Information Sheet on Ciliopathy Testing
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Educational Paper Ciliopathies
Eur J Pediatr (2012) 171:1285–1300 DOI 10.1007/s00431-011-1553-z REVIEW Educational paper Ciliopathies Carsten Bergmann Received: 11 June 2011 /Accepted: 3 August 2011 /Published online: 7 September 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract Cilia are antenna-like organelles found on the (NPHP) . Ivemark syndrome . Meckel syndrome (MKS) . surface of most cells. They transduce molecular signals Joubert syndrome (JBTS) . Bardet–Biedl syndrome (BBS) . and facilitate interactions between cells and their Alstrom syndrome . Short-rib polydactyly syndromes . environment. Ciliary dysfunction has been shown to Jeune syndrome (ATD) . Ellis-van Crefeld syndrome (EVC) . underlie a broad range of overlapping, clinically and Sensenbrenner syndrome . Primary ciliary dyskinesia genetically heterogeneous phenotypes, collectively (Kartagener syndrome) . von Hippel-Lindau (VHL) . termed ciliopathies. Literally, all organs can be affected. Tuberous sclerosis (TSC) . Oligogenic inheritance . Modifier. Frequent cilia-related manifestations are (poly)cystic Mutational load kidney disease, retinal degeneration, situs inversus, cardiac defects, polydactyly, other skeletal abnormalities, and defects of the central and peripheral nervous Introduction system, occurring either isolated or as part of syn- dromes. Characterization of ciliopathies and the decisive Defective cellular organelles such as mitochondria, perox- role of primary cilia in signal transduction and cell isomes, and lysosomes are well-known -
Unraveling the Genetics of Joubert and Meckel-Gruber Syndromes
Journal of Pediatric Genetics 3 (2014) 65–78 65 DOI 10.3233/PGE-14090 IOS Press Unraveling the genetics of Joubert and Meckel-Gruber syndromes Katarzyna Szymanska, Verity L. Hartill and Colin A. Johnson∗ Department of Ophthalmology and Neuroscience, University of Leeds, Leeds, UK Received 27 May 2014 Revised 11 July 2014 Accepted 14 July 2014 Abstract. Joubert syndrome (JBTS) and Meckel-Gruber syndrome (MKS) are recessive neurodevelopmental conditions caused by mutations in proteins that are structural or functional components of the primary cilium. In this review, we provide an overview of their clinical diagnosis, management and molecular genetics. Both have variable phenotypes, extreme genetic heterogeneity, and display allelism both with each other and other ciliopathies. Recent advances in genetic technology have significantly improved diagnosis and clinical management of ciliopathy patients, with the delineation of some general genotype-phenotype correlations. We highlight those that are most relevant for clinical practice, including the correlation between TMEM67 mutations and the JBTS variant phenotype of COACH syndrome. The subcellular localization of the known MKS and JBTS proteins is now well-described, and we discuss some of the contemporary ideas about ciliopathy disease pathogenesis. Most JBTS and MKS proteins localize to a discrete ciliary compartment called the transition zone, and act as structural components of the so-called “ciliary gate” to regulate the ciliary trafficking of cargo proteins or lipids. Cargo proteins include enzymes and transmembrane proteins that mediate intracellular signaling. The disruption of transition zone function may contribute to the ciliopathy phenotype by altering the composition of the ciliary membrane or axoneme, with impacts on essential developmental signaling including the Wnt and Shh pathways as well as the regulation of secondary messengers such as inositol-1,4,5-trisphosphate (InsP3) and cyclic adenosine monophosphate (cAMP). -
Leber Congenital Amaurosis Due to CEP290 Mutations – Severe Vision Impairment with a High Unmet Medical Need: a Review Author and Journal Details: Bart P
This plain-language summary (or PLS) describes a paper on Leber congenital amaurosis 10 that was published in a medical journal called “Retina”. Title of the paper: Leber congenital amaurosis due to CEP290 mutations – severe vision impairment with a high unmet medical need: a review Author and journal details: Bart P. Leroy, David G. Birch, Jacque L. Duncan, Byron L. Lam, Robert K. Koenekoop, Fernanda B. O. Porto, Stephen R. Russel, Aniz Girach. Retina 2021;doi:10.1097/IAE.0000000000003133. Online ahead of print. What does this paper report on? • The authors of this paper reviewed what scientists know about the genetic eye disease called Leber congenital amaurosis 10 (also known as LCA10). They looked at the scientific articles on this subject that have been published in high-quality medical journals Why was this research needed? • Tying together separate pieces of scientific evidence about a disease can help us to understand the disease better. It also helps identify where there may be areas of care for people with the disease that need to be improved. We call these gaps “unmet medical needs” • Bringing evidence together in this way is especially important for rare diseases as it improves awareness among healthcare professionals of the needs of people living with the disease The authors of the paper are expert eye doctors working at specialist centers in Belgium, Brazil, Canada, and the USA; one of the authors is an employee of ProQR Therapeutics. This PLS has been developed in collaboration with Bart Leroy (an author on the original paper), Francesca Diodati and Matthew Carr, with medical writing assistance provided by ApotheCom. -
Ciliopathies Gene Panel
Ciliopathies Gene Panel Contact details Introduction Regional Genetics Service The ciliopathies are a heterogeneous group of conditions with considerable phenotypic overlap. Levels 4-6, Barclay House These inherited diseases are caused by defects in cilia; hair-like projections present on most 37 Queen Square cells, with roles in key human developmental processes via their motility and signalling functions. Ciliopathies are often lethal and multiple organ systems are affected. Ciliopathies are London, WC1N 3BH united in being genetically heterogeneous conditions and the different subtypes can share T +44 (0) 20 7762 6888 many clinical features, predominantly cystic kidney disease, but also retinal, respiratory, F +44 (0) 20 7813 8578 skeletal, hepatic and neurological defects in addition to metabolic defects, laterality defects and polydactyly. Their clinical variability can make ciliopathies hard to recognise, reflecting the ubiquity of cilia. Gene panels currently offer the best solution to tackling analysis of genetically Samples required heterogeneous conditions such as the ciliopathies. Ciliopathies affect approximately 1:2,000 5ml venous blood in plastic EDTA births. bottles (>1ml from neonates) Ciliopathies are generally inherited in an autosomal recessive manner, with some autosomal Prenatal testing must be arranged dominant and X-linked exceptions. in advance, through a Clinical Genetics department if possible. Referrals Amniotic fluid or CV samples Patients presenting with a ciliopathy; due to the phenotypic variability this could be a diverse set should be sent to Cytogenetics for of features. For guidance contact the laboratory or Dr Hannah Mitchison dissecting and culturing, with ([email protected]) / Prof Phil Beales ([email protected]) instructions to forward the sample to the Regional Molecular Genetics Referrals will be accepted from clinical geneticists and consultants in nephrology, metabolic, laboratory for analysis respiratory and retinal diseases. -
Phosphoinositide 3-Kinase-C2α Regulates Polycystin-2 Ciliary Entry
BASIC RESEARCH www.jasn.org Phosphoinositide 3-Kinase-C2a Regulates Polycystin-2 Ciliary Entry and Protects against Kidney Cyst Formation † Irene Franco,* Jean Piero Margaria,* Maria Chiara De Santis,* Andrea Ranghino, ‡ Daniel Monteyne, Marco Chiaravalli,§ Monika Pema,§ Carlo Cosimo Campa,* ‡| Edoardo Ratto,* Federico Gulluni,* David Perez-Morga, Stefan Somlo,¶ Giorgio R. Merlo,* Alessandra Boletta,§ and Emilio Hirsch* *Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Torino, Turin, Italy; †Renal Transplantation Center “A. Vercellone”, Division of Nephrology, Dialysis and Transplantation, Department of Medical Sciences, Città della Salute e della Scienza, Hospital and Research Center for Experimental Medicine (CeRMS) and Center for Molecular Biotechnology, University of Torino, Turin, Italy; ‡Laboratoire de Parasitologie Moléculaire, Institut de Biologie et de Médecine Moléculaires (IBMM), Université Libre de Bruxelles, Gosselies, Charleroi, Belgium; §Division of Genetics and Cell Biology, Dibit San Raffaele Scientific Institute, Milan, Italy; |Center for Microscopy and Molecular Imaging (CMMI), Université Libre de Bruxelles, Gosselies, Belgium; and ¶Section of Nephrology, Yale University School of Medicine, New Haven, Connecticut. ABSTRACT Signaling from the primary cilium regulates kidney tubule development and cyst formation. However, the mechanism controlling targeting of ciliary components necessary for cilium morphogenesis and signaling is largely unknown. Here, we studied the function of class II phosphoinositide 3-kinase-C2a (PI3K-C2a)inrenal tubule-derived inner medullary collecting duct 3 cells and show that PI3K-C2a resides at the recycling endo- some compartment in proximity to the primary cilium base. In this subcellular location, PI3K-C2a controlled the activation of Rab8, a key mediator of cargo protein targeting to the primary cilium. -
Evidence of Oligogenic Inheritance in Nephronophthisis
JASN Express. Published on September 12, 2007 as doi: 10.1681/ASN.2007020243 CLINICAL RESEARCH www.jasn.org Evidence of Oligogenic Inheritance in Nephronophthisis Julia Hoefele,*† Matthias T.F. Wolf,* John F. O’Toole,* Edgar A. Otto,* Ulla Schultheiss,* Georges Deˆschenes,‡ Massimo Attanasio,* Boris Utsch,* Corinne Antignac,§ and ʈ Friedhelm Hildebrandt* ʈ Departments of *Pediatrics and Human Genetics, University of Michigan, Ann Arbor, Michigan; †Department of Pediatrics, University Children’s Hospital, University of Munich, Munich, Germany; and ‡Hoˆpital Robert Debre´, Pediatric Nephrology, AP-HP, and §INSERM, U574, Universite´ Paris Descartes, Faculte de Me´dicine Rene´ Descartes, and Hoˆpital Necker-Enfants Malades, AP-HP, Department of Genetics, Paris, France ABSTRACT Nephronophthisis is a recessive cystic renal disease that leads to end-stage renal failure in the first two decades of life. Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified. Because oligogenic inheritance has been described for the related Bardet-Biedl syndrome, we evaluated whether mutations in more than one gene may also be detected in cases of nephronophthisis. Because the nephrocystins 1 to 4 are known to interact, we examined patients with nephronophthisis from 94 different families and sequenced all exons of the NPHP1, NPHP2, NPHP3, and NPHP4 genes. In our previous studies involving 44 families, we detected two mutations in one of the NPHP1–4 genes. Here, we detected in six families two mutations in either NPHP1, NPHP3, or NPHP4, and identified a third mutation in one of the other NPHP genes. Furthermore, we found possible digenic disease by detecting one individual who carried one mutation in NPHP2 and a second mutation in NPHP3. -
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. -
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. -
Intrafamilial Variability and Clinical Heterogeneity in Two Siblings With
r Biomar ula ke c rs le o & M D f i a o g l Journal of Molecular Biomarkers n a o n Nabhan, et al., J Mol Biomark Diagn 2015, 6:2 r s i u s o J DOI: 10.4172/2155-9929.1000217 ISSN: 2155-9929 & Diagnosis Case Report Open Access Intrafamilial Variability and Clinical Heterogeneity in Two Siblings with NPHP4 loss of Function Mutations Marwa M Nabhan1,2, Susann Brenzinger3, Sahar N Saleem4, Edgar A Otto3, Friedhelm Hildebrandt3,5 and Neveen A Soliman1,2* 1Center of Pediatric Nephrology and Transplantation, Department of Pediatrics, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt 2Egyptian Group for Orphan Renal Diseases (EGORD), Cairo, Egypt 3Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 4Radiology Department, Kasr Al Ainy School of Medicine, Cairo University, Cairo, Egypt 5Howard Hughes Medical Institute, Chevy Chase, USA *Corresponding author: Neveen A Soliman, Center of Pediatric Nephrology & Transplantation, Department of Pediatrics, Kasr Al Aini School of Medicine, Cairo University, Cairo, Egypt, Tel: 0201062132300; Fax: 020223630039; E-mail: [email protected] Rec date: Nov 27, 2014; Acc date: Jan 26, 2015; Pub date: Jan 28, 2015 Copyright: © 2015 Nabhan MM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Abstract Joubert syndrome–related disorders (JSRDs) are a group of clinically and genetically pleiotropic conditions that share a midbrain-hindbrain malformation, the pathognomonic molar tooth sign (MTS) visible on brain imaging, with variable involvement of other organs and systems mainly the eyes and the kidneys. -
Clinical Utility Gene Card For: Joubert Syndrome - Update 2013
European Journal of Human Genetics (2013) 21, doi:10.1038/ejhg.2013.10 & 2013 Macmillan Publishers Limited All rights reserved 1018-4813/13 www.nature.com/ejhg CLINICAL UTILITY GENE CARD UPDATE Clinical utility gene card for: Joubert syndrome - update 2013 Enza Maria Valente*,1,2, Francesco Brancati1, Eugen Boltshauser3 and Bruno Dallapiccola4 European Journal of Human Genetics (2013) 21, doi:10.1038/ejhg.2013.10; published online 13 February 2013 Update to: European Journal of Human Genetics (2011) 19, doi:10.1038/ejhg.2011.49; published online 30 March 2011 1. DISEASE CHARACTERISTICS 1.6 Analytical methods 1.1 Name of the disease (synonyms) Direct sequencing of coding genomic regions and splice site junctions; Joubert syndrome (JS); Joubert-Boltshauser syndrome; Joubert syn- multiplex microsatellite analysis for detection of NPHP1 homozygous drome-related disorders (JSRD), including cerebellar vermis hypo/ deletion. Possibly, qPCR or targeted array-CGH for detection of aplasia, oligophrenia, congenital ataxia, ocular coloboma, and hepatic genomic rearrangements in other genes. fibrosis (COACH) syndrome; cerebellooculorenal, or cerebello-oculo- renal (COR) syndrome; Dekaban-Arima syndrome; Va´radi-Papp 1.7 Analytical validation syndrome or Orofaciodigital type VI (OFDVI) syndrome; Malta Direct sequencing of both DNA strands; verification of sequence and syndrome. qPCR results in an independent experiment. 1.2 OMIM# of the disease 1.8 Estimated frequency of the disease 213300, 243910, 216360, 277170. (incidence at birth-‘birth prevalence’-or population prevalence) No good population-based data on JSRD prevalence have been published. A likely underestimated frequency between 1/80 000 and 1.3 Name of the analysed genes or DNA/chromosome segments 1/100 000 live births is based on unpublished data. -
Perkinelmer Genomics to Request the Saliva Swab Collection Kit for Patients That Cannot Provide a Blood Sample As Whole Blood Is the Preferred Sample
Eye Disorders Comprehensive Panel Test Code D4306 Test Summary This test analyzes 211 genes that have been associated with ocular disorders. Turn-Around-Time (TAT)* 3 - 5 weeks Acceptable Sample Types Whole Blood (EDTA) (Preferred sample type) DNA, Isolated Dried Blood Spots Saliva Acceptable Billing Types Self (patient) Payment Institutional Billing Commercial Insurance Indications for Testing Individuals with an eye disease suspected to be genetic in origin Individuals with a family history of eye disease Individuals suspected to have a syndrome associated with an eye disease Test Description This panel analyzes 211 genes that have been associated with ocular disorders. Both sequencing and deletion/duplication (CNV) analysis will be performed on the coding regions of all genes included (unless otherwise marked). All analysis is performed utilizing Next Generation Sequencing (NGS) technology. CNV analysis is designed to detect the majority of deletions and duplications of three exons or greater in size. Smaller CNV events may also be detected and reported, but additional follow-up testing is recommended if a smaller CNV is suspected. All variants are classified according to ACMG guidelines. Condition Description Diseases associated with this panel include microphtalmia, anophthalmia, coloboma, progressive external ophthalmoplegia, optic nerve atrophy, retinal dystrophies, retinitis pigementosa, macular degeneration, flecked-retinal disorders, Usher syndrome, albinsm, Aloprt syndrome, Bardet Biedl syndrome, pulmonary fibrosis, and Hermansky-Pudlak -
Ciliary Genes Arl13b, Ahi1 and Cc2d2a Differentially Modify Expression of Visual Acuity
bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY 4.0 International license. 1 Ciliary Genes arl13b, ahi1 and cc2d2a Differentially Modify Expression of Visual Acuity 2 Phenotypes but do not Enhance Retinal Degeneration due to Mutation of cep290 in Zebrafish 3 4 Short title: Retinal degeneration in cep290 mutant zebrafish 5 6 7 Emma M. Lessieur1,2,4, Ping Song1,4, Gabrielle C. Nivar1, 8 Ellen M. Piccillo1, Joseph Fogerty1, Richard Rozic3, and Brian D. Perkins1,2 9 10 1Department of Ophthalmic Research, Cole Eye Institute, 11 Cleveland Clinic, Cleveland, OH 44195 United States 12 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, 13 Case Western Reserve University, Cleveland, OH 44195 United States 14 3Department of Biomedical Engineering, Lerner Research Institute, 15 Cleveland Clinic, Cleveland, OH 44195 United States 16 17 4These authors contributed equally to this work 18 Correspondence to: 19 Brian D. Perkins, Ph.D. 20 Department of Ophthalmic Research 21 Cleveland Clinic 22 9500 Euclid Ave 23 Building i3-156 24 Cleveland, OH 44195, USA 25 (Ph) 216-444-9683 26 (Fax) 216-445-3670 27 [email protected] 28 29 1 bioRxiv preprint doi: https://doi.org/10.1101/569822; this version posted March 6, 2019. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.