnostic odyssey. The two primary outcomes of FORGE were novel gene discovery and the identification of mutations in genes known to cause disease. In the latter instance, WES identified mutations in known disease genes for 105 of 362 families studied (29%), thereby informing the impact of WES in the setting of the diagnostic odyssey. Our analysis of this dataset showed that these known disease genes were not identified prior to WES enrollment for two key reasons: genetic heterogeneity associated with a clinical diagnosis and atypical presentation of known, clinically recognized diseases. What is becoming increasingly clear is that WES will be paradigm altering for patients and families with rare genetic diseases.
308 citations
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TL;DR: Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.
Abstract: The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.
273 citations
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TL;DR: It is shown that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia, and genetic deletion of Parp1 rescued normal Cerebellar ADP-ribose levels and reduced the loss of cerebellary neurons and ataxic mice in Xrcc1-defective mice.
Abstract: XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair. Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia. Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation. This latter phenotype is recapitulated in a related syndrome caused by mutations in the XRCC1 partner protein PNKP and implicates hyperactivation of poly(ADP-ribose) polymerase/s as a cause of cerebellar ataxia. Indeed, remarkably, genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice, identifying a molecular mechanism by which endogenous single-strand breaks trigger neuropathology. Collectively, these data establish the importance of XRCC1 protein complexes for normal neurological function and identify PARP1 as a therapeutic target in DNA strand break repair-defective disease.
192 citations
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TL;DR: There is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ in boys with Duchenne muscular dystrophy, and enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended.
Abstract: Duchenne muscular dystrophy is a progressive neuromuscular condition that has a high rate of cognitive and learning disabilities as well as neurobehavioral disorders, some of which have been associated with disruption of dystrophin isoforms. Retrospective cohort of 59 boys investigated the cognitive and neurobehavioral profile of boys with Duchenne muscular dystrophy. Full-scale IQ of < 70 was seen in 27%; learning disability in 44%, intellectual disability in 19%; attention-deficit/hyperactivity disorder in 32%; autism spectrum disorders in 15%; and anxiety in 27%. Mutations affecting Dp260 isoform and 5'untranslated region of Dp140 were observed in 60% with learning disability, 50% intellectual disability, 77% with autism spectrum disorders, and 94% with anxiety. No statistically significant correlation was noted between comorbidities and dystrophin isoforms; however, there is a trend of cumulative loss of dystrophin isoforms with declining full-scale IQ. Enhanced psychology testing to include both cognitive and neurobehavioral disorders is recommended for all individuals with Duchenne muscular dystrophy.
148 citations
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Montreal Children's Hospital1, Centre Hospitalier Universitaire Sainte-Justine2, Children's Mercy Hospital3, VU University Medical Center4, Montreal Neurological Institute and Hospital5, Scripps Research Institute6, University of Toronto7, University of Szeged8, Children's Hospital at Westmead9, University of Duisburg-Essen10, Radboud University Nijmegen11, The Chinese University of Hong Kong12, University of Bordeaux13, French Institute of Health and Medical Research14, George Washington University15, University of Queensland16, Université de Montréal17
TL;DR: This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukODYstrophy.
Abstract: A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes' availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy.
121 citations
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TL;DR: A human pluripotent stem cell-derived three-dimensional organoid culture system that develops various discrete, although interdependent, brain regions that include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes is developed.
Abstract: The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue
3,508 citations
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TL;DR: The roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-stranded break repair and the stabilization of replication forks, and in modulating chromatin structure are discussed.
Abstract: Cells are exposed to various endogenous and exogenous insults that induce DNA damage, which, if unrepaired, impairs genome integrity and leads to the development of various diseases, including cancer. Recent evidence has implicated poly(ADP-ribose) polymerase 1 (PARP1) in various DNA repair pathways and in the maintenance of genomic stability. The inhibition of PARP1 is therefore being exploited clinically for the treatment of various cancers, which include DNA repair-deficient ovarian, breast and prostate cancers. Understanding the role of PARP1 in maintaining genome integrity is not only important for the design of novel chemotherapeutic agents, but is also crucial for gaining insights into the mechanisms of chemoresistance in cancer cells. In this Review, we discuss the roles of PARP1 in mediating various aspects of DNA metabolism, such as single-strand break repair, nucleotide excision repair, double-strand break repair and the stabilization of replication forks, and in modulating chromatin structure.
928 citations
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TL;DR: An exhaustive review of the clinical genetics and research genetics literature in an attempt to collate all genes and recurrent genomic imbalances that have been implicated in the etiology of ASD shows that autism is not a single clinical entity but a behavioral manifestation of tens or perhaps hundreds of genetic and genomic disorders.
851 citations
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TL;DR: There are numerous overlapping phenotypic features between the RASopathies, including characteristic facial features, cardiac defects, cutaneous abnormalities, neurocognitive delay and a predisposition to malignancies.
681 citations
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TL;DR: An overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals is described and several members of the machinery can undergo post-translational modifications modulating these processes.
Abstract: Mitochondria are highly dynamic organelles undergoing coordinated cycles of fission and fusion, referred as ‘mitochondrial dynamics’, in order to maintain their shape, distribution and size Their transient and rapid morphological adaptations are crucial for many cellular processes such as cell cycle, immunity, apoptosis and mitochondrial quality control Mutations in the core machinery components and defects in mitochondrial dynamics have been associated with numerous human diseases These dynamic transitions are mainly ensured by large GTPases belonging to the Dynamin family Mitochondrial fission is a multi-step process allowing the division of one mitochondrion in two daughter mitochondria It is regulated by the recruitment of the GTPase Dynamin-related protein 1 (Drp1) by adaptors at actin- and endoplasmic reticulum-mediated mitochondrial constriction sites Drp1 oligomerization followed by mitochondrial constriction leads to the recruitment of Dynamin 2 to terminate membrane scission Inner mitochondrial membrane constriction has been proposed to be an independent process regulated by calcium influx Mitochondrial fusion is driven by a two-step process with the outer mitochondrial membrane fusion mediated by mitofusins 1 and 2 followed by inner membrane fusion, mediated by optic atrophy 1 In addition to the role of membrane lipid composition, several members of the machinery can undergo post-translational modifications modulating these processes Understanding the molecular mechanisms controlling mitochondrial dynamics is crucial to decipher how mitochondrial shape meets the function and to increase the knowledge on the molecular basis of diseases associated with morphology defects This article will describe an overview of the molecular mechanisms that govern mitochondrial fission and fusion in mammals
678 citations