DOCSLIB.ORG

Exon-Level Array CGH in a Large Clinical Cohort Demonstrates Increased Sensitivity of Diagnostic Testing for Mendelian Disorders

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Exon-Level Array CGH in a Large Clinical Cohort Demonstrates Increased Sensitivity of Diagnostic Testing for Mendelian Disorders ORIGINAL RESEARCH ARTICLE ©American College of Medical Genetics and Genomics Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders Swaroop Aradhya, PhD1, Rachel Lewis, MS1, Tahrra Bonaga, BS1, Nnenna Nwokekeh, MS1, Amanda Stafford, MS1, Barbara Boggs, PhD1, Kathleen Hruska, PhD1, Nizar Smaoui, MD1, John G. Compton, PhD1, Gabriele Richard, MD1 and Sharon Suchy, PhD1 Purpose: Mendelian disorders are most commonly caused by muta- somal dominant disorders, with a detection rate of 2.9%. For auto- tions identifiable by DNA sequencing. Exonic deletions and duplica- somal recessive disorders, array CGH was usually performed after a tions can go undetected by sequencing, and their frequency in most single mutation was identified by sequencing. Among 138 individu- Mendelian disorders is unknown. als tested for recessive disorders, 10.1% had intragenic deletions. For X-linked disorders, 3.5% of 313 patients carried a deletion or Methods: We designed an array comparative genomic hybridiza- duplication. tion (CGH) test with probes in exonic regions of 589 genes. Targeted testing was performed for 219 genes in 3,018 patients. We demon- Conclusion: Our results demonstrate that exon-level array CGH strate for the first time the utility of exon-level array CGH in a large provides a robust option for intragenic copy number analysis and clinical cohort by testing for 136 autosomal dominant, 53 autosomal should routinely supplement sequence analysis for Mendelian recessive, and 30 X-linked disorders. disorders. Results: Overall, 98 deletions and two duplications were identified Genet Med 2012:14(6):594–603 in 53 genes, corresponding to a detection rate of 3.3%. Approxi- Key words: array CGH; copy number; deletion; duplication; exon; mately 40% of positive findings were deletions of only one or two Mendelian exons. A high frequency of deletions was observed for several auto- INTRODUCTION clinical setting.5,6 We constructed a custom high-density oligo- The majority of mutations in Mendelian disorders are detected nucleotide array with probes targeted to the individual exons of by DNA sequencing. However, in recent years the significance 589 genes associated with known genetic disorders to identify and frequency of pathogenic intragenic deletions or duplications whole and partial gene deletions or duplications. Our results (copy number mutations) have become increasingly evident. from testing 3,018 patients with this array demonstrate that Quantitative methods are now used for molecular diagnosis of exon array CGH complements DNA sequencing and increases a limited number of disorders.1 In a variety of genetic disor- the mutation detection rate in the molecular diagnosis of auto- ders, including Rett syndrome, Smith–Magenis syndrome, and somal and X-linked Mendelian disorders. Prader–Willi syndrome, routine testing includes copy number analysis by multiplex ligation-dependent amplification (MLPA) MATERIALS AND METHODS assay, quantitative PCR (qPCR), or fluorescence in situ hybrid- Array design ization. The same methods have also been used to identify The 3,018 clinical cases tested by exon array CGH were ana- larger chromosomal rearrangements, including those affecting lyzed on one of the two array versions. On the first array version, subtelomeric regions.2,3 Array comparative genomic hybridiza- 1,584 cases were tested; 1,434 cases were tested on the second. tion (CGH) has proven to be a powerful tool for copy number The first version included two or more probes in most exons of analysis but has been used mostly for cytogenetic analysis to 465 targeted genes and three probes in each intron, regardless detect large genomic deletions and duplications that extend of size. Coverage of some small exons included probes in the hundreds of kilobases to megabases.4 Some recent reports have intronic sequence immediately flanking the exon, based on the shown that high-resolution array CGH with probes densely premise that any deletion/duplication of that exon would prob- distributed across individual genes can detect small deletions or ably extend into the intron. Genes with unprocessed pseudo- duplications, but this approach has not been widely applied in a genes were not included in the target list. The second version 1GeneDx, Gaithersburg, Maryland, USA. Correspondence: Swaroop Aradhya ([email protected]) Submitted 21 September 2011; accepted 28 November 2011; advance online publication 1 March 2012. doi:10.1038/gim.2011.65 594 Volume 14 | Number 6 | June 2012 | GENETICS in MEDICINE Exon-level array CGH | ARADHYA et al ORIGINAL RESEARCH ARTICLE of the exon array included seven probes across each exon and online Universal Probe Library assay design center (https:// the flanking 250-bp intronic sequence on either side. The array www.roche-applied-­science.com). Seventy nanograms each was designed to include probe coverage of 589 genes, including of patient sample and control DNA samples were added to all 465 genes from the first array version. Intronic regions other separate reaction mixtures containing a TaqMan probe and than the 250-bp exonic flanks were not covered, and deletions FastStart TaqMan mastermix (Roche) and locus-­specific prim- or duplications in those regions would not be detected. Genes ers. The amplification was carried out at 60 °C annealing tem- with processed pseudogenes (e.g., PTEN) were furnished with perature for 45 cycles on a Stratagene Mx3000P/3005P machine extra probe coverage within the 250-bp exon-flanking intronic (Agilent Technologies). Three normal genomes were tested in sequences. Untranslated regions of the exons were also covered triplicate along with the patient sample. In a valid positive assay, if part of those exons included coding sequences. The average the Ct for the clinical sample showed a difference of at least one gene size and the exon size in this collection of 589 genes were PCR cycle relative to the normal sample, the triplicates devi- 104 kb and 741 bp, respectively. Each array version was vali- ated by <0.30 Ct, and all negative controls showed normal copy dated with 60–80 DNA samples that previously showed either number for the locus tested. The assay used an internal nor- normal copy number or a known MLPA- or qPCR-confirmed malizing target (SOD1 gene in 21q22.11) to ensure that equal deletion or duplication in one of a variety of genes (data not amounts of DNA were used in all tested samples. The difference shown). in Ct ­values between the clinical sample and one normal control Following validation of the exon array, prospective studies sample was expressed as a fold change in the copy number of were performed on blood samples from patients referred to our the target gene. clinical laboratory for deletion/duplication testing for various Mendelian disorders. For autosomal recessive disorders, dele- RESULTS tion/duplication testing was performed if DNA sequencing Clinical testing of 3,018 cases identified only a single mutation. For individuals with an auto- Exon array CGH was used to examine 3,018 patients for dele- somal dominant disorder or for female carriers of an X-linked tions or duplications in 219 genes. More than one gene was disorder (affected or unaffected), deletion/duplication testing analyzed in 307 individuals affected with a genetically heteroge- was either offered as a second test if gene sequencing was nega- neous disorder. Therefore, a total of 4,354 genes were analyzed tive or in combination with the sequencing test when that dis- in the 3,018 individuals. Exon array CGH identified 98 partial order had a known high frequency of deletions. or whole-gene deletions and two duplications, corresponding to a detection rate of 3.3% in the individuals tested (Figure 1). Array hybridization and data analysis qPCR, MLPA, or whole-genome array CGH confirmed copy DNA was extracted from blood samples on the QiaCube number mutations detected by exon array CGH. Table 1 and (Qiagen, Valencia, CA) automated system. Labeling was carried Supplementary Table S5 online lists all the copy number out with the Enzo CGH labeling kit for oligo arrays (Enzo Life mutations identified in our cohort, andFigure 2 shows selected Sciences, Plymouth Meeting, PA). Array CGH was performed examples of partial gene deletions or duplications detected by with 0.5 μg of DNA according to the manufacturer’s protocol exon array CGH. Copy number mutations were identified in (Agilent Technologies, Santa Clara, CA). The data for each 53 of the 219 genes tested. No deletions or duplications were patient were examined only for the specific gene (or gene panel) found in the remaining 166 genes, although most of these were requested. Data were analyzed using the ADM-1 algorithm in evaluated in 10 cases or fewer. Forty percent of the 3,018 cases DNA Analytics/Genomic Workbench software. Reportable 12.0 data were based on log2 ratio deviations >0.25 and including two or more adjacent probes. 10.1% 10.0 Confirmation of array findings es 8.0 Probe deviations including two or more adjacent probes were confirmed by qPCR with custom-designed primers, MLPA or, 6.0 5.2% 5.3% in one case, whole-genome array CGH. MLPA was performed 3.5% 4.0 2.9% 3.3% according to the manufacturer’s protocols (MRC-Holland, ercentage of positiv 2.0 Amsterdam, The Netherlands). The following SALSA MLPA P kits were validated for clinical use: P067 PTCH1, kit P187 0.0 Holoprosencephaly HPE, P225-B1 PTEN, P101 STK11, P219-B1 AD AD except AR XL All All except PTEN PTEN PAX6, P313 CREBBP, P215 EXT, P180 Limb Malformations-2, Cases by category and P015 MECP2. qPCR analysis was performed using a TaqMan assay based on the Human Universal Probe Library Figure 1 Percentage of exon array CGH results classified according to mode of inheritance in 100 positive cases. Results are shown with set from Roche Applied Science (Roche, Indianapolis, IN; and without the PTEN cases included.
Load more

Recommended publications
  • 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]
  • Megalencephaly and Macrocephaly
    277 Megalencephaly and Macrocephaly KellenD.Winden,MD,PhD1 Christopher J. Yuskaitis, MD, PhD1 Annapurna Poduri, MD, MPH2 1 Department of Neurology, Boston Children’s Hospital, Boston, Address for correspondence Annapurna Poduri, Epilepsy Genetics Massachusetts Program, Division of Epilepsy and Clinical Electrophysiology, 2 Epilepsy Genetics Program, Division of Epilepsy and Clinical Department of Neurology, Fegan 9, Boston Children’s Hospital, 300 Electrophysiology, Department of Neurology, Boston Children’s Longwood Avenue, Boston, MA 02115 Hospital, Boston, Massachusetts (e-mail: [email protected]). Semin Neurol 2015;35:277–287. Abstract Megalencephaly is a developmental disorder characterized by brain overgrowth secondary to increased size and/or numbers of neurons and glia. These disorders can be divided into metabolic and developmental categories based on their molecular etiologies. Metabolic megalencephalies are mostly caused by genetic defects in cellular metabolism, whereas developmental megalencephalies have recently been shown to be caused by alterations in signaling pathways that regulate neuronal replication, growth, and migration. These disorders often lead to epilepsy, developmental disabilities, and Keywords behavioral problems; specific disorders have associations with overgrowth or abnor- ► megalencephaly malities in other tissues. The molecular underpinnings of many of these disorders are ► hemimegalencephaly now understood, providing insight into how dysregulation of critical pathways leads to ►
    [Show full text]
  • Level Estimates of Maternal Smoking and Nicotine Replacement Therapy During Pregnancy
    Using primary care data to assess population- level estimates of maternal smoking and nicotine replacement therapy during pregnancy Nafeesa Nooruddin Dhalwani BSc MSc Thesis submitted to the University of Nottingham for the degree of Doctor of Philosophy November 2014 ABSTRACT Background: Smoking in pregnancy is the most significant preventable cause of poor health outcomes for women and their babies and, therefore, is a major public health concern. In the UK there is a wide range of interventions and support for pregnant women who want to quit. One of these is nicotine replacement therapy (NRT) which has been widely available for retail purchase and prescribing to pregnant women since 2005. However, measures of NRT prescribing in pregnant women are scarce. These measures are vital to assess its usefulness in smoking cessation during pregnancy at a population level. Furthermore, evidence of NRT safety in pregnancy for the mother and child’s health so far is nebulous, with existing studies being small or using retrospectively reported exposures. Aims and Objectives: The main aim of this work was to assess population- level estimates of maternal smoking and NRT prescribing in pregnancy and the safety of NRT for both the mother and the child in the UK. Currently, the only population-level data on UK maternal smoking are from repeated cross-sectional surveys or routinely collected maternity data during pregnancy or at delivery. These obtain information at one point in time, and there are no population-level data on NRT use available. As a novel approach, therefore, this thesis used the routinely collected primary care data that are currently available for approximately 6% of the UK population and provide longitudinal/prospectively recorded information throughout pregnancy.
    [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]
  • Should 45,X/46,XY Boys with No Or Mild Anomaly of External Genitalia
    3 179 L Dumeige and others 45,X/46,XY phenotypic boys, 179:3 181–190 Clinical Study not so benign? Should 45,X/46,XY boys with no or mild anomaly of external genitalia be investigated and followed up? Laurence Dumeige1,2, Livie Chatelais3, Claire Bouvattier4, Marc De Kerdanet5, Capucine Hyon6, Blandine Esteva7, Dinane Samara-Boustani8, Delphine Zenaty1, Marc Nicolino9, Sabine Baron10, Chantal Metz-Blond11, Catherine Naud-Saudreau12, Clémentine Dupuis13, Juliane Léger1, Jean-Pierre Siffroi6, Bruno Donadille14, Sophie Christin-Maitre14, Jean-Claude Carel1, Regis Coutant3 and Laetitia Martinerie1,2 1Pediatric Endocrinology Department, CHU Robert Debré, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris and Université Paris Diderot, Sorbonne Paris Cité, Paris, France, 2INSERM UMR-S1185, Le Kremlin Bicêtre, France, 3Pediatric Department, CHU Angers, Angers, France, 4Pediatric Endocrinology Department, CHU Bicêtre, Centre de Référence des Anomalies du Développement Génital, Assistance-Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France, 5Pediatric Department, CHU Rennes, Rennes, France, 6Genetic Department, 7Pediatric Endocrinology Department, CHU Armand Trousseau, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris, Paris, France, 8Pediatric Endocrinology Department, CHU Necker-Enfants Malades, Centre de Référence des Maladies Endocriniennes Rares de la Croissance, Assistance-Publique Hôpitaux de Paris, Paris, France, 9Pediatric
    [Show full text]
  • Orphanet Report Series Rare Diseases Collection
    Marche des Maladies Rares – Alliance Maladies Rares Orphanet Report Series Rare Diseases collection DecemberOctober 2013 2009 List of rare diseases and synonyms Listed in alphabetical order www.orpha.net 20102206 Rare diseases listed in alphabetical order ORPHA ORPHA ORPHA Disease name Disease name Disease name Number Number Number 289157 1-alpha-hydroxylase deficiency 309127 3-hydroxyacyl-CoA dehydrogenase 228384 5q14.3 microdeletion syndrome deficiency 293948 1p21.3 microdeletion syndrome 314655 5q31.3 microdeletion syndrome 939 3-hydroxyisobutyric aciduria 1606 1p36 deletion syndrome 228415 5q35 microduplication syndrome 2616 3M syndrome 250989 1q21.1 microdeletion syndrome 96125 6p subtelomeric deletion syndrome 2616 3-M syndrome 250994 1q21.1 microduplication syndrome 251046 6p22 microdeletion syndrome 293843 3MC syndrome 250999 1q41q42 microdeletion syndrome 96125 6p25 microdeletion syndrome 6 3-methylcrotonylglycinuria 250999 1q41-q42 microdeletion syndrome 99135 6-phosphogluconate dehydrogenase 67046 3-methylglutaconic aciduria type 1 deficiency 238769 1q44 microdeletion syndrome 111 3-methylglutaconic aciduria type 2 13 6-pyruvoyl-tetrahydropterin synthase 976 2,8 dihydroxyadenine urolithiasis deficiency 67047 3-methylglutaconic aciduria type 3 869 2A syndrome 75857 6q terminal deletion 67048 3-methylglutaconic aciduria type 4 79154 2-aminoadipic 2-oxoadipic aciduria 171829 6q16 deletion syndrome 66634 3-methylglutaconic aciduria type 5 19 2-hydroxyglutaric acidemia 251056 6q25 microdeletion syndrome 352328 3-methylglutaconic
    [Show full text]
  • Metacarpophalangeal Pattern Profile Analysis in Sotos Syndrome
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE HHS Public Access provided by IUPUIScholarWorks Author manuscript Author ManuscriptAuthor Manuscript Author Am J Med Manuscript Author Genet. Author Manuscript Author manuscript; available in PMC 2017 September 12. Published in final edited form as: Am J Med Genet. 1985 April ; 20(4): 625–629. doi:10.1002/ajmg.1320200408. Metacarpophalangeal Pattern Profile Analysis in Sotos Syndrome Merlin G. Butler, Department of Biology, University of Notre Dame and North Central Regional Genetics Center, Memorial Hospital, South Bend, Indiana Department of Medical Genetics, Indiana University School of Medicine F. John Meaney, Department of Medical Genetics, Indiana University School of Medicine Genetic Diseases Section, Indiana State Board of Health, Indianapolis Smita Kittur, Pediatric Genetics Department, Children’s Medical and Surgical Center, Johns Hopkins Hospital, Baltimore Joseph H. Hersh, and Child Evaluation Center, Department of Pediatrics, University of Louisville School of Medicine Lusia Hornstein Cincinnati Center for Developmental Disorders, Children’s Hospital Medical Center Abstract The metacarpophalangeal pattern profile (MCPP) was analyzed on 16 Sotos syndrome patients. A mean Sotos syndrome profile was produced. Correlation studies confirm clinical homogeneity of Sotos syndrome individuals. Discriminant analysis of Sotos syndrome patients and normal individuals produces a function of two MCPP variables and age, which may provide a useful tool for diagnosis. Keywords Sotos syndrome; metacarpophalangeal pattern profile (MCPP); discriminant analysis; correlation studies INTRODUCTION Sotos syndrome, or cerebral gigantism, was first described by Sotos et al [1964]; at least 100 cases were reported subsequently. This syndrome is characterized by large size at birth, large hands and feet, advanced osseous maturation, macrocephaly with prominent forehead and Address reprint requests to Merlin G.
    [Show full text]
  • Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders
    International Journal of Molecular Sciences Review Diagnostic Utility of Genome-Wide DNA Methylation Analysis in Mendelian Neurodevelopmental Disorders Sadegheh Haghshenas 1,2 , Pratibha Bhai 2, Erfan Aref-Eshghi 3 and Bekim Sadikovic 1,2,4,* 1 Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; [email protected] 2 Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada; [email protected] 3 Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; [email protected] 4 Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5C1, Canada * Correspondence: [email protected] Received: 22 November 2020; Accepted: 4 December 2020; Published: 6 December 2020 Abstract: Mendelian neurodevelopmental disorders customarily present with complex and overlapping symptoms, complicating the clinical diagnosis. Individuals with a growing number of the so-called rare disorders exhibit unique, disorder-specific DNA methylation patterns, consequent to the underlying gene defects. Besides providing insights to the pathophysiology and molecular biology of these disorders, we can use these epigenetic patterns as functional biomarkers for the screening and diagnosis of these conditions. This review summarizes our current understanding of DNA methylation episignatures in rare disorders and describes the underlying technology and analytical approaches. We discuss the computational parameters, including statistical and machine learning methods, used for the screening and classification of genetic variants of uncertain clinical significance. Describing the rationale and principles applied to the specific computational models that are used to develop and adapt the DNA methylation episignatures for the diagnosis of rare disorders, we highlight the opportunities and challenges in this emerging branch of diagnostic medicine.
    [Show full text]
  • 349 D.R. Laub Jr. (Ed.), Congenital Anomalies of the Upper
    Index A dermatological anomalies , 182 Abductor digiti minimi (ADM) transfer , 102–103 skeletal abnormalities , 182 Abductor pollicis brevis (APB) , 186–187 upper extremity anomalies , 182, 183 ABS. See Amniotic band syndrome (ABS) visceral anomalies , 182 Achondroplasia defi nition of , 179 classifi cation/characterization , 338 description , 32, 33 defi nition of , 337–338 epidemiology of , 181 genetics , 338 genetics and embryology management , 338 molecular etiology , 180 Acrocephalosyndactyly syndrome , 32, 33, 179 prenatal diagnosis , 180–181 Acrosyndactyly repair, ABS , 300–302 molecular basis of , 180 Adactylic group IV symbrachydactyly , 129, 131 postoperative care and complications , 187 Al-Awadi syndrome , 154 treatment Amniotic band syndrome (ABS) APB release , 186–187 acrosyndactyly repair , 300–302 border digits syndactylies , 184 anesthesia concerns of fi rst web space release , 186 induction and maintenance of anesthesia , 43 patient age , 183 postoperative concerns , 43 secondary revisions , 187 preoperative preparation , 42–43 symphalangism , 184 classifi cation , 298 syndactyly ( see Syndactyly) clinical presentation thumb radial clinodactyly , 186–187 acrosyndactyly , 297–298 type II apert hand , 187–188 digital malformation , 297 Apical ectodermal ridge (AER) , 3–5 distal skeletal bones tapering , 297–298 Arthrogryposis , 210 hand deformity , 297 classic arthrogryposis , 305–306, 308 complications , 302 classifi cation , 305, 306 constriction band release defi nition of , 229, 230, 305 Upton’s technique , 299, 301 de-rotation osteotomy, shoulder , 308, 309 z-plasty , 299–300 distal , 230–231 ( see Distal arthrogryposis) diagnosis of , 296 elbow treatment digital hypoplasia reconstruction , 302 muscle transfers , 310–311 etiology of , 295–296 nonoperative management , 308 preoperative considerations , 299 posterior elbow capsular release , 309 treatment , 299 radial head dislocations , 311 Amniotic constriction band syndrome.
    [Show full text]
  • Regional Genetic Consultation Service
    Regional Genetic Consultation Service Contract 5889BD01 July 1, 2018 through June 30, 2019 Congenital & Inherited Disorders Division of Health Promotion & Chronic Disease Prevention, Phone: 1-800-383-3826 http://idph.iowa.gov/genetics Regional Genetic Consultation Service: A contract established by IDPH in the Division of Health Promotion & Chronic Disease Prevention, Contract # 5888BD01 Administrative Code, Chapter 4:641-4.5(136A) Iowa Department of Public Health Advancing Health Through the Generations Kimberly Reynolds Adam Gregg Gerd Clabaugh Governor Lt. Governor Director Authorized State Official for this contract: Brenda Dobson, Director, Division of Health Promotion and Chronic Disease Prevention (515) 281-7769 University of Iowa Stead Family Department of Pediatrics (319) 356-2675 Hatem El-Shanti, MD, Division Director John A. Bernat, MD, PhD, Clinical Director Hannah Bombei, MS, CGC, Program Coordinator Page | 2 Congenital & Inherited Disorders Division of Health Promotion & Chronic Disease Prevention, Phone: 800-383-3826 http://idph.iowa.gov/genetics In collaboration with the Iowa Department of Public Health & The Stead Family Department of Pediatrics Division of Medical Genetics & Genomics University of Iowa Stead Family Children’s Hospital & Clinical Outreach Services University of Iowa Hospitals and Clinics Page | 3 What is the Regional Genetic Consultation Service? Iowa Administrative Code 641—4.5(136A) Regional Genetic Consultation Service (RGCS). This program provides comprehensive genetic and genomic services statewide through outreach clinics. 4.5(1) Provision of comprehensive genetic and genomic services. The department shall contract with the Division of Medical Genetics & Genomics within the Stead Family Department of Pediatrics at the University of Iowa to provide genetic and genomic health care and education outreach services for individuals and families within Iowa.
    [Show full text]
  • Hemimegalencephaly with Bannayan-Riley-Ruvalcaba Syndrome
    Journal Identification = EPD Article Identification = 0954 Date: February 15, 2018 Time: 10:35 am Original article Epileptic Disord 2018; 20 (1): 30-4 Hemimegalencephaly with Bannayan-Riley-Ruvalcaba syndrome Ryan Ghusayni 1, Monisha Sachdev 1, William Gallentine 1, Mohamad A Mikati 1,a, Marie T McDonald 2,a 1 Division of Pediatric Neurology, Department of Pediatrics, Duke University, Durham 2 Division of Medical Genetics, Department of Pediatrics, Duke University, Durham, USA a Authors contributed equally Received August 30, 2017; Accepted January 09, 2018 ABSTRACT – Hemimegalencephaly is known to occur in Proteus syn- drome, but has not been reported, to our knowledge, in the other PTEN mutation-related syndrome of Bannayan-Riley-Ruvalcaba. Here, we report a patient with Bannayan-Riley-Ruvalcaba syndrome who also had hemimegalencephaly and in whom the hemimegalencephaly was evident well before presentation of the characteristic manifestations of Bannayan- Riley-Ruvalcaba syndrome. An 11-year-old boy developed drug-resistant focal seizures on the fifth day of life. MRI revealed left hemimegalencephaly. He later showed macrocephaly,developmental delay,athetotic quadriplegic cerebral palsy, and neuromuscular scoliosis. Freckling of the penis, which is characteristic of Bannayan-Riley-Ruvalcaba syndrome, was not present at birth but was observed at 9 years of age. Gene analysis revealed a c.510 T>G PTEN mutation. This patient and his other affected family members, his father and two siblings, were started on the tumour screening procedures recommended for patients with PTEN mutations. This case highlights the importance of early screening for PTEN mutations in cases of hemimegalen- cephaly not otherwise explained by another disorder, even in the absence of signs of Proteus syndrome or the full manifestations of Bannayan-Riley Ruvalcaba syndrome.
    [Show full text]
  • PTEN Hamartoma Tumor Syndromes
    European Journal of Human Genetics (2008) 16, 1289–1300 & 2008 Macmillan Publishers Limited All rights reserved 1018-4813/08 $32.00 www.nature.com/ejhg PRACTICAL GENETICS In association with PTEN hamartoma tumor syndromes The PTEN hamartoma tumor syndromes (PHTS) are a collection of rare clinical syndromes characterized by germline mutations of the tumor suppressor PTEN. These syndromes are driven by cellular overgrowth, leading to benign hamartomas in virtually any organ. Cowden syndrome (CS), the prototypic PHTS syndrome, is associated with increased susceptibility to breast, thyroid, and endometrial cancer. PTEN is located on chromosome 10q22–23 and negatively regulates the prosurvival PI3K/Akt/mTOR pathway through its lipid phosphatase activity. Loss of PTEN activates this pathway and leads to increased cellular growth, migration, proliferation, and survival. Clinical management of patients with PHTS, particularly those with CS, should include early and frequent screening, surveillance, and preventive care for associated malignancies. Concomitant with improved understanding of the biology of PTEN and the PI3K/Akt/mTOR pathway, inhibitors of this pathway are being developed as anticancer agents. These medications could have applications for patients with PHTS, for whom no medical options currently exist. In brief Adult onset LD is considered a variant of CS character- ized by dysplastic gangliocytoma of the cerebellum PHTS is an autosomal dominant spectrum of hamarto- often leading to increased intracranial pressure, ataxia, matous overgrowth disorders with variable phenotypic and seizures. manifestations characterized by germline mutations of BRRS is characterized by the developmental delay, the tumor suppressor gene PTEN located at 10q22–23. macrocephaly, lipomas, hemangiomas, and pigmented These syndromes include Cowden syndrome (CS), speckled macules of the glans penis in males.
    [Show full text]