DOCSLIB.ORG

Date Due Date Due Date Due

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Date Due Date Due Date Due PLACE ll RETURN BOX to roman this chockout from your mood. TO AVOID FINES Mom on or baton dd. duo. DATE DUE DATE DUE DATE DUE MSU In An Affirmative Action/Equal Opponfirmy Inflation mm: SCREENING FOR MUTATIONS IN PAX3 AND MITF IN WAARDENBURG SYNDROME AND WAARDENBURG SYNDROME-LIKE INDIVIDUALS By Melisa Lynn Carey A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for a degree of MASTER OF SCIENCE Department of Zoology 1 996 ABSTRACT SCREENING FOR MUTATIONS IN PAX3 AND MITF IN WAARDENBURG SYNDROME AND WAARDENBURG SYNDROME-LIKE INDIVIDUALS BY Melisa L. Carey Waardenburg Syndrome (WS) is an autosomal dominant disorder characterized by pigmentary and facial anomalies and congenital deafness. Mutations causing WS have been reported in PAX3 and MITF. The goal of this study was to characterize the molecular defects in 33 unrelated WS individuals. Mutation detection was performed using Single Strand Conformational Polymorphism (SSCP) analysis and sequencing methods. Among the 33 WS individuals, a total of eight mutations were identified, seven in PAX3 and one in MITF. In this study, one of the eight mutations was identified and characterized in PAX3 exon seven in a WSI family (UoM1). The proband of UoM1 also has Septo-Optic Dysplasia. In a large family (MSU22) with WS-Iike dysmorphology and additional craniofacial anomalies, linkage was excluded to PAX3 and no mutations were identified in MITF. Herein I review the status of mutation detection in our proband screening set and add to the understanding of the role of PAX3 and MITF in development by exploring new phenotypic characteristics associated with WS. ACKNOWLEDGMENTS I would like to thank Drs. Tom Friedman and Jim H. Asher Jr. for their encouragement, support, patience and guidance. A special thanks to Dr. Asher for all of his efforts in collecting families for this study. His dedication and conviction were admirable and he will be missed. I would also like to thank Tom Barber, Aihui Wang, Yong Liang, Rob Morell, Lori Swenson and Maki Saitoh for their enlightening discussions both scientific and social. A special thanks to Tim Cloutier for his assistance with the project. I would like to thank my committee members, Dr. John Fyfe, Dr. Emanuel Hackel and Dr. Jeff Innis for their helpful suggestions. A thanks to all of our collaborators and the families represented in this project; whose cooperation is greatly appreciated. I would like to to take a moment to thank my parents, Barbara and Patrick Carey and the rest of my family, Mike, Donna, Courtney, Kyle and Brandon; who gave me both the encouragement and the necessary outlet to get through the trials of graduate school. This work was supported by Grant DC 01160-04 from the National Institute on Deafness and Communication Disorders, National Institute of Health. TABLE OF CONTENTS LIST OF TABLES ...................................................................... vii LIST OF FIGURES ................................................................................. ix BACKGROUND AND SIGNIFICANCE ................................................... 1 Waardenburg Syndrome Phenotype ................................. 3 Mouse Models for Waardenburg Syndrome ...................... 2 The PAX family ................................................................. 6 PAX genes responsible for several disorders ................... 8 PAX3 expression pattern .................................................. 9 Mutations in human PAX3 .................................................. 10 Micropthalmia ..................................................................... 15 Other genes causing Waardenburg Syndrome ................. 20 Understanding function ...................................................... 20 CHAPTER ONE: Screening for mutations in PAX3 and MITF in families with classical Waardenburg Syndrome (WS) and Waardenburg Syndrome-like phenotypes. INTRODUCTION ........................................................................... 22 The goals of this study ............................................... 22 Description of the proband screening set ....................... 26 RESULTS ...................................................................................... 28 SSCP analysis of PAX3 .................................................... 29 SSCP analysis of MITF ...................................................... 29 Cycle sequencing analysis of PAX3 and MITF 31 DISCUSSION ................................................................................ 32 SSCP analysis .................................................................... 33 Cycle sequencing ............................................................... 34 Mutation detection .............................................................. 36 Evaluation of clinical data .................................................. 38 Mutations due to deletions ................................................... 40 Mutations in regulatory regions ..................................... 41 Mutations of alternative transcripts ................................... 41 Technical obstacles with SSCP ........................................... 42 Mutations in other genes ..................................................... 45 CONCLUSION .............................................................................. 46 MATERIALS AND METHODS ..................................................... 48 Family identification and DNA isolation ............................. 48 Polymerase chain reaction .................................................. 49 Single strand conformational polymorphism ....................... 50 Allele specific amplification .................................................. 51 Cloning fragments ................................................................ 52 Sequencing .......................................................................... 53 CHAPTER TWO: Waardenburg Syndrome in conjunction with Septo—Optic Dysplasia. INTRODUCTION ........................................................................... 55 Septo-Optic Dysplasia ....................................................... 55 Ascertainment of an individual with WSI and SOD .............. 59 RESULTS ...................................................................................... 61 SSCP analysis of PAX3 ...................................................... 61 Mutation indentification in MITF ........................................... 69 Other individuals with SOD ................................................. 70 DISCUSSION ................................................................................. 71 Description of UoM1 ............................................................. 71 Mutational analysis of PAX3 and MITF ............................. 72 Other individuals with SOD .................................................. 74 CONCLUSION ................................................................................ 76 CHAPTER THREE: Waardenburg Syndrome co-segregating with other severe craniofacial anomalies. INTRODUCTION ........................................................................... 77 Genes causing craniofacial anomalies .............................. 77 Description of MSU22 .......................................................... 78 Craniofacial syndromes ...................................................... 78 RESULTS ........................................................................................ 82 Mutational analysis ........................................................... 82 Linkage analysis to PAX3 .................................................... 82 DISCUSSION ................................................................................. 88 Description of MSU22 .......................................................... 88 SSCP and sequence analysis .............................................. 91 Linkage analysis ................................................................... 91 CONCLUSIONS ........................................................................... 93 APPENDIX A: Additional Tables .............................................................. 94 APPENDIX 8: Additional lnforrnation ....................................................... 109 Blank foms .......................................................................... 109 Reprints ............................................................................... 1 15 LIST OF REFERENCES .......................................................................... 134 vi LIST OF TABLES Table 1 Waardenburg Syndrome Diagnostic Criteria 2 Table 2 PAX3/Splotch Mutations .................................................... 4 Table 3 Mi Mouse Mutations ........................................................... 5 Table 4 PAX Genes ......................................................................... 6 Table 5 PAX3 Mutations ................................................................... 12 Table 6 MITF Mutations ................................................................... 16 Table 7 Proband Screening Set ....................................................... 24 Table 8 PAX3 PCR Primers .............................................................. 94 Table 9 MITF PCR Primers .............................................................. 95 Table 10 Cycle Sequencing Primers .................................................. 98 Table 11 Collaborators for Each WS and WS-like Family ............... 99 Table 12 PAX3 Linked
Load more

Recommended publications
  • Pfeiffer Syndrome Type II Discovered Perinatally
    Diagnostic and Interventional Imaging (2012) 93, 785—789 CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector LETTER / Musculoskeletal imaging Pfeiffer syndrome type II discovered perinatally: Report of an observation and review of the literature a,∗ a a a H. Ben Hamouda , Y. Tlili , S. Ghanmi , H. Soua , b c b a S. Jerbi , M.M. Souissi , H. Hamza , M.T. Sfar a Unité de néonatologie, service de pédiatrie, CHU Tahar Sfar, 5111 Mahdia, Tunisia b Service de radiologie, CHU Tahar Sfar, 5111 Mahdia, Tunisia c Service de gynéco-obstétrique, CHU Tahar Sfar, 5111 Mahdia, Tunisia Pfeiffer syndrome, described for the first time by Pfeiffer in 1964, is a rare hereditary KEYWORDS condition combining osteochondrodysplasia with craniosynostosis [1]. This syndrome is Pfeiffer syndrome; also called acrocephalosyndactyly type 5, which is divided into three sub-types. Type I Cloverleaf skull; is the classic Pfeiffer syndrome, with autosomal dominant transmission, often associated Craniosynostosis; with normal intelligence. Types II and III occur as sporadic cases in individuals who have Syndactyly; craniosynostosis with broad thumbs, broad big toes, ankylosis of the elbows and visceral Prenatal diagnosis abnormalities [2]. We report a case of Pfeiffer syndrome type II, discovered perinatally, which is distinguished from type III by the skull appearing like a cloverleaf, and we shall discuss the clinical, radiological and evolutive features and the advantage of prenatal diagnosis of this syndrome with a review of the literature. Observation The case involved a male premature baby born at 36 weeks of amenorrhoea with multiple deformities at birth. The parents were not blood-related and in good health who had two other boys and a girl with normal morphology.
    [Show full text]
  • FGFR2 Mutations in Pfeiffer Syndrome
    © 1995 Nature Publishing Group http://www.nature.com/naturegenetics correspondent FGFR2 mutations in Pfeiffer syndrome Sir-In the past few months, several genetic diseases have been ascribed to mutations in genes of the fibroblast growth factor receptor (FGFR) family, including achondroplasia (FGFR3) J-z, Crouzon syndrome (FGFR2)3 and 4 m/+ Pfeiffer syndrome (FGFR1) • In D321A addition, two clinically distinct N:Jl GIJ; AM craniosynostotic conditions, Jackson­ ~ Weiss and Crouzon syndromes, have c been ascribed to allelic mutations in the FGFR2 gene, suggesting that FGFR2mutations might have variable 5 phenotypic effects • We have recently FGFR2 found point mutations in the m/+ gene in two unrelated cases of Pfeiffer syndrome supporting the view that this craniosynostotic syndrome, is a 4 6 genetically heterogenous condition • • Pfeiffer syndrome is an autosomal dominant form of acrocephalo­ Fig. 1 Mutations of FGFR2 in two unrelated patients with craniofacial, hand syndactyly (ACS) characterized by and foot anomalies characteristic of Pfeiffer syndrome. Note midface craniosynostosis (brachycephaly retrusion, hypertelorism, proptosis and radiological evidence of enlargement type) with deviation and enlargement of thumb, with ankylosis of the second and third phalanges and the short, broad and deviated great toes. m, mutation; +, wild type sequence. The of the thumbs and great toes, sequence of wild type and mutant genes are shown and the arrow indicates brachymesophalangy, with pha­ the base substitution resulting in the mutation. langeal ankylosis and a varying degree of soft tissue syndactyly7.8. One of our sporadic cases and one familial form of ACS fulfilled the clinical criteria ofthe Pfeiffer syndrome, with particular respect to interphalangeal an aspartic acid into an alanine in the Elisabeth Lajeunie ankylosis (Fig.
    [Show full text]
  • Crouzon Syndrome Genetic and Intervention Review
    Journal of Oral Biology and Craniofacial Research 9 (2019) 37–39 Contents lists available at ScienceDirect Journal of Oral Biology and Craniofacial Research journal homepage: www.elsevier.com/locate/jobcr Crouzon syndrome: Genetic and intervention review ∗ T N.M. Al-Namnama, , F. Haririb, M.K. Thongc, Z.A. Rahmanb a Department of Oral Biology, Faculty of Dentistry, University of MAHSA, 42610, Jenjarum, Selangor, Malaysia b Department of Oro-Maxillofacial Clinical Science, Faculty of Dentistry, University of Malaya, 50603, Kuala Lumpur, Malaysia c Department of Paediatrics, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia ARTICLE INFO ABSTRACT Keywords: Crouzon syndrome exhibits considerable phenotypic heterogeneity, in the aetiology of which genetics play an Crouzon syndrome important role. FGFR2 mediates extracellular signals into cells and the mutations in the FGFR2 gene cause this Molecular pathology syndrome occurrence. Activated FGFs/FGFR2 signaling disrupts the balance of differentiation, cell proliferation, Genetic phenotype and apoptosis via its downstream signal pathways. However, very little is known about the cellular and mole- cular factors leading to severity of this phenotype. Revealing the molecular pathology of craniosynostosis will be a great value for genetic counselling, diagnosis, prognosis and early intervention programs. This mini-review summarizes the fundamental and recent scientific literature on genetic disorder of Crouzon syndrome and presents a graduated strategy for the genetic approach, diagnosis and the management of this complex cra- niofacial defect. 1. Introduction known. CS commonly starts at the first three years of life.4 Craniosy- nostosis can be suspected during antenatal stage via ultrasound scan Craniosynostosis is a birth defect characterized by premature fusion otherwise is often detected at birth from its classic crouzonoid features of one or more of the calvarial sutures before the completion of brain of the newborn.
    [Show full text]
  • Advances in Understanding the Genetics of Syndromes Involving Congenital Upper Limb Anomalies
    Review Article Page 1 of 10 Advances in understanding the genetics of syndromes involving congenital upper limb anomalies Liying Sun1#, Yingzhao Huang2,3,4#, Sen Zhao2,3,4, Wenyao Zhong1, Mao Lin2,3,4, Yang Guo1, Yuehan Yin1, Nan Wu2,3,4, Zhihong Wu2,3,5, Wen Tian1 1Hand Surgery Department, Beijing Jishuitan Hospital, Beijing 100035, China; 2Beijing Key Laboratory for Genetic Research of Skeletal Deformity, Beijing 100730, China; 3Medical Research Center of Orthopedics, Chinese Academy of Medical Sciences, Beijing 100730, China; 4Department of Orthopedic Surgery, 5Department of Central Laboratory, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China Contributions: (I) Conception and design: W Tian, N Wu, Z Wu, S Zhong; (II) Administrative support: All authors; (III) Provision of study materials or patients: All authors; (IV) Collection and assembly of data: Y Huang; (V) Data analysis and interpretation: L Sun; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Wen Tian. Hand Surgery Department, Beijing Jishuitan Hospital, Beijing 100035, China. Email: [email protected]. Abstract: Congenital upper limb anomalies (CULA) are a common birth defect and a significant portion of complicated syndromic anomalies have upper limb involvement. Mostly the mortality of babies with CULA can be attributed to associated anomalies. The cause of the majority of syndromic CULA was unknown until recently. Advances in genetic and genomic technologies have unraveled the genetic basis of many syndromes- associated CULA, while at the same time highlighting the extreme heterogeneity in CULA genetics. Discoveries regarding biological pathways and syndromic CULA provide insights into the limb development and bring a better understanding of the pathogenesis of CULA.
    [Show full text]
  • 2018 Etiologies by Frequencies
    2018 Etiologies in Order of Frequency by Category Hereditary Syndromes and Disorders Count CHARGE Syndrome 958 Down syndrome (Trisomy 21 syndrome) 308 Usher I syndrome 252 Stickler syndrome 130 Dandy Walker syndrome 119 Cornelia de Lange 102 Goldenhar syndrome 98 Usher II syndrome 83 Wolf-Hirschhorn syndrome (Trisomy 4p) 68 Trisomy 13 (Trisomy 13-15, Patau syndrome) 60 Pierre-Robin syndrome 57 Moebius syndrome 55 Trisomy 18 (Edwards syndrome) 52 Norrie disease 38 Leber congenital amaurosis 35 Chromosome 18, Ring 18 31 Aicardi syndrome 29 Alstrom syndrome 27 Pfieffer syndrome 27 Treacher Collins syndrome 27 Waardenburg syndrome 27 Marshall syndrome 25 Refsum syndrome 21 Cri du chat syndrome (Chromosome 5p- synd) 16 Bardet-Biedl syndrome (Laurence Moon-Biedl) 15 Hurler syndrome (MPS I-H) 15 Crouzon syndrome (Craniofacial Dysotosis) 13 NF1 - Neurofibromatosis (von Recklinghausen dis) 13 Kniest Dysplasia 12 Turner syndrome 11 Usher III syndrome 10 Cockayne syndrome 9 Apert syndrome/Acrocephalosyndactyly, Type 1 8 Leigh Disease 8 Alport syndrome 6 Monosomy 10p 6 NF2 - Bilateral Acoustic Neurofibromatosis 6 Batten disease 5 Kearns-Sayre syndrome 5 Klippel-Feil sequence 5 Hereditary Syndromes and Disorders Count Prader-Willi 5 Sturge-Weber syndrome 5 Marfan syndrome 3 Hand-Schuller-Christian (Histiocytosis X) 2 Hunter Syndrome (MPS II) 2 Maroteaux-Lamy syndrome (MPS VI) 2 Morquio syndrome (MPS IV-B) 2 Optico-Cochleo-Dentate Degeneration 2 Smith-Lemli-Opitz (SLO) syndrome 2 Wildervanck syndrome 2 Herpes-Zoster (or Hunt) 1 Vogt-Koyanagi-Harada
    [Show full text]
  • Genes in Eyecare Geneseyedoc 3 W.M
    Genes in Eyecare geneseyedoc 3 W.M. Lyle and T.D. Williams 15 Mar 04 This information has been gathered from several sources; however, the principal source is V. A. McKusick’s Mendelian Inheritance in Man on CD-ROM. Baltimore, Johns Hopkins University Press, 1998. Other sources include McKusick’s, Mendelian Inheritance in Man. Catalogs of Human Genes and Genetic Disorders. Baltimore. Johns Hopkins University Press 1998 (12th edition). http://www.ncbi.nlm.nih.gov/Omim See also S.P.Daiger, L.S. Sullivan, and B.J.F. Rossiter Ret Net http://www.sph.uth.tmc.edu/Retnet disease.htm/. Also E.I. Traboulsi’s, Genetic Diseases of the Eye, New York, Oxford University Press, 1998. And Genetics in Primary Eyecare and Clinical Medicine by M.R. Seashore and R.S.Wappner, Appleton and Lange 1996. M. Ridley’s book Genome published in 2000 by Perennial provides additional information. Ridley estimates that we have 60,000 to 80,000 genes. See also R.M. Henig’s book The Monk in the Garden: The Lost and Found Genius of Gregor Mendel, published by Houghton Mifflin in 2001 which tells about the Father of Genetics. The 3rd edition of F. H. Roy’s book Ocular Syndromes and Systemic Diseases published by Lippincott Williams & Wilkins in 2002 facilitates differential diagnosis. Additional information is provided in D. Pavan-Langston’s Manual of Ocular Diagnosis and Therapy (5th edition) published by Lippincott Williams & Wilkins in 2002. M.A. Foote wrote Basic Human Genetics for Medical Writers in the AMWA Journal 2002;17:7-17. A compilation such as this might suggest that one gene = one disease.
    [Show full text]
  • Generalized Hypertrichosis
    Letters to the Editor case of female. Ambras syndrome is a type of universal Generalized hypertrichosis affecting the vellus hair, where there is uniform overgrowth of hair over the face and external hypertrichosis ear with or without dysmorphic facies.[3] Patients with Gingival fi bromaatosis also have generalized hypertrichosis Sir, especially on the face.[4] Congenital hypertrichosis can A 4-year-old girl born out of non-consanguinous marriage occur due to fetal alcohol syndrome and fetal hydentoin presented with generalized increase in body hair noticed syndrome.[5] Prepubertal hypertrichosis is seen in otherwise since birth. None of the other family members were healthy infants and children. There is involvement of affected. Hair was pigmented and soft suggesting vellus hair. face back and extremities Distribution of hair shows an There was generalized increase in body hair predominantly inverted fi r-tree pattern on the back. More commonly seen affecting the back of trunk arms and legs [Figures 1 and 2]. in Mediterranean and South Asian descendants.[6] There is Face was relatively spared except for fore head. Palms and soles were spared. Scalp hair was normal. Teeth and nail usually no hormonal alterations. Various genodermatosis were normal. There was no gingival hypertrophy. No other associated with hypertrichosis as the main or secondary skeletal or systemic abnormalities were detected clinically. diagnostic symptom are: Routine blood investigations were normal. Hormonal Lipoatrophy (Lawrernce Seip syndrome) study was within normal limit for her age. With this Cornelia de Lange syndrome clinical picture of generalized hypertrichosis with no other Craniofacial dysostosis associated anomalies a diagnosis of universal hypertrichosis Winchester syndrome was made.
    [Show full text]
  • The First Non-Invasive Prenatal Test That Screens for Single-Gene Disorders
    The first non-invasive prenatal test that screens for single-gene disorders the evolution of NIPT A non-invasive prenatal test that screens multiple genes for mutations causing severe genetic disorders in the fetus analyses circulating cell- free fetal DNA (cfDNA) from a maternal blood sample. The test is performed after 10 weeks of pregnancy. works as a complementary screen to traditional and genome- wide NIPT . It screens for several life-altering genetic disorders that are not screened with current NIPT technology, allowing a complete picture of the risk of a pregnancy being affected by a genetic disorder. 2 facilitates early diagnosis of single-gene disorders. It involves 3 different levels of screening: This test screens for 5 common inherited recessive genetic disorders, such as Cystic Fibrosis, Beta-Thalassemia, Sickle INHERITED cell anaemia, Deafness autosomal recessive type 1A, Deafness autosomal recessive type 1B. Genes screened: CFTR, CX26 (GJB2), CX30 (GJB6), HBB This test screens for 44 severe genetic disorders due to de novo mutations (a gene mutation that is not inherited) in 25 genes DE NOVO Genes screened: ASXL1, BRAF, CBL, CHD7, COL1A1, COL1A2 , COL2A1, FGFR2, FGFR3, HDAC8, JAG1, KRAS, MAP2K1, MAP2K2, MECP2, NIPBL, NRAS, NSD1, PTPN11, RAF1, RIT1, SETBP1, SHOC2, SIX3, SOS1 This test screens for both inherited and de novo single-gene disorders and represents a combination of the tests INHERITED COMPLETE and DE NOVO providing a complete picture of the pregnancy risk. 3 allows detection of common inherited genetic disorders in INHERITED the fetus GENE GENETIC DISORDER CFTR Cystic Fibrosis CX26 (GJB2) Deafness autosomal recessive type 1A CX30 (GJB6) Deafness autosomal recessive type 1B HBB Beta-Thalassemia HBB Sickle cell anemia The inherited recessive disorders screened by INHERITED are the most common in the European population 4 identifies fetal conditions that could be missed by traditional DE NOVO prenatal screening.
    [Show full text]
  • Pfeiffer Syndrome
    orphananesthesia Anaesthesia recommendations for patients suffering from Pfeiffer syndrome Disease name: Pfeiffer syndrome ICD 10: Q87.0 Synonyms: ACS5, Acrocephalosyndactyly type V, noack syndrome, cranio-facial- dermatological dysplasia Pfeiffer syndrome is a rare autosomal dominant disorder, characterized by malformations of the skull, face, hands and feet. Crouzon, Apert and Pfeiffer syndromes are the most recognizable of the syndromic craniosynostoses. Diagnoses can be established from the typical phenotype accompanied by molecular genetic testing. Medicine in progress Perhaps new knowledge Every patient is unique Perhaps the diagnostic is wrong Find more information on the disease, its centres of reference and patient organisations on Orphanet: www.orpha.net 1 Disease summary Most cases can be attributed to mutations in the fibroblast growth factor receptor genes FGFR-1 or FGFR-2. However there are phenotypes that cannot be related to FGFR abnormalities. Based on the severity of malformations it is divided into three clinical subtypes. Type 1 “classic” Pfeiffer syndrome is by far the most common subtype and presents with mild manifestations of brachycephaly, midface hypoplasia and broad fingers and toes; it is associated with normal intelligence and generally good outcome. Type 2 consists of cloverleaf skull, extreme proptosis, finger and toe abnormalities, elbow ankylosis or synostosis, airway malformations, developmental delay, neurological complications and decreased life span. Type 3 is similar to type 2 but without a cloverleaf skull. Clinical overlap between the three types may occur. Craniosyostois (premature fusion of one or more of the cranial sutures) most often involves coronal and lambdoid sutures. This prevents further growth of the skull, affects the shape of the head and face and may lead to increased intracranial pressures.
    [Show full text]
  • Blueprint Genetics Craniosynostosis Panel
    Craniosynostosis Panel Test code: MA2901 Is a 38 gene panel that includes assessment of non-coding variants. Is ideal for patients with craniosynostosis. About Craniosynostosis Craniosynostosis is defined as the premature fusion of one or more cranial sutures leading to secondary distortion of skull shape. It may result from a primary defect of ossification (primary craniosynostosis) or, more commonly, from a failure of brain growth (secondary craniosynostosis). Premature closure of the sutures (fibrous joints) causes the pressure inside of the head to increase and the skull or facial bones to change from a normal, symmetrical appearance resulting in skull deformities with a variable presentation. Craniosynostosis may occur in an isolated setting or as part of a syndrome with a variety of inheritance patterns and reccurrence risks. Craniosynostosis occurs in 1/2,200 live births. Availability 4 weeks Gene Set Description Genes in the Craniosynostosis Panel and their clinical significance Gene Associated phenotypes Inheritance ClinVar HGMD ALPL Odontohypophosphatasia, Hypophosphatasia perinatal lethal, AD/AR 78 291 infantile, juvenile and adult forms ALX3 Frontonasal dysplasia type 1 AR 8 8 ALX4 Frontonasal dysplasia type 2, Parietal foramina AD/AR 15 24 BMP4 Microphthalmia, syndromic, Orofacial cleft AD 8 39 CDC45 Meier-Gorlin syndrome 7 AR 10 19 EDNRB Hirschsprung disease, ABCD syndrome, Waardenburg syndrome AD/AR 12 66 EFNB1 Craniofrontonasal dysplasia XL 28 116 ERF Craniosynostosis 4 AD 17 16 ESCO2 SC phocomelia syndrome, Roberts syndrome
    [Show full text]
  • 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
    [Show full text]
  • 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
    [Show full text]