ADVANCES IN 22HUMAN GENETICS

CONTRIBUTORS TO THIS VOLUME

Matteo AdinolfiDivision ofMedical &Molecular GeneticsUnited Medical and Dental SchoolsGuy's and St. Thomas's HospitalsLondon Bridge, London, England

John CrollaWessex Regional Genetics LaboratorySalisbury District HospitalSalisbury, Wiltshire, England

Harry C. DietzDepanments ofPediatrics, Medicine,and Molecular Biology and GeneticsJohns Hopkins School ofMedicineBaltimore, Maryland

Regen DrouinResearch Unit inHuman andMolecular GeneticsSaint Francis ofAssisi HospitalResearch CenterLaval University, Montreal, Quebec, Canada

Vincent J.Hearing, Jr.Laboratory ofCell BiologyNational Cancer InstituteNational Institutes ofHealthBethesda, Maryland

Gerald P. HolmquistDivision ofBiologyBeckman Research Institute of the City ofHopeDuane, California

James R. LupskiDepanments ofMolecular and HumanGenetics,Pediatrics and Human Genome CenterBaylor College of MedicineHouston, Texas, and Texas Children's HospitalHouston, Texas

Francesco RamirezBrookdale Center for Molecular BiologyMount Sinai School ofMedicineNew York, New York

Claude-Lise RicherDepanmentofAnatomyUniversity ofMontreal,Montreal, Quebec, Canada, andDepartment ofPathology and PediatricResearch CenterSaint Justine Hospital, Montreal, Quebec,Canada

Benjamin B. RcaDepartment ofMolecular and Human GeneticsBaylor College ofMedicineHouston, Texas

Lynn S. SakaiShriners Hospital forCrippled Childrenand Department ofBiochemistryand Molecular BiologyOregon Health Sciences UniversityPortland, Oregon

Richard A. SpritzDepartments ofMedical Genetics andPediatricsUniversity ofWisconsinMadison, Wisconsin

A Continuation Order Plan is available for this series . A continuation order will bring delivery ofeach new volume immediately upon publication. Volumes are billed only upon actual shipment.For further information please contact the publisher.

ADVANCES INHUMAN GENETICS

Edited by

Harry HarrisFormer Harnwel/ Professor ofHuman GeneticsLate of University ofPennsylvania, Philadelphia

and

Kurt HirschhornHerbert H. Lehman Professor and Chairman ofPediatricsMount Sinai School of Medicine of The City Univers ity of New York

22

Springer Science+Business Media, LLC

The Library of Congress catalogued the first volume of this title as follows:

Advances in human genetics. 1­New York, PLenum Press, 1970­

(1) v. iIIus. 24-cm.Editors: V. 1- H. Harris and K. Hirschhorn.

1. Human genetics-Collected works. I. Harris, Harry, ed. II. Hirschhorn, Kurt,1926- joint ed.

QH431 .A1A32 573.2'1 77-84583

ISBN 978-1-4757-9064-1 ISBN 978-1-4757-9062-7 (eBook)

DOI 10.1007/978-1-4757-9062-7

©1994 Springer Science+Business Media New YorkOriginally published by Plenum Press, New York in 1994.Softcover reprint of the hardcover Ist edition 1994

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted inany form or by any means, electronic, mechanical, photocopying, microfilming,recording, or otherwise, without written permission from the Publisher

HARRY HARRIS, M.D.

September 1919-July 1994

It is with great sadness that I note the passing of my dear friend and co-editor,Harry Harris, M.D. He, more than anyone in the field, was the ultimate symbolof Human Biochemical Genetics. His numerous contributions over the yearsdeveloped and clarified the concept of biochemical polymorphism to demonstrategenetic individuality and uniqueness of all human beings. His careful study of

biochemical variation included, as well , the clarification of a number of inbornerrors of metabolism. In that, he was the natural heir of Garrod , who was one of

his heroes.

I first met Harry when I was a Fellow in Human Genetics and visited him at theLondon Hospital where he had begun his work on electrophoresis andchromatography to demonstrate individual variation in enzymes. I spent twomagnificent Sabbaticals with him, the first at Kings College Medical School andthe second at the Galton Laboratory. These experiences allowed me to appreciate

Harry as one of the truly great minds in the field of Human Genetics .

This series, Advances in Human Genetics, was founded during a discussion withthe late Alan Liss, at that time the Vice President of Plenum Press, during aninformal conversation on a beach in Cape Cod. While Harry, always a skeptic,expressed doubts that we could fill even a single volume, the response of all in thefield led to the 110 contributions in the 22 volumes so far published. This current

volume is dedicated to his memory. It is in his memory that I will continue to workon additional volumes of the series, and I am most gratified that Robert J. Desnick,Ph.D., M.D., Chairman of the Department of Human Genetics at Mount SinaiSchool of Medicine, will join me as the new co-editor in this effort.

-KH

ARTICLES PLANNED FOR FUTURE VOLUMES

Biochemic al Defects in Immunodeficiency • Rochelle HirschhornAdvances in Prenatal Genetic Diagnosis. John C. Hobbins and Maurice J. MahoneyMalformation Syndromes Caused by Single Gene Defects • Judith G. HallGenetic Screening Using the Tay Sachs Model. Michael M. KabackGenetics of Hormone Receptors and Their Abnormalities • Jesse Roth and Simeon I. TaylorTheory and Practice of Gene Mapping, Including Multipoint Linkage Analysis «Eric S. LanderOrganization and Genet ics of Satellite DNA Families in the Human Genome.

Huntington F. WillardPrimary Sex Determination and Its Aberrations in Man • MalcolmA. Ferguson-SmithThe Molecular Genet ics of Polycystic Kidney Disease • Stephen T. ReedersTriplet Amplification • C. Thomas Caskey and Huda Zoghbi

CONTENTS OF EARLIER VOLUMES

VOLUME 1 (1970)Analysis of Pedigree Data • J. H. EdwardsAutoradiography in Human Cytogenetics • Orlando J. MillerGenetics of Immunoglobulins • H. Hugh Fudenberg and Noel E. Wam erHuman Genetics of Membrane Transport with Emphasis on Amino Acids •

Charles R. Scriver and Peter HechtmanGenetics of Disorders of Intestinal Digestion and Absorption • Jean Frezal and Jean Rey

VOLUME 2 (1971)Glucose-6-Phosophate Dehydrogenase • Henry N. KirkmanAlbinism • Carl J. Witkop. Jr.Acatalasemia • Hugo Aebi and Hedi SuterChromosomes and Abortion • D. H. CarrA Biochemical Genet ic View of Human Cell Culture • William J. Mellman

VOLUME 3 (1972)Prenatal Detection of Genetic Disorders • Henry I. NadlerGanglioside Storage Diseases. John S. 0 ' BrienInduced Chromosomal Aberrat ions in Man • Arthur D. BloomLinkage Analys is Using Somatic Cell Hybrids • Frank H. RuddleThe Structure and Function of Chromatin • David E. Comings

VOLUME 4 (1973)Genetic Screen ing • Harvey L LevyHuman Population Structure • Chris Cannings and L. Cavalli -SforzaStatus and Prospects of Research in Hereditary Deafness • Walter E. Nance and

Freeman E. McConnellCongenital Adrenal Hyperplasia • Maria I. New and Lenore S. LevineCytogenet ic Aspects of Human Male Meiosis • Maj Hulten and J. Lindsten

vii

viii Contents of Earlier Volumes

VOLUME 5 (1975)The Chondrodystrophies • David L RimoinNew Techniques in the Study of Human Chromosomes: Methods and Applicat ions •

Bernard Dutrillaux and Jerome LejeuneThe Thalassem ias: Models for Analysis of Quantitative Gene Control • David Kabat and

Robert D. KolerSpontaneous Mutation in Man • FriedrichVogeland RudigerRathenbergGenet ic Screening Legislation • Philip Reilly

VOLUME 6 (1976)Vitamin-Responsive Inherited Metabolic Disorders. Leon E. RosenbergInherited Deficiency of Hypoxanthine-Guanine Phosphoribosyltransferase in X-Linked Uric

Aciduria • J. Edwin SeegmillerHered itary Hemolytic Anemia Due to Enzyme Defects of Glycolysis • Sergio Piomelli and

Laurence CorashPopulation Structure of the Aland Islands, Finland • James H. Mielke, Peter L Workman.

Johan Fellman, and Aldur W. ErikssonPopulation Genetics amd Health Care Delivery : The Quebec Experience • Claude Laberge

VOLUME 7 (1976)Biochemical Genetics of Carbonic Anhydrase • RichardE. Tashian and Nicholas D. CarterHuman Behavior Genetics • Barton Childs, Joan M. Finucci, MalcolmS. Preston, and

Ann E. PulverMammalian X-Chromosome Inactivation • Stanley M. Gartlerand Robert J. AndinoGenetics of the Complement System • ChesterA. Alper and FredS. RosenSelective Systems in Somatic Cell Genetics • Ernest H. Y. Chu and SandraS. Powell

VOLUME 8 (1977)Genetics and Etiology of Human Cancer. Alfred G. Knudson, Jr.Population Genetics Theory in Relation to the Neutralist-Selectionist Controversy.

Warren J. EwensThe Human a-Amylases • A. Donald Merrit and Robert C. KamThe Genetic Aspects of Facial Abnormalities • Robert J. Gorlin and WilliamS. BoggsSome Facts and Fancies Relating to Chromosome Structure in Man • H. J. Evans

VOLUME 9 (1979)Chromosome and Neoplasia • David G. Harndenand A. M. R. TaylorTerminological, Diagnostic Nosological , and Anatomical-Developmental Aspects of

Developmental Defects in Man • John M. Opitz. JiirgenHerrmann, James C. Pettersen.Edward T. Bersu, and Sharon C. Colacino

Human Alphafetoprotein 1956-1978 • Matteo AdinolfiGenetic Mechanisms Contributing to the Expression of the Human Hemoglobin Loci •

William P. Winter. Samir M. Hanash, and Donald L RucknagelGenetic Aspects of Folate Metabolism • Richard W. Erbe

Contents of Earlier Volumes

VOLUME 10 (1980)Biochemi stry and Genetics of the ABO, Lewis, and P Blood Group Systems •

Winifred M. WatkinsHLA- A Central Immunological Agency of Man • D. Bernard Amos and D. D. KostyuLinkage Analysis in Man • P. Michael Conneally and Marian L RivasSister Chromatid Exchanges • Samuel A. Latt, Rhona R. Schreck. Kenneth S. Loveday,

Charlotte P. Dougherty, and Charles F. ShulerGenetic Disorders of Male Sexual Differentiation. Kaye R. Fichman, Barbara R. Mige on,

and Claude J. Migeon

VOLUME 11 (1981)The Pi Polymorphism: Genetic, Biochemical , and Clinical Aspects of Human a -Antitrypsin

• Magne K. Fagerhol and Diane Wilson CoxSegregation Analysis • R. C. ElstonGenetic, Metabolic, and Biochemical Aspects of the Prophyrias • Shigeru Sassa and

Attallah KappasThe Molecular Genetics of Thalassemia • Stuart H. Orkin and David G. NathanAdvances in the Treatment of Inherited Metabolic Diseases • Robert J. Desni ck and

Gregory A. Gravowski

VOLUME 12 ( 1982)Genetic Disorders of Collagen Metaboli sm • David W. Hollister, Peter H. Beyers. and

Karen A. HolbrookAdvances in Genetics in Dermatolog y • Howard P. Baden and Philip A. HookerHaptoglobin: The Evolut ionary Product of Duplication, Unequal Crossing over, and Point

Mutation • Barbara H. Bowman and Alexander KuroskyModels of Human Genetic Disease in Domestic Animals • D. F. Patterson, M. E. Haskins.

and P. F. JezykMapping the Human Genome, Cloned Genes, DNA Polymorphisms, and Inherited Disea.e •

Thomas B. Shows, Alan Y. Sakaguchi. and Susan L Naylor

ix

VOLUME 13 (1983)The Genetics of Blood Coagulation • John B. Graham, Emily S. Barrow. Howard M. Reisner.

and Cora -Jean S. EdgellMarker (Xj-Linked Mental Retardation • Gillian Turner and Patr icia JacobsHuman Antibody Genes: Evolutionary and Molecular Genetic Perspectives •

Jay W. Ellison and Leroy E. HoodMutations Affecting Trace Elements in Humans and Animals : A Genetic Approach to an

Understanding of Trace Elements. D. M. Danks and J. CamakarisPhenylketonuria and Its Variants • Seymour Kaufman

VOLUME 14 (1985)Cytogenetics of Pregnancy Wastage • Andre Boue, Alfred Gropp. and Joelle BoueMuMutation in Human Populations • James F. Crow and Carter DennistonGenetic Mutations Affecting Human Lipoprotein Metabolism • Vassili s I. Zanni s and

Jan L BreslowGlucose -6-Phosphate Dehydrogenase • L Luzzato and G. Banistut zi

x Contents of Earlier Volumes

Steroid Sulfatase Deficiency and the Genetics of the Short Arm of theHuman X Chromosome• Larry J. Shapiro

VOLUME 15 (1986)Chromosomal Abnormalities in Leukemia and Lymphoma: Clinical and Biological

Significance • Michelle M. Le BeauandJanet D. RowleyAn Algorithm for Comparing Two-Dimensional Electrophoretic Gels, with Particular

Reference to the Study of Mutation • MichaelM. SkolnickandJames V. NeelThe Human Argininosuccinate Synthetase Locus and Citrullinemia • Arthur L Beaudet.

William E. O'Brian. Hans-Georg O. Bock,Svend O. Freytag. andTsung-Sheng SuMolecular Genetics of the Human Histocompatibility Complex. CharlesAuffrayand

Jack L StromingerGenetics of Human Alcohol and Aldehyde Dehydrogenases • MoyraSmith

VOLUME 16 (1987)Genetics of Lactose Digest ion in Humans • GebhardFlat;Perspectives in the Teaching of Human Genetics • RonaldG. Davidsonand BartonChildsInvestigation of Genet ic Linkage in Human Families • Ray Whiteand Jean-MarkLalouelChronic Granulomatous Disease • John T. CurnutteandBernardM. BabiorGenetics of Steroid Receptors and Their Disorders • LeonardPinkskyand Morris Kaufman

VOLUME 17 (1988)Chorionic Villus Sampling • James D. Goldbergand MitchellS. GlobusThe Molecular Genetics of Hemophilia A and B in Man: Factor VIII and Factor IX Deficiency

• Stylianos E. AntonarakisCloning of the DuchennelBecker Muscular Dystrophy Locus • AnthonyP. Monaco and

Louis M. KunkelTrisomy 21: Molecular and Cytogenetic Studies of Nondisjunct ion • GordonD. Stewart,

Terry J. Hassold, and David M. KurnitMolecular Gentics of Human Salivary Proteins and Their Polymorph isms • EdwinA. Azen

and Nobuyo Maeda

VOLUME 18 (1989)The Molecular Basis of HLA-Disease Association • J. I. Bell. J. A. Todd. and H. O. McDevittChromosome Instability Syndromes • MaimonM. Cohenand HowardP. LevyLacticademia: Biochemical, Clinical and Genetic Considerations • BrianH. RobinsonA Comprehensive and Critical Assessment of Overgrowth and Overgrowth Syndromes •

M. Michael Cohen. Jr.Genetics of Growth Hormone and Its Disorders • John A. PhillipsIII and

CindyL Ynencak-Iones

VOLUME 19 (1990)The Lethal Osteochondrodysplasias • JurgenSprangerand PierreMaroteauxMutations in Type I Procollagen Genes that Cause Osteogenesis Imperfecta •

Darwin J. Prockop, ClintonT. Baldwin, and Constantinos D. ConstantinouStructural Defects in Inherited and Giant Platelet Disorders • James G. WhiteGenetic Aspects of Immunoglobulin A Deficiency • Charlotte Cunningham-RundlesOxidative Phosphorylation Diseases : Disorders of Two Genomes • JohnM. ShoffnerIV and

Douglas C. Wallace

Contents of Earlier Volumes

VOLUME 20 (1991)Clinical and Molecular Genetics of Congenital Adrenal Hyperplasia Due to 2 I-Hydroxylase

Deficiency • YvesMorel and WalterL. MillerGenetic Aspects of Amyloidosis • DanielR. Jacobsonand Joel N. BuxbaumHuntington's Disease. James F. GusellaBiochemical and Molecular Genetics of Cystic Fibrosis • Lap-CheeTsui and

Manuel BuchwaldMolecular Genetics of von ReckJinghausen Neurofibromatosis • MargaretR. Wallace and

Francis S. Collins

VOLUME 21 (1993)Peroxisomal Diseases • Hugo W. MoserX-Linked Immunodeficiencies • JenniferM. PuckGenetic Mutations Affecting Human Lipoprote ins, The ir Receptors, and Their Enzymes •

Vassilis I. Zannis, Dimitris Kardassis, and Eleni Economou ZanniGenet ic Aspects of Cancer • Audrey D. Goddardand EllenSolomonGaucher Disease : Enzymology, Genetics, and Treatment • GregoryA. Grabowski

xi

Preface to Volume 1

During the last few years the science of human genetics has been expanding almost

explosively. Original papers dealing with different aspects of the subject are

appearing at an increasingly rapid rate in a very wide range of journals, and it

becomes more and more difficult for the geneticist and virtually impossible for thenongeneticist to keep track of the developments. Furthermore , new observationsand discoveries relevant to an overall understanding of the subject result frominvestigations using very diverse techniques and methodologies and originatingin a variety of different disciplines. Thus, investigations in such various fields asenzymology, immunology, protein chemistry, cytology, pediatrics, neurology,

internal medicine, anthropology, and mathematical and statistical genetics, toname but a few, have each contributed results and ideas of general significanceto the study of human genetics. Not surprisingly it is often difficult for workersin one branch of the subject to assess and assimilate findings made in another. Thiscan be a serious limiting factor on the rate of progress.

Thus , there appears to be a real need for critical review which summarizes thepositions reached in different areas, and it is hoped that Advances in HumanGenetics will help to meet this requirement.

Each of the contributors has been asked to write an account of the positionthat has been reached in the investigations of a specific topic in one of the branchesof human genetics. The reviews are intended to be critical and to deal with thetopic in depth from the writer's own point of view. It is hoped that the articles willprovide workers in other branches of the subject, and in related disciplines, with adetailed account of the results so far obtained in the particular area , and helpthem to assess the relevance of these discoveries to aspects of their own work, as

well as to the science as a whole . The reviews are also intended to give the readersome idea of the nature of the technical and methodological problems involved,and to indicate new directions stemming from recent advances.

The contributors have not been restricted in the arrangement or organi zation

xiii

xlv Prefaceto Volume 1

of their material or in the manner of its presentation, so that the reader should beable to appreciate something of the individuality of approach which goes to makeup the subject of human genetics, and which, indeed, gives it much of itsfascination.

HARRY HARRIS

The Galton LaboratoryUniversity College London

KURT HIRSCHHORN

Division of Medical GeneticsDepartment of Pediatrics

Mount Sinai School of Medicine

Preface to Volume 10

This is the tenth volume of Advances in Human Genetics and some fifty different

reviews covering a very wide range of topics have now appeared. Many of theearlier articles still stand as valuable sources of reference . But the subjectcontinues to move forward at an increasing speed and its vitality is indicated by itsremarkable recruitment of young investigators. New areas of research which could

hardly have been envisaged only a few years ago have emerged, and quiteunexpectedly discoveries have been made in part s of the subject which onlyrecently had come to be thought as fully explored. So there continues to be a needfor authoritative and critical reviews intended to keep workers in the various

branches of this seemingly ever-expanding subject fully informed about theprogress that is being made and also , of course , to provide a ready and access ibleaccount of new developments in human geneti cs for those whose primary interestsare in other fields of biological and medical research .

We see no reason to alter the general policy which was outlined in the prefaceto the first volume . We believe that it has served our readers well. The subjec tseems to us to be just as exciting and intellectually stimulating and rewarding asit did when this series was first started. We expect the next decade of research inhuman genetics to be as innovative and productive as the last and our aim is to

record its progress in Advances in Human Genetics .

H ARRY H ARRIS

University of Pennsylvania, Philadelphia

K URT HIRSCHHORN

Mount Sinai School of Medicine of the CityUniversity of New York

xv

Contents

Chapter J

Genetic Disorders of Pigmentation

Richard A . Spritz and Vincent J. Hearing , Jr.

Introduction IThe Mammalian Pigmentary System 2

Disorders of Melanocyte Function 8Albinism 8Type I (Tyrosinase-Deficient) OCA (MIM #203100) 8

Type II (Tyrosinase-Positive) OCA (MIM #203200) 15Type IV (Brown) OCA (MIM #203290) . . . . . . . . . . . . . . . . . . . . . . . . 19X-linked Recessive Ocular Albinism , Nettleship-Falls Type (OA I ;

MIM #300500) 20Disorders of Melanocyte Development: Piebaldism and Waardenburg

Syndrome 21Piebaldi sm (MIM # 172800) 21Waardenburg Syndrome (MIM # 193500) 26

Other Cloned Gene s Affecting Pigmentation in the Mouse 29

Mottled . . . . . . . . . .. .. . . . . . . . .. . . .. . . . . . . . . . . . . . . . . . . . . . . . .. 30Pallid 30Pearl 31Microphthalmia 31Dilute 32Exten sion 32Agouti 32Slaty 33

xvii

xviii Contents

Silver 34References 34

Chapter 2

High-Resolution Replication Bands Compared with MorphologicG- and R-Bands

Regen Drouin, Gerald P. Holmquist, and Claude-Lise Richer

Introduct ion 47Arrest of DNA Replication by DNA Synthesis Inhibitors . . . . . . . . . . . . . 51BrdUrd Incorporation and S-Phase 53BrdUrd Detection 58

Fluorochrome-Photolysis-Giemsa Staining Technique . . . . . . . . . . . . . . 59BrdUrd Antibody-Binding (BAB) Technique . . . . . . . . . . . . . . . . . . . . . 68

Comparative Band Pattern Analysis 70Replication Band Patterns 70Replication Band Patterns versus Morphologic Band Patterns 73Juxtacentromeric Area . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 85C-band Area 85Telomeric Area 86Inactive X-Chromosome 87Homolog Discordance 88Lateral Asymmetry 90

RIG Transition and 3C Pause 92Quantification of R-, G- and C-band Chromatin . . . . . . . . . . . . . . . . . . . . 93Condensation and Replication: Two Interrelated Phenomena 95Features of R- and G-bands 99Conclusion 100Acknowledgments 101References 10I

Chapter 3

Molecular Genetics of Charcot-Marie-Tooth Neuropathy

Benjamin B. Roa and James R. Lupski

Introduction 117

Contents xix

Pathological Features I 18Charcot-Marie-Tooth Disease 118Inherited Primary Peripheral Neuropathies Related to CMT I 19

Genetic Heterogeneity of Charcot-Marie-Tooth Disease . . . . . . . . . . . . . . 120Gene Dosage as a Novel Mechanism for CMT Type IA 121

DNA Duplication as the Major Cause of CMTl A 121The Region Duplicated in CMTlA is Flanked by Large Regions of

Homology 122Evidence Supporting the Gene Dosage Model for CMTlA 124

The PMP22 Gene in Charcot-Marie-Tooth Disease and InheritedPrimary Peripheral Neuropathy 128

PMP22 and Charcot-Marie-Tooth Disease Type IA 128PMP22 and the Dejerine-Sottas Syndrome 129PMP22 and Hereditary Neuropathy with Liability to Pressure Palsies 129

Genes Associated with Other Forms of CMT 132The Myelin Protein Zero (MPZ) Gene and CMTl B . . . . . . . . . . . . . . . 132MPZ and Dejerine-Sottas Syndrome 133The Cx32 Gene and X-linked CMT . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133

Implications of CMT Studies on Peripheral Nerve Biology 133Genetic Diagnosis for CMT and Associated Neuropathies 135

Detection of the CMTl A Duplication 135Mutation Analysis of Genes Associated with CMT 138

Molecular Insights Related to the CMT IA Duplication 139CMTlA Duplication and HNPP Deletion at the 17pl1.2pl2 Region 139Homologous Recombination in Model Systems 140DNA Rearrangements Associated with Disease Phenotypes 141

Conclusions 143Acknowledgments 145References 145

Chapter 4

Marfan's Syndrome and Other Microfibrillar Diseases

Harry C. Dietz, Francesco Ramirez , and Lynn Y. Sakai

Introduction 153Elastic Fibers and Microfibrils 154

Organization and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

xx Contents

Composition 157Fibrillins 161

Protein Structure 161Gene Structure 166Microfibrillar Assembly 166

Marfan's Syndrome 168Clinical Features 168Clinical Management 172Fibrillin Mutations 173Intrafamilial Variability 178

Marfan-Like Conditions 180Conclusions and Future Prospectives 181Acknowledgments 182References 182

Chapter 5

Nonisotopic in Situ HybridizationClinical Cytogenetics and Gene Mapping Applications

Matteo Adinolfi and John Crolla

Introduction 187The Probes 190Detection by NISH of Chromosomal Disorders in Metaphase Spreads . . 194

Translocations and Isochromosomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195Marker Chromosomes 198Deletions and Duplications 204

Detection by NISH of Chromosomal Abnormalities in Cells inInterphase 215

Prenatal Tests on Cells in Interphase by NISH 215Detection of Mosaicism 221Radiation Induced Chromosomal Damage . . . . . . . . . . . . . . . . . . . . . . . 222Somatic Pairing 223

NISH and the Mapping of the Human Genome 223Metaphase Mapping 224Interphase Mapping 227

Cancer and NISH Analysis of Chromosomal Defects . . . . . . . . . . . . . . . . 228Evolution 232

Contents xxi

Conclusions 234Acknowledgments 235

References 235

Index 257

ADVANCES IN 22HUMAN GENETICS