Targeted Exon Skipping of a CEP290 Mutation Rescues Joubert Syndrome Phenotypes in Vitro and in a Murine Model
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Ciliopathiesneuromuscularciliopathies Disorders Disorders Ciliopathiesciliopathies
NeuromuscularCiliopathiesNeuromuscularCiliopathies Disorders Disorders CiliopathiesCiliopathies AboutAbout EGL EGL Genet Geneticsics EGLEGL Genetics Genetics specializes specializes in ingenetic genetic diagnostic diagnostic testing, testing, with with ne nearlyarly 50 50 years years of of clinical clinical experience experience and and board-certified board-certified labor laboratoryatory directorsdirectors and and genetic genetic counselors counselors reporting reporting out out cases. cases. EGL EGL Genet Geneticsics offers offers a combineda combined 1000 1000 molecular molecular genetics, genetics, biochemical biochemical genetics,genetics, and and cytogenetics cytogenetics tests tests under under one one roof roof and and custom custom test testinging for for all all medically medically relevant relevant genes, genes, for for domestic domestic andand international international clients. clients. EquallyEqually important important to to improving improving patient patient care care through through quality quality genetic genetic testing testing is is the the contribution contribution EGL EGL Genetics Genetics makes makes back back to to thethe scientific scientific and and medical medical communities. communities. EGL EGL Genetics Genetics is is one one of of only only a afew few clinical clinical diagnostic diagnostic laboratories laboratories to to openly openly share share data data withwith the the NCBI NCBI freely freely available available public public database database ClinVar ClinVar (>35,000 (>35,000 variants variants on on >1700 >1700 genes) genes) and and is isalso also the the only only laboratory laboratory with with a a frefree oen olinnlein dea dtabtaabsaes (eE m(EVmCVlaCslas)s,s f)e, afetuatruinrgin ag vaa vraiarniatn ctl acslasisfiscifiactiaotino sne saercahrc ahn adn rde rpeoprot rrte rqeuqeuset sint tinetrefarcfaec, ew, hwichhic fha cfailcitialiteatse rsa praidp id interactiveinteractive curation curation and and reporting reporting of of variants. -
American Board of Psychiatry and Neurology, Inc
AMERICAN BOARD OF PSYCHIATRY AND NEUROLOGY, INC. CERTIFICATION EXAMINATION IN NEUROLOGY 2015 Content Blueprint (January 13, 2015) Part A Basic neuroscience Number of questions: 120 01. Neuroanatomy 3-5% 02. Neuropathology 3-5% 03. Neurochemistry 2-4% 04. Neurophysiology 5-7% 05. Neuroimmunology/neuroinfectious disease 2-4% 06. Neurogenetics/molecular neurology, neuroepidemiology 2-4% 07. Neuroendocrinology 1-2% 08. Neuropharmacology 4-6% Part B Behavioral neurology, cognition, and psychiatry Number of questions: 80 01. Development through the life cycle 3-5% 02. Psychiatric and psychological principles 1-3% 03. Diagnostic procedures 1-3% 04. Clinical and therapeutic aspects of psychiatric disorders 5-7% 05. Clinical and therapeutic aspects of behavioral neurology 5-7% Part C Clinical neurology (adult and child) The clinical neurology section of the Neurology Certification Examination is comprised of 60% adult neurology questions and 40% child neurology questions. Number of questions: 200 01. Headache disorders 1-3% 02. Pain disorders 1-3% 03. Epilepsy and episodic disorders 1-3% 04. Sleep disorders 1-3% 05. Genetic disorders 1-3% 2015 ABPN Content Specifications Page 1 of 22 Posted: Certification in Neurology AMERICAN BOARD OF PSYCHIATRY AND NEUROLOGY, INC. 06. Congenital disorders 1-3% 07. Cerebrovascular disease 1-3% 08. Neuromuscular diseases 2-4% 09. Cranial nerve palsies 1-3% 10. Spinal cord diseases 1-3% 11. Movement disorders 1-3% 12. Demyelinating diseases 1-3% 13. Neuroinfectious diseases 1-3% 14. Critical care 1-3% 15. Trauma 1-3% 16. Neuro-ophthalmology 1-3% 17. Neuro-otology 1-3% 18. Neurologic complications of systemic diseases 2-4% 19. -
Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell Polarity
BASIC RESEARCH www.jasn.org Intraflagellar Transport Proteins Are Essential for Cilia Formation and for Planar Cell Polarity Ying Cao, Alice Park, and Zhaoxia Sun Department of Genetics, Yale University School of Medicine, New Haven, Connecticut ABSTRACT The highly conserved intraflagellar transport (IFT) proteins are essential for cilia formation in multiple organisms, but surprisingly, cilia form in multiple zebrafish ift mutants. Here, we detected maternal deposition of ift gene products in zebrafish and found that ciliary assembly occurs only during early developmental stages, supporting the idea that maternal contribution of ift gene products masks the function of IFT proteins during initial development. In addition, the basal bodies in multiciliated cells of the pronephric duct in ift mutants were disorganized, with a pattern suggestive of defective planar cell polarity (PCP). Depletion of pk1, a core PCP component, similarly led to kidney cyst formation and basal body disorganization. Furthermore, we found that multiple ift genes genetically interact with pk1. Taken together, these data suggest that IFT proteins play a conserved role in cilia formation and planar cell polarity in zebrafish. J Am Soc Nephrol 21: 1326–1333, 2010. doi: 10.1681/ASN.2009091001 The cilium is a cell surface organelle that is almost In zebrafish, mutants of ift57, ift81, ift88, and ubiquitously present on vertebrate cells. Pro- ift172 have numerous defects commonly associated truding from the cell into its environment, the with ciliary abnormalities.13,14 -
Joubert Syndrome Genereview
Title: Joubert Syndrome GeneReview — Molecular Genetics: Less Common Genetic Causes Authors: Parisi M, Glass I Updated: June 2017 Note: The following information is provided by the authors listed above and has not been reviewed by GeneReviews staff. Joubert Syndrome: Less Common Genetic Causes ARL13B B9D1 B9D2 CEP41 IFT172 KIF7 OFD1 (CXORF5) PDE6D POC1B TCTN1 TCTN3 TMEM138 TMEM231 TMEM237 (ALS2CR4) TTC21B ARL13B Gene structure. ARL13B is a ten-exon gene that encodes a 428-amino acid protein. Pathogenic variants. Two families with a phenotype typical of classic Joubert syndrome had missense and/or nonsense variants in this gene; one of these individuals also had evidence of a retinopathy [Cantagrel et al 2008]. Normal gene product. ARL13B encodes ADP-ribosylation factor-like protein 13B, a member of the ADP-ribosylation factor-like family. Multiple transcript variants result from alternate splicing; two protein isoforms are known. The AR13B protein is a small GTPase in the Ras superfamily that contains both N-terminal and C-terminal guanine nucleotide-binding motifs. It is localized to the cilia and plays a role in cilia formation and maintenance as well as sonic hedgehog signaling. Abnormal gene product. In C elegans, pathogenic variants in the homolog arl13 exhibit defective cilium morphology, localization, and anterograde intraflagellar transport [Cevik et al 2010]. Mice with defects in the murine ortholog have neural tube defects and polydactyly, as well as an embryonic-lethal phenotype [Cantagrel et al 2008, Doherty 2009]. B9D1. See Tables A and B. B9D2. See Tables A and B. CEP41 Gene structure. The gene consists of 11 exons and spans approximately 50 kb. -
Joubert Syndrome and Related Disorders
Brancati et al. Orphanet Journal of Rare Diseases 2010, 5:20 http://www.ojrd.com/content/5/1/20 REVIEW Open Access JoubertReview Syndrome and related disorders Francesco Brancati1,2, Bruno Dallapiccola3 and Enza Maria Valente*1,4 Abstract Joubert syndrome (JS) and related disorders (JSRD) are a group of developmental delay/multiple congenital anomalies syndromes in which the obligatory hallmark is the molar tooth sign (MTS), a complex midbrain-hindbrain malformation visible on brain imaging, first recognized in JS. Estimates of the incidence of JSRD range between 1/80,000 and 1/ 100,000 live births, although these figures may represent an underestimate. The neurological features of JSRD include hypotonia, ataxia, developmental delay, intellectual disability, abnormal eye movements, and neonatal breathing dysregulation. These may be associated with multiorgan involvement, mainly retinal dystrophy, nephronophthisis, hepatic fibrosis and polydactyly, with both inter- and intra-familial variability. JSRD are classified in six phenotypic subgroups: Pure JS; JS with ocular defect; JS with renal defect; JS with oculorenal defects; JS with hepatic defect; JS with orofaciodigital defects. With the exception of rare X-linked recessive cases, JSRD follow autosomal recessive inheritance and are genetically heterogeneous. Ten causative genes have been identified to date, all encoding for proteins of the primary cilium or the centrosome, making JSRD part of an expanding group of diseases called "ciliopathies". Mutational analysis of causative genes is available in few laboratories worldwide on a diagnostic or research basis. Differential diagnosis must consider in particular the other ciliopathies (such as nephronophthisis and Senior-Loken syndrome), distinct cerebellar and brainstem congenital defects and disorders with cerebro-oculo-renal manifestations. -
Renal Cystic Disorders Infosheet 6-14-19
Next Generation Sequencing Panel for Renal Cystic Disorders Clinical Features: Renal cystic diseases are a genetically heterogeneous group of conditions characterized By isolated renal disease or renal cysts in conjunction with extrarenal features (1). Age of onset of renal cystic disease ranges from neonatal to adult onset. Common features of renal cystic diseases include renal insufficiency and progression to end stage renal disease (ESRD). Identification of the genetic etiology of renal cystic disease can aid in appropriate clinical management of the affected patient. Our Renal Cystic Disorders Panel includes sequence and deletion/duplicaton analysis of all 79 genes listed below. Renal Cystic Disorders Sequencing Panel AHI1 BMPER HNF1B NEK8 TCTN3 WDPCP ANKS6 C5orf42 IFT27 NOTCH2 TFAP2A WDR19 ARL13B CC2D2A IFT140 NPHP1 TMEM107 XPNPEP3 ARL6 CDC73 IFT172 NPHP3 TMEM138 ZNF423 B9D1 CEP104 INPP5E NPHP4 TMEM216 B9D2 CEP120 INVS OFD1 TMEM231 BBIP1 CEP164 IQCB1 PDE6D TMEM237 BBS1 CEP290 JAG1 PKD2 TMEM67 BBS10 CEP41 KIAA0556 PKHD1 TRIM32 BBS12 CEP83 KIAA0586 REN TSC1 BBS2 CRB2 KIF14 RPGRIP1L TSC2 BBS4 CSPP1 KIF7 SALL1 TTC21B BBS5 DCDC2 LZTFL1 SDCCAG8 TTC8 BBS7 GLIS2 MKKS TCTN1 UMOD BBS9 GLIS3 MKS1 TCTN2 VHL Disorder Genes Inheritance Clinical features/molecular genetics Bardet Biedl ARL6 AR Bardet-Biedl syndrome (BBS) is an autosomal syndrome BBS1 recessive multi-systemic ciliopathy characterized By BBS10 retinal dystrophy, oBesity, postaxial polydactyly, BBS12 leaning difficulties, renal involvement and BBS2 genitourinary abnormalities (2). Visual prognosis is BBS4 poor, and the mean age of legal Blindness is 15.5 BBS5 years. Birth weight is typically normal But significant BBS7 weight gain Begins within the first year. Renal BBS9 disease is a major cause of morBidity and mortality. -
Autism Spectrum Disorders—A Genetics Review Judith H
GENETEST REVIEW Genetics in Medicine Autism spectrum disorders—A genetics review Judith H. Miles, MD, PhD TABLE OF CONTENTS Prevalence .........................................................................................................279 Adenylosuccinate lyase deficiency ............................................................285 Clinical features................................................................................................279 Creatine deficiency syndromes..................................................................285 Core autism symptoms...................................................................................279 Smith-Lemli-Opitz syndrome.....................................................................285 Diagnostic criteria and tools..........................................................................280 Other single-gene disorders.......................................................................285 Neurologic and medical symptoms .............................................................281 Developmental syndromes of undetermined etiology..............................286 Genetics of autism...........................................................................................281 Moebius syndrome or sequence...............................................................286 Chromosomal disorders and CNVS..............................................................282 Landau-Kleffner syndrome .........................................................................286 Single-gene -
Psykisk Utviklingshemming Og Forsinket Utvikling
Psykisk utviklingshemming og forsinket utvikling Genpanel, versjon v03 Tabellen er sortert på gennavn (HGNC gensymbol) Navn på gen er iht. HGNC >x10 Andel av genet som har blitt lest med tilfredstillende kvalitet flere enn 10 ganger under sekvensering x10 er forventet dekning; faktisk dekning vil variere. Gen Gen (HGNC Transkript >10x Fenotype (symbol) ID) AAAS 13666 NM_015665.5 100% Achalasia-addisonianism-alacrimia syndrome OMIM AARS 20 NM_001605.2 100% Charcot-Marie-Tooth disease, axonal, type 2N OMIM Epileptic encephalopathy, early infantile, 29 OMIM AASS 17366 NM_005763.3 100% Hyperlysinemia OMIM Saccharopinuria OMIM ABCB11 42 NM_003742.2 100% Cholestasis, benign recurrent intrahepatic, 2 OMIM Cholestasis, progressive familial intrahepatic 2 OMIM ABCB7 48 NM_004299.5 100% Anemia, sideroblastic, with ataxia OMIM ABCC6 57 NM_001171.5 93% Arterial calcification, generalized, of infancy, 2 OMIM Pseudoxanthoma elasticum OMIM Pseudoxanthoma elasticum, forme fruste OMIM ABCC9 60 NM_005691.3 100% Hypertrichotic osteochondrodysplasia OMIM ABCD1 61 NM_000033.3 77% Adrenoleukodystrophy OMIM Adrenomyeloneuropathy, adult OMIM ABCD4 68 NM_005050.3 100% Methylmalonic aciduria and homocystinuria, cblJ type OMIM ABHD5 21396 NM_016006.4 100% Chanarin-Dorfman syndrome OMIM ACAD9 21497 NM_014049.4 99% Mitochondrial complex I deficiency due to ACAD9 deficiency OMIM ACADM 89 NM_000016.5 100% Acyl-CoA dehydrogenase, medium chain, deficiency of OMIM ACADS 90 NM_000017.3 100% Acyl-CoA dehydrogenase, short-chain, deficiency of OMIM ACADVL 92 NM_000018.3 100% VLCAD -
A Ciliopathy-Associated COPD Endotype
Perotin et al. Respir Res (2021) 22:74 https://doi.org/10.1186/s12931-021-01665-4 LETTER TO THE EDITOR Open Access CiliOPD: a ciliopathy-associated COPD endotype Jeanne‑Marie Perotin1,2, Myriam Polette1,3, Gaëtan Deslée1,2 and Valérian Dormoy1* Abstract The pathophysiology of chronic obstructive pulmonary disease (COPD) relies on airway remodelling and infam‑ mation. Alterations of mucociliary clearance are a major hallmark of COPD caused by structural and functional cilia abnormalities. Using transcriptomic databases of whole lung tissues and isolated small airway epithelial cells (SAEC), we comparatively analysed cilia‑associated and ciliopathy‑associated gene signatures from a set of 495 genes in 7 datasets including 538 non‑COPD and 508 COPD patients. This bio‑informatics approach unveils yet undescribed cilia and ciliopathy genes associated with COPD including NEK6 and PROM2 that may contribute to the pathology, and suggests a COPD endotype exhibiting ciliopathy features (CiliOPD). Keywords: COPD, Cilia, Transcriptomic Introduction signatures in 7 datasets including 538 non-COPD and Cilia dysfunction is a hallmark of chronic obstructive 508 COPD patients. infammatory lung diseases [1]. Alterations of both cilia structure and function alter airway mucociliary clear- Methods ance. Epithelial remodelling is indicted in COPD patho- Gene selection genesis, including distal to proximal repatterning of the Human cilia-associated genes (n = 447) and ciliopathy- small airways and altered generation of motile and pri- associated genes (n = -
Ciliary Dysfunction Secondary to COVID-19. Explanation of the Pathogenesis from Analysis of Human Interactome with SARS
Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 25 December 2020 doi:10.20944/preprints202012.0663.v1 Ciliary dysfunction secondary to COVID-19. Explanation of the pathogenesis from analysis of human interactome with SARS- CoV-2 proteome MD Alejandro Jesús Bermejo-Valdés1, MD Alexander Ariel Padrón-González2, MD Jessica Archer Jiménez3 1Riojan Health Service, Emergency Service 061, Piqueras 98, 26006, Logroño, La Rioja, Spain 2Central Laboratory of Cerebrospinal Fluid (LABCEL), Ramón Pinto No. 202, Luyanó, Diez de Octubre, Havana Medical Sciences University, AP 10049, CP 11000, Havana, Cuba 3Riojan Health Service, Emergency Service 061, Piqueras 98, 26006, Logroño, La Rioja, Spain Abstract Coronavirus Disease-2019 (COVID-19) is an infectious disease caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There is sufficient experimental evidence to confirm that SARS-CoV-2 infection produces states of ciliary and flagellar dysfunction. However, these studies are unable to explain the observed effects molecularly, because they lack a sufficient understanding of the interaction between human proteins and virus proteins. Using the physical-chemical study of the human interactome in interaction with the SARS-CoV-2 proteome, we found evidence of interactions to explain the experimental effects from a molecular perspective. We found that ten viral proteins interact with key components in the maintenance of the molecular structure of axoneme. Additionally, we evaluated the pulmonary and extrapulmonary pathogenesis of COVID-19 from the point of view of ciliary dysfunction, and warned about other possible complications such as episodes of transient infertility that, due to the limitations of our work, would need verification. -
Blueprint Genetics Comprehensive Growth Disorders / Skeletal
Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel Test code: MA4301 Is a 374 gene panel that includes assessment of non-coding variants. This panel covers the majority of the genes listed in the Nosology 2015 (PMID: 26394607) and all genes in our Malformation category that cause growth retardation, short stature or skeletal dysplasia and is therefore a powerful diagnostic tool. It is ideal for patients suspected to have a syndromic or an isolated growth disorder or a skeletal dysplasia. About Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders This panel covers a broad spectrum of diseases associated with growth retardation, short stature or skeletal dysplasia. Many of these conditions have overlapping features which can make clinical diagnosis a challenge. Genetic diagnostics is therefore the most efficient way to subtype the diseases and enable individualized treatment and management decisions. Moreover, detection of causative mutations establishes the mode of inheritance in the family which is essential for informed genetic counseling. For additional information regarding the conditions tested on this panel, please refer to the National Organization for Rare Disorders and / or GeneReviews. Availability 4 weeks Gene Set Description Genes in the Comprehensive Growth Disorders / Skeletal Dysplasias and Disorders Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ACAN# Spondyloepimetaphyseal dysplasia, aggrecan type, AD/AR 20 56 Spondyloepiphyseal dysplasia, Kimberley -
Blueprint Genetics Comprehensive Skeletal Dysplasias and Disorders
Comprehensive Skeletal Dysplasias and Disorders Panel Test code: MA3301 Is a 251 gene panel that includes assessment of non-coding variants. Is ideal for patients with a clinical suspicion of disorders involving the skeletal system. About Comprehensive Skeletal Dysplasias and Disorders This panel covers a broad spectrum of skeletal disorders including common and rare skeletal dysplasias (eg. achondroplasia, COL2A1 related dysplasias, diastrophic dysplasia, various types of spondylo-metaphyseal dysplasias), various ciliopathies with skeletal involvement (eg. short rib-polydactylies, asphyxiating thoracic dysplasia dysplasias and Ellis-van Creveld syndrome), various subtypes of osteogenesis imperfecta, campomelic dysplasia, slender bone dysplasias, dysplasias with multiple joint dislocations, chondrodysplasia punctata group of disorders, neonatal osteosclerotic dysplasias, osteopetrosis and related disorders, abnormal mineralization group of disorders (eg hypopohosphatasia), osteolysis group of disorders, disorders with disorganized development of skeletal components, overgrowth syndromes with skeletal involvement, craniosynostosis syndromes, dysostoses with predominant craniofacial involvement, dysostoses with predominant vertebral involvement, patellar dysostoses, brachydactylies, some disorders with limb hypoplasia-reduction defects, ectrodactyly with and without other manifestations, polydactyly-syndactyly-triphalangism group of disorders, and disorders with defects in joint formation and synostoses. Availability 4 weeks Gene Set Description