DOCSLIB.ORG

Molecular Screening for Smith-Magenis Syndrome Among Patients with Mental Retardation of Unknown Cause J L Struthers, N Carson, M Mcgill, M M Khalifa

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Screening for Smith-Magenis Syndrome Among Patients with Mental Retardation of Unknown Cause J L Struthers, N Carson, M Mcgill, M M Khalifa 1of6 ELECTRONIC LETTER J Med Genet: first published as 10.1136/jmg.39.10.e59 on 1 October 2002. Downloaded from Molecular screening for Smith-Magenis syndrome among patients with mental retardation of unknown cause J L Struthers, N Carson, M McGill, M M Khalifa ............................................................................................................................. J Med Genet 2002;39:e59(http://www.jmedgenet.com/cgi/content/full/39/5/e59) mith-Magenis syndrome is a rare, multiple congenital anomaly/mental retardation syndrome (MCA/MR) asso- ciated with interstitial deletion of chromosome 17p11.2. S 1 Smith et al first described this condition in two patients. To date, more than 150 cases have been described. Patients with SMS display a variable expression of subtle dysmorphic features, MR, short stature, brachydactyly, visual and auditory impairment, behavioural problems, sleep disturbance, and cardiac and renal malformations.23 Almost all cases are de novo, non-mosaic, and of either maternal or paternal origin.45Although the abnormalities associated with SMS are well described, their subtlety and variable expression make clinical diagnosis often difficult, particularly in neonates and young infants.67 The SMS deleted region ranges in size from <1.5 Mb to 9 Mb and the majority of patients have a ∼5 Mb deletion (∼10- 11% of chromosome 17).48In general, there is no obvious cor- relation between the size of the deletion and the severity of the phenotype.8 In the majority of cases, this deletion is visible on careful routine cytogenetic analysis. Despite this, in several cases the deletion has been missed.79Using a FISH probe spe- cific for SMS has enhanced detection of the syndrome, especially in equivocal cases.10–12 Elsea et al13 reported a patient with a typical SMS phenotype and a normal karyotype at 650 http://jmg.bmj.com/ band resolution. This patient was subsequently diagnosed Figure 1 Densitometric analysis of D17S258:DXS70 allelic ratios with SMS by FISH.12 of SMS and normal subjects. (A) Diagram of the predicted banding patterns using the two EcoRI non-polymorphic probes; the X Current estimates of the incidence of SMS, based on ascer- 4 chromosome control probe, DXS70, corresponds to the 5.2 kb band taining cases in genetics centres, are between 1 in 25 000 and and the SMS deletion specific probe, D17S258, corresponds to the 1in5000014 births. Because the diagnosis of SMS can be 4.9 kb band. Grey shading indicates a single copy of the probe, missed both clinically and cytogenetically, it is generally black shading is indicative of a double copy. The D17S258/DXS70 believed that this syndrome might be underdiagnosed. In this density ratio for each lane is shown at the bottom. (B) Southern blot study, we screened a large population of patients with MR/DD of DNA from normal male and female controls and male and female on September 29, 2021 by guest. Protected copyright. SMS patients digested with EcoRI and cohybridised with DXS70 and D17S258 probes. The D17S258:DXS70 allelic ratios in normal males and females were approximately twice that of their SMS Key points counterparts, illustrating the ability of this screening method to detect the SMS deletion. • Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with of unknown cause to determine the frequency of SMS in this deletion 17p11.2. The prevalence of this syndrome in group and to estimate its prevalence in the general population. the general population and its frequency among patients with mental retardation/developmental delay MATERIAL AND METHODS (MR/DD) is unknown. It is generally believed that this Study population syndrome might be underdiagnosed because of its phe- A total of 1618 DNA samples were screened in this study, notypic and cytogenetic variability. which was approved by the Queen’s University Research Eth- 15 • In this study we screened a large number of patients with ics Board. These samples were referred during the period unexplained MR/DD to determine the frequency of SMS between 1996 and 1999 for FRAX testing. among this population. The screening involved Southern Screening strategy for detecting SMS deletion blotting and dosage comparison between non- A several stage screening strategy for detection of SMS was polymorphic markers, SMS deletion specific and control formulated using available patient material. The screening probes. All samples suspected to have the SMS deletion were subjected to confirmatory testing. • Of 1205 patients successfully screened, we detected ............................................................. two SMS patients. The prevalence of SMS in the general Abbreviations: SMS, Smith-Magenis syndrome; MCA/MR, multiple population is estimated. congenital anomaly/mental retardation; MR, mental retardation; DD, developmental delay www.jmedgenet.com 2of6 Electronic letter J Med Genet: first published as 10.1136/jmg.39.10.e59 on 1 October 2002. Downloaded from Table 1 DNA markers used for molecular screening by Southern hybridisation Probe Locus Location Enzyme Allele size (kb) Heterozygosity p1516-R4 D17S258 17p11.2 EcoRI* 4.9 0%† p18-55 DXS70 Xp22.3 EcoRI* 5.2 0%† pYNZ22 D17S5 17p13.3 EcoRI/BssHII* 3.05–4.20 83.5%† Data obtained from GDBTM Human Genome Database (database online). *Additional digestion with BssHII did not alter the allele size or heterozygosity. †Present study. Table 2 DNA markers used for PCR analysis of SMS deletion interval Marker Sequence name Location* Heterozygosity Product size (bp) Label D17S1857 AFM357yg9a/m Distal to common deletion 65.0% 177–187 HEX D17S2206 YL63-64 Within deletion, distal to middle SMS-REP 91.7%* 141–165 6-FAM D17S2207 YL601-602 Within deletion, distal to middle SMS-REP 42.0%* 135–155 HEX D17S805 AFM234ta1a/m Within deletion, proximal to middle SMS-REP 58.8% 216–228 6-FAM D17S841 AFM238vb10a/m Proximal to common deletion 65.4% 253–273 HEX Data obtained from GDBTM Human Genome Database (database online). *Potocki et al.3 involved dosage comparison between SMS deletion specific at 65°C, followed by a stringent wash in 0.1 × SSC, 0.1% SDS (D17S258) and X chromosome control (DXS70) markers. Ini- at 65°C for 20 minutes.17 tially, Southern blots, originally prepared for FRAX testing and Band intensity indicating the number of copies for each containing EcoRI/BssHII digested DNA were lightly stripped probe was initially estimated visually. Densitometry was from the FRAX hybridisation and then cohybridised with performed using scanned autoradiographs into Corel Photo- radiolabelled D17S258 and DXS70 probes. Because these Paint software version 9 as described previously.18 To estimate markers are non-polymorphic for the enzyme(s) used, each the number of copies of the SMS allele, the intensity of the probe produced a single band. These probes were chosen autosomal band was divided by the intensity of the X because the resultant bands were close in size (D17S258 = 4.9 chromosome band. kb band, DXS70 =5.2 kb band), which facilitated dosage To minimise the risk of missing any SMS patients, all sam- comparison. Normal males (46,XY) display two copies of the ples, which showed even minimal deviation from normal band D17S258 band relative to a single copy of DXS70. Normal intensity patterns, were selected for further evaluation. females (46,XX) display two copies of each band. SMS males would display only a single copy of the D17S258 allele and a Fluorescence in situ hybridisation (FISH) single copy of the X chromosome allele, while SMS females Patients who consistently exhibited an unexplainable dosage http://jmg.bmj.com/ would display a single copy of the D17S258 allele and two difference on repeat screening were contacted through their copies of the DXS70 allele. This method was validated before referring physicians to obtain fresh blood samples for FISH. screening using normal male and female controls and SMS Metaphase FISH analysis was performed according to the patients, equal dpm of each labelled probe, and variable expo- manufacturer’s protocols using a Vysis HYBriteTM Hybridiza- sures for each blot to ensure optimal representation of signal tion System and the Oncor D17S258 Smith-Magenis Chromo- intensities (fig 1). For some experiments, another chromo- some Region Probe or the dual-colour Vysis Locus Specific some 17 probe (D17S5) was also included for dosage control. Identifier Smith-Magenis Microdeletion Probe. In the second stage, patients who deviated from the on September 29, 2021 by guest. Protected copyright. expected banding patterns and were suspected of having the PCR analysis of DNA markers within and flanking the SMS deletion were subjected to a repeat of the screening assay, SMS deletion region using their banked DNA and new Southern blots. Finally, PCR heterozygosity analysis was performed for cases where a patients consistently exhibiting suspicious results were inves- fresh blood sample could not be obtained, or repeat screening tigated further using confirmatory testing by FISH and/or PCR was not adequately performed owing to poor DNA quality. microsatellite genotyping. Characteristics of the markers used Fluorescent labelled primers for highly polymorphic se- in this study are listed in tables 1 and 2. quences within and flanking the SMS common deletion were used for DNA amplification (table 2). Normal subjects were Southern blot analysis and densitometry expected to display two alleles at most loci tested, while SMS Southern blotting was performed as described previously.16 A patients were expected to be hemizygous for all loci within the total of 50 ng of probe insert was labelled with 50 µCi α-(32p) deletion interval. Amplified fragments were electrophoresed dCTP (3000 Ci/mmol) by random priming according to the on a 5% denaturing polyacrylamide gel in an ABI 373 DNA manufacturer’s instructions (Random Primers Labeling Sys- Sequencer and recorded by computer assisted laser. The tem, GIBCO BRL). Blots were hybridised in 1 mol/l NaCl, 1% forward primer of each pair, end labelled with either 6-FAM SDS, 10% dextran sulphate, and 0.1 mg/ml salmon sperm (blue) or HEX (green) dye, was synthesised by the University DNA at 65°C overnight.
Load more

Recommended publications
  • Opposite Deletions/Duplications of the X Chromosome: Two Novel Reciprocal Rearrangements
    European Journal of Human Genetics (2000) 8, 63–70 © 2000 Macmillan Publishers Ltd All rights reserved 1018–4813/00 $15.00 y www.nature.com/ejhg ARTICLE Opposite deletions/duplications of the X chromosome: two novel reciprocal rearrangements Sabrina Giglio1, Barbara Pirola1,2 , Giulia Arrigo2, Paolo Dagrada3, Barbara Bardoni1, Franca Bernardi4, Giovanni Russo5, Luisa Argentiero3, Antonino Forabosco6, Romeo Carrozzo7 and Orsetta Zuffardi1,2 1Biologia Generale e Genetica Medica, Universit`a di Pavia, Pavia; 2Laboratorio di Citogenetica, Ospedale San Raffaele, Milan; 3Citogenetica, ASL Provincia di Lodi, Lodi; 4Servizio Patologia Genetica e Prenatale, Ospedale Borgo Roma, Verona; 5Clinica Pediatria III, Universit`a di Milano, Ospedale San Raffaele, Milan; 6Istologia, Embriologia e Genetica, Universit`a di Modena, Modena; 7Servizio di Genetica Medica, Ospedale San Raffaele, Milan, Italy Paralogous sequences on the same chromosome allow refolding of the chromosome into itself and homologous recombination. Recombinant chromosomes have microscopic or submicroscopic rearrangements according to the distance between repeats. Examples are the submicroscopic inversions of factor VIII, of the IDS gene and of the FLN1/emerin region, all resulting from misalignment of inverted repeats, and double recombination. Most of these inversions are of paternal origin possibly because the X chromosome at male meiosis is free to refold into itself for most of its length. We report on two de novo rearrangements of the X chromosome found in four hypogonadic females. Two of them had an X chromosome deleted for most of Xp and duplicated for a portion of Xq and two had the opposite rearrangement (class I and class II rearrangements, respectively). The breakpoints were defined at the level of contiguous YACs.
    [Show full text]
  • Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17P11.2 and the Syntenic Region of the Mouse
    Downloaded from genome.cshlp.org on September 25, 2021 - Published by Cold Spring Harbor Laboratory Press Article Genes in a Refined Smith-Magenis Syndrome Critical Deletion Interval on Chromosome 17p11.2 and the Syntenic Region of the Mouse Weimin Bi,1,6 Jiong Yan,1,6 Paweł Stankiewicz,1 Sung-Sup Park,1,7 Katherina Walz,1 Cornelius F. Boerkoel,1 Lorraine Potocki,1,3 Lisa G. Shaffer,1 Koen Devriendt,4 Małgorzata J.M. Nowaczyk,5 Ken Inoue,1 and James R. Lupski1,2,3,8 Departments of 1Molecular & Human Genetics, 2Pediatrics, Baylor College of Medicine, 3Texas Children’s Hospital, Houston, Texas 77030, USA; 4Centre for Human Genetics, University Hospital Gasthuisberg, Catholic University of Leuven, B-3000 Leuven, Belgium; 5Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario L8S 4J9, Canada Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with behavioral abnormalities and sleep disturbance. Most patients have the same ∼4 Mb interstitial genomic deletion within chromosome 17p11.2. To investigate the molecular bases of the SMS phenotype, we constructed BAC/PAC contigs covering the SMS common deletion interval and its syntenic region on mouse chromosome 11. Comparative genome analysis reveals the absence of all three ∼200-kb SMS-REP low-copy repeats in the mouse and indicates that the evolution of SMS-REPs was accompanied by transposition of adjacent genes. Physical and genetic map comparisons in humans reveal reduced recombination in both sexes. Moreover, by examining the deleted regions in SMS patients with unusual-sized deletions, we refined the minimal Smith-Magenis critical region (SMCR) to an ∼1.1-Mb genomic interval that is syntenic to an ∼1.0-Mb region in the mouse.
    [Show full text]
  • Genomic Organization of the Approximately 1.5 Mb Smith
    European Journal of Human Genetics (2001) 9, 892 ± 902 ã 2001 Nature Publishing Group All rights reserved 1018-4813/01 $15.00 www.nature.com/ejhg ARTICLE Genomic organisation of the ~1.5 Mb Smith-Magenis syndrome critical interval: Transcription map, genomic contig, and candidate gene analysis Rebecca E Lucas1, Christopher N Vlangos1, Parimal Das4, Pragna I Patel4 and Sarah H Elsea*,1,2,3 1Genetics Graduate Program, Michigan State University, East Lansing, Michigan, MI 48824, USA; 2Department of Zoology, Michigan State University, East Lansing, Michigan, MI 48824, USA; 3Department of Pediatrics and Human Development, Michigan State University, East Lansing, Michigan, MI 48824, USA; 4Department of Neurology, Baylor College of Medicine, Houston, Texas, TX 77030, USA Smith-Magenis syndrome (SMS) is a multiple congenital anomalies/mental retardation syndrome associated with an interstitial deletion of chromosome 17 involving band p11.2. SMS is hypothesised to be a contiguous gene syndrome in which the phenotype arises from the haploinsufficiency of multiple, functionally-unrelated genes in close physical proximity, although the true molecular basis of SMS is not yet known. In this study, we have generated the first overlapping and contiguous transcription map of the SMS critical interval, linking the proximal 17p11.2 region near the SMS-REPM and the distal region near D17S740 in a minimum tiling path of 16 BACs and two PACs. Additional clones provide greater coverage throughout the critical region. Not including the repetitive sequences that flank the critical interval, the map is comprised of 13 known genes, 14 ESTs, and six genomic markers, and is a synthesis of Southern hybridisation and polymerase chain reaction data from gene and marker localisation to BACs and PACs and database sequence analysis from the human genome project high-throughput draft sequence.
    [Show full text]
  • Product Description SALSA MLPA Probemix P369-A2 Smith-Magenis
    MRC-Holland ® Product Description version A2-01; Issued 26 September 2018 MLPA Product Description SALSA ® MLPA ® Probemix P369-A2 Smith-Magenis Syndrome To be used with the MLPA General Protocol. Version A2. For complete product history see page 6. Catalogue numbers: • P369-025R: SALSA MLPA Probemix P369 Smith-Magenis, 25 reactions. • P369-050R: SALSA MLPA Probemix P369 Smith-Magenis, 50 reactions. • P369-100R: SALSA MLPA Probemix P369 Smith-Magenis, 100 reactions. To be used in combination with a SALSA MLPA reagent kit, available for various number of reactions. MLPA reagent kits are either provided with FAM or Cy5.0 dye-labelled PCR primer, suitable for Applied Biosystems and Beckman capillary sequencers, respectively (see www.mlpa.com ). Certificate of Analysis: Information regarding storage conditions, quality tests, and a sample electropherogram from the current sales lot is available at www.mlpa.com . Precautions and warnings: For professional use only. Always consult the most recent product description AND the MLPA General Protocol before use: www.mlpa.com . It is the responsibility of the user to be aware of the latest scientific knowledge of the application before drawing any conclusions from findings generated with this product. General information: The SALSA MLPA Probemix P369 Smith-Magenis syndrome is a research use only (RUO) assay for the detection of deletions or duplications in the 17p11.2 chromosomal region, including RAI1 . Deletion of this region is associated with Smith-Magenis syndrome (SMS), whereas duplication of this region is associated with Potocki-Lupski syndrome (PTLS). Furthermore, two probes targeting the 2q37.3 region are included, among which one probe for the HDAC4 gene.
    [Show full text]
  • Downloaded Per Proteome Cohort Via the Web- Site Links of Table 1, Also Providing Information on the Deposited Spectral Datasets
    www.nature.com/scientificreports OPEN Assessment of a complete and classifed platelet proteome from genome‑wide transcripts of human platelets and megakaryocytes covering platelet functions Jingnan Huang1,2*, Frauke Swieringa1,2,9, Fiorella A. Solari2,9, Isabella Provenzale1, Luigi Grassi3, Ilaria De Simone1, Constance C. F. M. J. Baaten1,4, Rachel Cavill5, Albert Sickmann2,6,7,9, Mattia Frontini3,8,9 & Johan W. M. Heemskerk1,9* Novel platelet and megakaryocyte transcriptome analysis allows prediction of the full or theoretical proteome of a representative human platelet. Here, we integrated the established platelet proteomes from six cohorts of healthy subjects, encompassing 5.2 k proteins, with two novel genome‑wide transcriptomes (57.8 k mRNAs). For 14.8 k protein‑coding transcripts, we assigned the proteins to 21 UniProt‑based classes, based on their preferential intracellular localization and presumed function. This classifed transcriptome‑proteome profle of platelets revealed: (i) Absence of 37.2 k genome‑ wide transcripts. (ii) High quantitative similarity of platelet and megakaryocyte transcriptomes (R = 0.75) for 14.8 k protein‑coding genes, but not for 3.8 k RNA genes or 1.9 k pseudogenes (R = 0.43–0.54), suggesting redistribution of mRNAs upon platelet shedding from megakaryocytes. (iii) Copy numbers of 3.5 k proteins that were restricted in size by the corresponding transcript levels (iv) Near complete coverage of identifed proteins in the relevant transcriptome (log2fpkm > 0.20) except for plasma‑derived secretory proteins, pointing to adhesion and uptake of such proteins. (v) Underrepresentation in the identifed proteome of nuclear‑related, membrane and signaling proteins, as well proteins with low‑level transcripts.
    [Show full text]
  • Problem Behavior in Fragile X and Smith-Magenis
    Title Page with All Author Contact Information RUNNING HEAD: PROBLEM BEHAVIOR IN FRAGILE X AND SMITH-MAGENIS SYNDROME An Indirect Examination of the Function of Problem Behavior Associated with Fragile X Syndrome and Smith-Magenis Syndrome Paul Langthorne Peter McGill Tizard Centre, University of Kent Abstract Fragile X syndrome (FXS) and Smith-Magenis syndrome (SMS) are associated with a number of specific topographies of problem behavior. Very few studies have examined the function served by problem behavior in these groups. Using the Questions About Behavioral Function scale (Matson & Vollmer, 1995) the current study examined group differences in the function of problem behavior displayed by children with FXS and SMS, in comparison to a control group of children with non-specific intellectual and developmental disabilities. Between- group analyses showed children with SMS were more likely to display problem behavior related to physical discomfort. Both within- and between-group analyses showed children with FXS were less likely to display attention-maintained problem behavior. These findings hold implications for the assessment, treatment and prevention of problem behavior associated with both FXS and SMS. Key words: functional assessment, problem behavior, fragile X syndrome, Smith-Magenis syndrome. [email protected] *BLIND Manuscript without contact information Click here to download BLIND Manuscript without contact information: JADD-09-246_categorical_only_11.2.11.docClick here to view linked References Problem behavior in fragile X and Smith-Magenis syndrome 1 An Indirect Examination of the Function of Problem Behavior Associated with Fragile X Syndrome and Smith-Magenis Syndrome Approximately 10% of children with severe intellectual and developmental disabilities (IDD) display problem behavior, such as self-injurious behavior (SIB), aggression or property destruction (Kiernan & Kiernan, 1994).
    [Show full text]
  • Carbohydrate Accumulation and Differential Transcript Expression in Winter Wheat Lines with Different Levels of Snow Mold and Fr
    plants Article Carbohydrate Accumulation and Differential Transcript Expression in Winter Wheat Lines with Different Levels of Snow Mold and Freezing Tolerance after Cold Treatment Erika B. Kruse 1, Samuel Revolinski 1, Jesse Aplin 2, Daniel Z. Skinner 3 , Timothy D. Murray 4 , Charles G. Edwards 2 and Arron H. Carter 1,* 1 Department of Crop and Soil Science, Washington State University, Pullman, WA 99164, USA; [email protected] (E.B.K.); [email protected] (S.R.) 2 School of Food Science, Washington State University, Pullman, WA 99164, USA; [email protected] (J.A.); [email protected] (C.G.E.) 3 Wheat Health, Genetics and Quality Research Unit, USDA-ARS, Pullman, WA 99164, USA; [email protected] 4 Department of Plant Pathology, Washington State University, Pullman, WA 99164, USA; [email protected] * Correspondence: [email protected] Received: 27 August 2020; Accepted: 17 October 2020; Published: 23 October 2020 Abstract: Winter wheat (Triticum aestivum L.) undergoes a period of cold acclimation in order to survive the ensuing winter, which can bring freezing temperatures and snow mold infection. Tolerance of these stresses is conferred in part by accumulation of carbohydrates in the crown region. This study investigates the contributions of carbohydrate accumulation during a cold treatment among wheat lines that differ in their snow mold tolerance (SMT) or susceptibility (SMS) and freezing tolerance (FrT) or susceptibility (FrS). Two parent varieties and eight recombinant inbred lines (RILs) were analyzed. The selected RILs represent four combinations of tolerance: SMT/FrT, SMT/FrS, SMS/FrT, and SMS/FrS. It is hypothesized that carbohydrate accumulation and transcript expression will differ between sets of RILs.
    [Show full text]
  • Diapositivo 1
    A complex chromosomal rearrangement in a child with developmental delay, fractious behavior, and craniofacial anomalies, compatible with Smith-Magenis Syndrome 1 1 1 1 1 2 3 4 5 1 1 Simão L , Alves C , Brito F , Marques B , Ferreira C , Gaspar I , Dieudonne V , Cabral P , Meneses I , Duarte G , Correia H 1Unidade de Citogenética, Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, INSA IP.Lisboa. 2Serviço de Genética Médica, Hospital Egas Moniz, Centro Hospitalar de Lisboa Ocidental (CHLO), EPE.Lisboa. 3Serviço de Pedopsiquiatria, Hospital de São Francisco Xavier, CHLO, EPE.Lisboa. 4Serviço de Neuropediatria, Hospital de São Francisco Xavier, CHLO, EPE.Lisboa 5Consulta de Cardiologia Pediátrica, Hospital de Santa Cruz, CHLO, EPE.Lisboa. INTRODUCTION Smith–Magenis syndrome (SMS) (OMIM No 182290) is a mental retardation syndrome characterised by behavioural abnormalities, including self injurious behaviour, sleep disturbance, and distinct craniofacial and skeletal anomalies. It is usually associated with deletion involving 17p11.2 and is estimated to occur in 1/25 000 births1. Approximately 90% of SMS cases have the 17p11.2 microdeletion2. Mutations leading to protein truncation in retinoic acid induced 1 gene (RAI1) have been identified in some individuals with phenotypic features consistent with SMS. RAI1 lies within the 17p11.2 locus, but these patients did not have 17p11.2 deletions1. Complex chromosome rearrangements (CCRs) are structural chromosome anomalies involving >2 chromosomes or >2 breakpoints3. Evaluation of CCRs and their potential phenotypic consequences is a common challenge in the genetics clinic and knowledge about the genotype/phenotype relationships are limited3,4,5. METHODS We report the case of a 14-year-old boy who was referred by SMS, presenting mental developmental delay, fractious behavior, reduced sensitivity to pain, macrocranium, speech delay, and distinctive facial features with face dismorfology, inaccurate teeth implanting and low ears implantation .
    [Show full text]
  • XLMR Genes: Update 2007
    European Journal of Human Genetics (2008) 16, 422–434 & 2008 Nature Publishing Group All rights reserved 1018-4813/08 $30.00 www.nature.com/ejhg REVIEW XLMR genes: update 2007 Pietro Chiurazzi*,1, Charles E Schwartz2, Jozef Gecz3,4 and Giovanni Neri*,1 1Institute of Medical Genetics, Catholic University, Rome, Italy; 2JC Self Research Institute of Human Genetics, Greenwood Genetic Center, Greenwood, SC, USA; 3Department of Genetic Medicine, Women’s and Children’s Hospital, Adelaide, South Australia, Australia; 4Department of Paediatrics, University of Adelaide, Adelaide, South Australia, Australia X-linked mental retardation (XLMR) is a common cause of inherited intellectual disability with an estimated prevalence of B1/1000 males. Most XLMR conditions are inherited as X-linked recessive traits, although female carriers may manifest usually milder symptoms. We have listed 215 XLMR conditions, subdivided according to their clinical presentation: 149 with specific clinical findings, including 98 syndromes and 51 neuromuscular conditions, and 66 nonspecific (MRX) forms. We also present a map of the 82 XLMR genes cloned to date (November 2007) and a map of the 97 conditions that have been positioned by linkage analysis or cytogenetic breakpoints. We briefly consider the molecular function of known XLMR proteins and discuss the possible strategies to identify the remaining XLMR genes. Final remarks are made on the natural history of XLMR conditions and on diagnostic issues. European Journal of Human Genetics (2008) 16, 422–434; doi:10.1038/sj.ejhg.5201994;
    [Show full text]
  • 12 Smith-Magenis Syndrome Deletion, Reciprocal Duplication Dup(17)(P11.2P11.2), and Other Proximal 17P Rearrangements
    Chapter 12 / SMS Deletion 179 12 Smith-Magenis Syndrome Deletion, Reciprocal Duplication dup(17)(p11.2p11.2), and Other Proximal 17p Rearrangements Pawel Stankiewicz, MD, PhD, Weimin Bi, PhD, and James R. Lupski, MD, PhD CONTENTS INTRODUCTION CONSTITUTIONAL RECURRENT GENOMIC DISORDERS IN PROXIMAL 17P SMS-REPS, LCR LOCATED AT THE BREAKPOINTS OF THE COMMON DELETION SUMMARY REFERENCES INTRODUCTION An approx 4-Mb genomic segment on chromosome 17p11.2 commonly deleted in 70–80% of patients with the Smith-Magenis syndrome (SMS) is flanked by large, complex, highly identical (approx 98.7%), and directly oriented, proximal (approx 256 kb) and distal (approx 176 kb) low-copy repeats (LCRs), termed SMS-REPs. These LCR copies mediate nonallelic homologous recombination (NAHR), resulting in both SMS deletion and the reciprocal dupli- cation dup(17)(p11.2p11.2). A third copy, the middle SMS-REP (approx 241 kb) is inverted and located between them. Several additional large LCR17ps have been identified fomented by breakpoint mapping in patients with deletions ascertained because of an SMS phenotype. LCRs in proximal 17p constitute more than 23% of the analyzed genome sequence, approx fourfold higher than predictions based on virtual analysis of the entire human genome. LCRs appear to play a significant role not only in common recurrent deletions and duplications, but also in other rearrangements including unusual sized (i.e., uncommon, recurrent and nonrecur- rent) chromosomal deletions, reciprocal translocations, and marker chromosomes. DNA sequence analysis from both common and unusual sized recurrent SMS deletions and common dup(17)(p11.2p11.2) reveals “recombination hotspots” or a remarkable positional preference for strand exchange in NAHR events.
    [Show full text]
  • Structure and Evolution of the Smith-Magenis Syndrome Repeat Gene Clusters, SMS-Reps
    Downloaded from genome.cshlp.org on October 1, 2021 - Published by Cold Spring Harbor Laboratory Press Article Structure and Evolution of the Smith-Magenis Syndrome Repeat Gene Clusters, SMS-REPs Sung-Sup Park,1,5,6 Paweł Stankiewicz,1,5 Weimin Bi,1 Christine Shaw,1 Jessica Lehoczky,4 Ken Dewar,4 Bruce Birren,4 and James R. Lupski1,2,3,7 Departments of 1Molecular and Human Genetics and 2Pediatrics, Baylor College of Medicine, 3Texas Children’s Hospital, Houston, Texas, 77030, USA; 4Whitehead Institute for Biomedical Research/MIT Center for Genome Research, Cambridge, Massachusetts 02141, USA An ∼4-Mb genomic segment on chromosome 17p11.2, commonly deleted in patients with the Smith-Magenis syndrome (SMS) and duplicated in patients with dup(17)(p11.2p11.2) syndrome, is flanked by large, complex low-copy repeats (LCRs), termed proximal and distal SMS-REP. A third copy, the middle SMS-REP, is located between them. SMS-REPs are believed to mediate nonallelic homologous recombination, resulting in both SMS deletions and reciprocal duplications. To delineate the genomic structure and evolutionary origin of SMS-REPs, we constructed a bacterial artificial chromosome/P1 artifical chromosome contig spanning the entire SMS region, including the SMS-REPs, determined its genomic sequence, and used fluorescence in situ hybridization to study the evolution of SMS-REP in several primate species. Our analysis shows that both the proximal SMS-REP (∼256 kb) and the distal copy (∼176 kb) are located in the same orientation and derived from a progenitor copy, whereas the middle SMS-REP (∼241 kb) is inverted and appears to have been derived from the proximal copy.
    [Show full text]
  • A Phenotype Map of the Mouse X Chromosome: Models for Human X-Linked Disease
    Downloaded from genome.cshlp.org on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Review A Phenotype Map of the Mouse X Chromosome: Models for Human X-linked Disease Yvonne Boyd,1,4 Helen J. Blair,2 Pamela Cunliffe,3 Walter K. Masson,1 and Vivienne Reed Medical Research Council (MRC) Mammalian Genetics Unit, Harwell, Oxon OX11 0RD UK The identification of many of the transcribed genes in man and mouse is being achieved by large scale sequencing of expressed sequence tags (ESTs). Attention is now being turned to elucidating gene function and many laboratories are looking to the mouse as a model system for this phase of the genome project. Mouse mutants have long been used as a means of investigating gene function and disease pathogenesis, and recently, several large mutagenesis programs have been initiated to fulfill the burgeoning demand of functional genomics research. Nevertheless, there is a substantial existing mouse mutant resource that can be used immediately. This review summarizes the available information about the loci encoding X-linked phenotypic mutants and variants, including 40 classical mutants and 40 that have arisen from gene targeting. Mammalian X-linked traits are easily recognized by describe the current status of the phenotype map of their inheritance patterns and their mode of expres- the mouse X chromosome for those working in the sion. Whereas hemizygous males carry one copy of X- field of genome research with an interest in X-linked linked loci and suffer from the full effect of any muta- disease. tion, heterozygous females carry two copies and have a Analyzing mouse mutants at the molecular and phenotype that reflects the relative expression, as de- phenotypic level is one of the most powerful ways of termined by X-inactivation status, of the mutated and understanding gene function in mammals.
    [Show full text]