Emery & Rimoin's Principles and Practice of Medical Genetics

For decades, __Emery & Rimoin’s Principles and Practice of Medical Genetics__ has provided the ultimate source for practicing clinicians to learn how the study of genetics can be integrated into practice. With advances in high-throughput technologies propelling the closer integration of lab and clinical work, this sixth edition bridges the gap between high-level molecular genetics and individual application. This comprehensive yet practical resource emphasizes theory and research fundamentals related to applications of medical genetics across the full spectrum of inherited disorders. Clinically oriented information is supported by expanded sections on basic principles of genetics, research approaches, and analytics to embrace the evolving population of students, researchers, and practitioners who are integrating their work to provide advanced diagnosis, prevention and treatment of human disease. Over 250 of the world's most trusted authorities in medical genetics will contribute to the new release of the revised electronic edition of the work. Regular updates and the integration of teaching tools such as videos and graphics will distinguish this work from the competition. Links to sites such as Online Mendelian Inheritance in Man (OMIM) and similar sites which provide up-to-date information on human genes and genetic phenotypes will make this product the ultimate source for students, researchers, and practitioners alike. * Features new contributions that encompass advances in cancer genetics, genomic technologies, and molecular genetics * Offers online image banks and animations which represent valuable resources for identification, concept illustration, and method processing serving the needs of students, professors, and instructors * Provides many hundreds of medline and full-text cross-references guide the reader in identifying related topics of which they may not have been aware PREFACE......Page 3 FOREWORD......Page 5 PERSONAL MEMORIES OF DAVID RIMOIN......Page 7 Basic Principles......Page 9 1.2 INTRODUCTION......Page 11 1.3 FOUNDATIONS OF MEDICAL GENETICS BEFORE 1956......Page 12 1.4 GROWTH AND DEVELOPMENT OF MEDICAL GENETICS: 1956 TO THE PRESENT......Page 18 1.5 THE FUTURE......Page 38 1.6 ADDENDUM (PSH)......Page 39 1.7 A TIMELINE FOR MEDICAL GENETICS......Page 41 REFERENCES......Page 45 FURTHER READING......Page 48 2.1 INTRODUCTION......Page 50 2.2 THE PRINCIPLES OF DISEASE......Page 51 2.3 DEFINING DISEASE......Page 52 2.4 THE HOW QUESTIONS......Page 53 2.6 THE WHY QUESTIONS......Page 58 2.7 PREVENTION AND TREATMENT......Page 61 2.8 CONCLUSION......Page 63 REFERENCES......Page 64 3.2 FREQUENCY OF GENETIC DISEASE......Page 67 3.3 MORBIDITY AND MORTALITY DUE TO GENETIC DISEASE......Page 69 REFERENCES......Page 70 4.2 GENOMICS......Page 71 4.3 MAPPING THE HUMAN GENOME......Page 72 4.5 CURRENT APPORACHES TO SEQUENCE PARTS OR THE WHOLE HUMAN GENOME......Page 74 4.6 AN APPROACH FOR CLONING HUMAN DISEASE GENES......Page 76 4.7 SEQUENCE-BASED METHODS FOR DETECTING CHROMOSOMAL ABNORMALITIES......Page 77 4.8 PROTEOMICS......Page 78 REFERENCES......Page 79 5.2 DOUBLE HELIX STRUCTURE, DNA REPLICATION, TRANSCRIPTION, AND MEIOTIC RECOMBINATION......Page 81 5.3 ORGANIZATION OF GENOMIC DNA......Page 83 5.4 GENE STRUCTURE AND THE MOLECULAR PATHWAY OF GENE EXPRESSION......Page 86 REFERENCES......Page 95 6.2 EPIGENETIC MECHANISMS: CHROMATIN, DNA METHYLATION AND LONG NONCODING RNAs......Page 97 6.3 EPIGENETIC REPROGRAMMING......Page 100 6.4 EPIGENETIC REGULATION OF X INACTIVATION......Page 101 6.5 GENOMIC IMPRINTING......Page 103 6.6 GENETIC DISORDERS DUE TO GENES AFFECTING CHROMATIN STRUCTURE......Page 109 6.8 CANCER EPIGENETICS......Page 112 6.10 ABNORMALITIES IN EPIGENETIC PROGRAMMING LINKED TO INFERTILITY AND ASSISTED REPRODUCTION......Page 114 6.12 GENETIC–EPIGENETIC INTERACTIONS......Page 115 REFERENCES......Page 116 WEBSITES......Page 125 7.1 INTRODUCTION......Page 129 7.2 MOLECULAR MECHANISMS OF MUTATION CAUSING HUMAN INHERITED DISEASE......Page 130 7.3 DISEASE-CAUSING MUTATIONS......Page 132 7.4 CONSEQUENCES OF MUTATIONS......Page 149 7.5 GENERAL PRINCIPLES OF GENOTYPE–PHENOTYPE CORRELATIONS......Page 164 7.6 WHY STUDY MUTATION?......Page 165 REFERENCES......Page 166 FURTHER READING......Page 175 8.2 PEDIGREE CONSTRUCTION......Page 177 8.3 UNIFACTORIAL INHERITANCE/ SINGLE-GENE DISORDERS......Page 178 8.4 DOMINANCE AND RECESSIVENESS......Page 179 8.5 AUTOSOMAL-DOMINANT INHERITANCE......Page 181 8.6 AUTOSOMAL RECESSIVE INHERITANCE......Page 183 8.8 X-LINKED RECESSIVE INHERITANCE......Page 186 8.9 X-LINKED DOMINANT INHERITANCE......Page 188 8.11 PARTIAL SEX LINKAGE......Page 189 REFERENCES......Page 193 9.1 INTRODUCTION TO LINKAGE ANALYSIS......Page 195 9.2 LINKAGE ANALYSIS: BASIC CONCEPTS......Page 196 9.3 EXTENDING PARAMETRIC LINKAGE ANALYSIS......Page 199 9.4 LINKAGE ANALYSIS FOR COMPLEX AND QUANTITATIVE TRAITS......Page 200 9.5 LINKAGE ANALYSIS: FUTURE DIRECTIONS......Page 201 FURTHER READING......Page 202 10.2 CHROMOSOME STRUCTURE......Page 204 10.3 CHROMOSOMES IN CELL DIVISION......Page 206 10.4 METHODS FOR STUDYING HUMAN CHROMOSOMES......Page 210 10.5 FUNCTIONAL ORGANIZATION OF CHROMOSOMES......Page 217 10.6 SEX CHROMOSOMES AND SEX DETERMINATION......Page 220 10.7 UNIPARENTAL DISOMY AND IMPRINTING......Page 222 10.8 CHROMOSOME ABNORMALITIES......Page 223 GLOSSARY......Page 225 REFERENCES......Page 226 ABBREVIATIONS......Page 230 11.1 MITOCHONDRIAL BIOLOGY AND GENETICS......Page 232 11.2 INHERITED NDNA MITOCHONDRIAL DISEASES......Page 293 11.3 MITOCHONDRIAL ETIOLOGY FOR COMMON METABOLIC AND VISCERAL DISEASES......Page 303 11.4 MITOCHONDRIAL ETIOLOGY FOR NEURODEGENERATIVE DISEASES......Page 305 11.5 MITOCHONDRIAL DEFECTS IN CANCER......Page 319 11.6 THERAPEUTIC APPROACHES TO MITOCHONDRIAL DISEASE......Page 322 11.7 A MITOCHONDRIAL PARADIGM FOR COMPLEX DISEASE......Page 327 REFERENCES......Page 329 FURTHER READING......Page 381 12.2 DEFINITIONS AND TERMINOLOGY......Page 383 12.3 DETERMINING THE GENETIC COMPONENT OF A TRAIT......Page 385 12.5 GENOME-WIDE ASSOCIATION STUDIES......Page 389 12.6 ASSOCIATION METHODS/ STATISTICAL ANALYSIS......Page 391 12.7 ANALYSIS OF RARE VARIANTS USING NEW TECHNOLOGIES......Page 392 REFERENCES......Page 393 13.2 HARDY–WEINBERG LAW......Page 398 13.3 FACTORS THAT AFFECT HARDY– WEINBERG EQUILIBRIUM......Page 402 13.4 APPLICATIONS IN POPULATION GENETICS......Page 407 FURTHER READING......Page 409 14.1 INTRODUCTION......Page 410 14.3 PHYSIOLOGIC HOMEOSTASIS......Page 411 14.5 ONTOGENESIS OF ANATOMIC STRUCTURES: ANGULAR HOMEOSTASIS......Page 413 14.6 PATHOGENETICS OF REFINED TRAITS......Page 415 14.7 PATHWAYS AND MULTIPLE-STAGE PROCESSES......Page 416 14.8 MOLECULAR PATHOGENETICS......Page 418 14.9 CONCLUSIONS......Page 420 REFERENCES......Page 421 15.1 INTRODUCTION AND OVERVIEW......Page 423 15.3 THE CONCEPT OF DEVELOPMENTAL FIELDS AND FIELD DEFECTS......Page 424 15.4 CELLULAR SIGNALING IN DEVELOPMENT: THE CONCEPTS OF INDUCTION AND COMPETENCE......Page 426 15.6 STEPS AND CONCEPTS IN EMBRYONIC DEVELOPMENT......Page 428 15.7 REGULATION OF GENE EXPRESSION IN DEVELOPMENT......Page 439 15.8 DEVELOPMENTAL GENE PATHWAYS AND FAMILIES......Page 448 15.9 ORGANOGENESIS......Page 458 REFERENCES......Page 475 16.2 DETERMINING ZYGOSITY......Page 486 16.6 TWINS IN GENETIC STUDIES......Page 487 16.7 DIZYGOTIC TWINS......Page 488 16.8 MONOZYGOTIC TWINS......Page 490 REFERENCES......Page 495 17.1 INTRODUCTION......Page 506 17.2 A GENETIC BASIS OF CANCER......Page 507 17.3 VIRAL ONCOGENES......Page 508 17.4 ONCOGENIC ALLELES IN HUMAN CANCERS......Page 509 17.5 TUMOR SUPPRESSOR GENES......Page 515 17.6 THE ROLE OF DNA DAMAGE REPAIR GENES IN INHERITED CANCER SYNDROMES......Page 533 REFERENCES......Page 544 18.2 WHAT IS AGING?......Page 550 18.3 WHY DO WE AGE?......Page 553 18.4 HOW DO WE AGE?......Page 557 18.5 PROGEROID SYNDROMES OF HUMANS......Page 560 REFERENCES......Page 563 19.1 INTRODUCTION......Page 569 19.2 FUNDAMENTAL ASPECTS OF CLINICAL PHARMACOLOGY......Page 570 19.3 CLASSICAL GENETICS AND PHARMACOGENETICS: 1900 TO APPROXIMATELY 1990......Page 572 19.4 ETHNIC DIFFERENCES IN GENE–DRUG INTERACTIONS......Page 577 19.5 PHARMACOGENOMICS......Page 578 REFERENCES......Page 588 FURTHER READING......Page 594 General Principles......Page 596 20.1 BACKGROUND......Page 598 20.2 THE PROCESS OF GENETIC EVALUATION FOR COMMON DISEASES......Page 599 20.3 INTEGRATING GENETIC INFORMATION INTO ROUTINE CLINICAL PRACTICE......Page 606 REFERENCES......Page 607 21.1 WHAT IS GENETIC COUNSELING?......Page 611 21.2 PROCESS OF GENETIC COUNSELING......Page 615 21.3 ADULT-ONSET DISORDERS......Page 634 21.4 GENETIC RISK ASSESSMENT AND CALCULATION IN THE CLINICAL SETTING......Page 639 REFERENCES......Page 647 FURTHER READING......Page 650 22.2 MILESTONES IN HUMAN CYTOGENETICS......Page 651 22.5 CHROMOSOME BANDING......Page 654 22.6 THE NORMAL HUMAN KARYOTYPE......Page 655 22.7 CHROMOSOME ABNORMALITIES......Page 656 22.8 IN SITU HYBRIDIZATION......Page 657 REFERENCES......Page 665 FURTHER READING......Page 667 23.2 INDICATIONS FOR MOLECULAR GENETIC TESTING......Page 669 23.3 TECHNICAL APPROACHES TO MOLECULAR GENETIC TESTING......Page 671 23.4 MOLECULAR GENETIC DIAGNOSIS OF PARTICULAR DISEASES......Page 676 23.5 MITOCHONDRIAL DNA DISORDERS......Page 689 23.6 OTHER TARGETS OF MOLECULAR GENETIC SCREENING......Page 690 23.8 QUALITY ASSURANCE, REIMBURSEMENT, AND REGULATORY ISSUES......Page 691 23.9 INTERNET RESOURCES FOR MOLECULAR GENETIC TESTING......Page 692 23.10 SOCIETAL IMPACT OF THE NEW GENETIC TECHNOLOGY......Page 693 REFERENCES......Page 695 24.2 CARRIER SCREENING IN CLINICAL PRACTICE......Page 700 24.3 CARRIER SCREENING IN INDIVIDUALS OF DEFINED SUBPOPULATION GROUPS......Page 701 24.5 METHODS AND TISSUES USED IN CARRIER IDENTIFICATION......Page 703 24.6 PROBLEMS IN HETEROZYGOTE DETECTION......Page 704 24.7 SENSITIVITY AND SPECIFICITY......Page 706 24.10 CONCLUSIONS......Page 707 REFERENCES......Page 708 25.2 NEURAL TUBE DEFECTS......Page 710 25.3 ANEUPLOIDY......Page 714 25.4 SUMMARY......Page 722 REFERENCES......Page 723 26.2 AMNIOCENTESIS......Page 733 26.3 CHORIONIC VILLUS SAMPLING......Page 739 26.4 FETAL BLOOD SAMPLING......Page 744 26.5 FETAL TISSUE SAMPLING......Page 745 26.6 COELOCENTESIS......Page 746 26.9 PREIMPLANTATION GENETIC DIAGNOSIS......Page 747 26.10 ULTRASONOGRAPHY......Page 748 26.11 FETAL CELLS AND FETAL DNA IN MATERNAL BLOOD......Page 751 REFERENCES......Page 752 27.2 HISTORICAL ASPECTS......Page 761 27.3 COMPONENTS OF SCREENING PROGRAMS......Page 762 27.4 POTENTIAL PROBLEMS IN NEWBORN SCREENING......Page 766 27.5 DISORDERS AND CONDITIONS DETECTED BY NEWBORN BLOOD SCREENING......Page 768 27.6 OTHER NEWBORN SCREENING......Page 773 27.7 ISSUES AND CONCERNS IN SCREENING......Page 775 GLOSSARY......Page 776 REFERENCES......Page 777 FURTHER READING......Page 780 28.1 INTRODUCTION......Page 782 28.2 ERT FOR LYSOSOMAL STORAGE DISEASES......Page 784 28.3 SUBSTRATE REDUCTION THERAPY......Page 794 28.4 PHARMACOLOGIC CHAPERONE THERAPY......Page 796 28.5 CONCLUSIONS AND FUTURE DIRECTIONS......Page 803 REFERENCES......Page 804 RELEVANT WEBSITES......Page 809 29.1 GENES AS MEDICINES— THE ORIGINS OF GENE THERAPY......Page 812 29.2 THE BASIC SCIENCE: GENE TRANSFER (TABLES 29-1–29-3)......Page 813 29.3 DEVELOPING CELL-TYPE-SPECIFIC AND REGULATABLE GENE DELIVERY VECTORS......Page 823 29.4 THE CLINICAL SCIENCE: TOWARD GENE THERAPY OF HUMAN DISEASE......Page 826 29.5 CODA......Page 835 REFERENCES......Page 836 30.1 INTRODUCTION......Page 844 30.3 GENETIC COUNSELING, TESTING AND SCREENING......Page 845 30.4 GOALS AND OUTCOMES OF GENETIC SERVICES......Page 846 30.5 NONDIRECTIVENESS IN GENETIC COUNSELING......Page 848 30.6 DIAGNOSTIC GENETIC TESTING......Page 849 30.7 PREDICTIVE GENETIC TESTING......Page 852 30.8 CONFIDENTIALITY......Page 853 30.9 GENETIC TESTING IN CHILDHOOD......Page 855 30.10 POPULATION GENETIC SCREENING......Page 857 30.11 NEWBORN SCREENING......Page 858 30.12 ANTENATAL SCREENING......Page 860 30.13 CARRIER SCREENING......Page 865 30.14 OTHER CHALLENGES IN GENETIC COUNSELING......Page 866 30.15 RESEARCH IN HUMAN GENETICS......Page 871 30.16 GENETICS, GENETICIZATION AND SOCIETY......Page 874 30.17 REPRODUCTIVE TECHNOLOGIES AND CLONING: “REPROGENETICS”......Page 876 REFERENCES......Page 878 WEBSITES......Page 882 31.1 INTRODUCTION......Page 884 31.2 GENETIC MALPRACTICE AND THE DUTY TO WARN......Page 885 31.3 GENETIC COUNSELING......Page 886 31.4 ABORTION......Page 887 31.6 SURROGACY......Page 888 31.7 FROZEN EMBRYOS......Page 889 31.8 NEWBORN SCREENING......Page 890 31.10 GENETIC DISCRIMINATION......Page 891 31.12 DIRECT TO CONSUMER GENETIC TESTING......Page 892 31.13 REGULATION OF HUMAN GENETIC RESEARCH......Page 893 31.15 GENES AND PATENTS......Page 894 31.16 THE ORPHAN DRUG ACT......Page 895 REFERENCES......Page 896 RELEVANT WEBSITES......Page 897 Applications to Clinical Problems......Page 899 32.2 THE DIAGNOSIS OF HYPOGONADISM......Page 901 32.6 HYPOGONADOTROPIC HYPOGONADISM......Page 903 32.7 HYPERGONADOTROPIC HYPOGONADISM......Page 911 REFERENCES......Page 919 33.1 MALE INFERTILITY— INTRODUCTION......Page 925 33.2 CHROMOSOME ANOMALIES......Page 926 33.3 GENE DEFECTS INVOLVED IN ENDOCRINE FORMS OF INFERTILITY......Page 930 33.4 MONOGENIC DEFECTS IN POSTTESTICULAR AND PRIMARY TESTICULAR FORMS OF MALE INFERTILITY......Page 935 33.5 SYNDROMIC MONOGENIC DEFECTS......Page 937 REFERENCES......Page 938 34.2 DEFINITION OF TERMS......Page 943 34.3 EARLY PREGNANCY LOSS......Page 944 34.4 LATE PREGNANCY LOSS......Page 954 34.6 CONCLUSIONS......Page 956 REFERENCES......Page 957 RELEVANT WEB SITES......Page 963 35.2 PRENATAL VERSUS POSTNATAL ONSET OF DEVELOPMENTAL PROBLEMS......Page 964 35.3 PRENATAL-ONSET PROBLEMS IN DEVELOPMENT......Page 966 35.5 CONCLUSION......Page 973 REFERENCES......Page 974 36.1 INTRODUCTION......Page 976 36.2 EVALUATING THE PATIENT AND HER EXPOSURE......Page 981 36.3 RECOGNIZED TERATOGENIC EXPOSURES......Page 984 36.5 CONCLUSION......Page 1003 REFERENCES......Page 1004 37.2 GLOBAL DEVELOPMENTAL DELAY......Page 1015 37.3 DEFINITION OF A DIAGNOSIS......Page 1016 37.5 DIAGNOSTIC TESTING OF PATIENTS WITH ID OF UNKNOWN CAUSE......Page 1017 REFERENCES......Page 1026 38.2 PATHOLOGIC SHORT STATURE......Page 1030 38.3 PATHOLOGIC OVERGROWTH......Page 1041 REFERENCES......Page 1049 RELEVANT WEB PAGES......Page 1053 39.1 INTRODUCTION......Page 1055 39.3 GENOME-WIDE ASSOCIATION STUDIES AND HUMAN INFECTION......Page 1056 39.4 CELL SURFACE PROTEINS......Page 1057 39.5 INTRACELLULAR PROTEINS......Page 1064 39.6 EXTRACELLULAR PROTEINS......Page 1066 39.7 CONCLUSION......Page 1070 REFERENCES......Page 1071 40.1 INTRODUCTION......Page 1079 40.2 THE PHYSIOLOGIC FUNCTION OF MHC MOLECULES......Page 1081 40.3 THE STRUCTURE OF HUMAN HISTOCOMPATIBILITY MOLECULES......Page 1082 40.4 THE CHROMOSOMAL ORGANIZATION OF THE HLA COMPLEX......Page 1083 40.5 MINOR HISTOCOMPATIBILITY SYSTEMS......Page 1087 40.6 SEROLOGIC METHODS FOR HLA TYPING......Page 1089 40.7 CELLULAR METHODS FOR HLA TYPING......Page 1091 40.8 MOLECULAR METHODS FOR HLA TYPING......Page 1092 40.9 CLINICAL SIGNIFICANCE OF HLA MOLECULAR TYPING......Page 1097 40.10 GENETICS OF XENOTRANSPLANTATION......Page 1100 40.11 STEM CELLS AND TRANSPLANTATION......Page 1102 40.12 CONCLUSION......Page 1103 REFERENCES......Page 1104 LIST OF USEFUL WEBSITES......Page 1110 41.1 INTRODUCTION......Page 1112 41.2 RESPIRATORY DISTRESS SYNDROME......Page 1113 41.3 BRONCHOPULMONARY DYSPLASIA......Page 1118 41.4 PATENT DUCTUS ARTERIOSUS......Page 1121 41.5 INTRAVENTRICULAR HEMORRHAGE......Page 1122 41.6 RETINOPATHY OF PREMATURITY......Page 1124 41.7 NECROTIZING ENTEROCOLITIS......Page 1126 REFERENCES......Page 1128 42.2 DISORDERS OF NUCLEOTIDE EXCISION REPAIR: XERODERMA PIGMENTOSUM AND COCKAYNE SYNDROME......Page 1134 42.4 DISORDERS OF MISMATCH REPAIR: LYNCH SYNDROME AND TURCOT SYNDROME......Page 1136 42.5 DISORDERS ASSOCIATED WITH DOUBLE STRAND BREAK RECOGNITION AND REPAIR: ATAXIA-TELANGIECTASIA AND RELATED CONDITIONS......Page 1138 42.6 CROSSLINK REPAIR AND HOMOLOGOUS RECOMBINATION DEFECTS: BREAST–OVARIAN CANCER AND FANCONI ANEMIA......Page 1141 42.7 DISORDERS ASSOCIATED WITH RECQ HELICASE DEFICIENCY: BLOOM, WERNER, AND ROTHMUND–THOMSON SYNDROMES......Page 1144 42.8 GENE–ENVIRONMENT INTERACTIONS: GORLIN–GOLTZ SYNDROME......Page 1146 REFERENCES......Page 1147 Applications to Specific Disorders......Page 1150 Chromosomal Disorders......Page 1152 43.2 GENETIC COUNSELING IN THE TRISOMIES......Page 1154 43.3 DOWN SYNDROME (TRISOMY 21)......Page 1155 43.4 TRISOMY 18......Page 1167 43.5 TRISOMY 13......Page 1170 REFERENCES......Page 1173 44.1 INTRODUCTION......Page 1181 44.2 THE EPIDEMIOLOGY OF SEX-CHROMOSOME ABNORMALITIES......Page 1182 44.3 TURNER SYNDROME......Page 1183 44.4 KLINEFELTER SYNDROME......Page 1190 44.5 47,XXX SYNDROME......Page 1195 44.7 SEX CHROMOSOME TETRASOMY AND PENTASOMY (POLYSOMY)......Page 1196 44.8 47,XYY KARYOTYPE......Page 1197 44.9 STRUCTURAL ABNORMALITIES OF THE Y CHROMOSOME......Page 1199 44.10 PRENATAL DIAGNOSIS OF SEX CHROMOSOME ABNORMALITIES......Page 1201 REFERENCES......Page 1203 CROSS REFERENCES......Page 1212 45.1 INTRODUCTION......Page 1213 45.2 TRANSLOCATIONS......Page 1216 45.4 DELETION......Page 1219 45.5 DUPLICATION......Page 1232 REFERENCES......Page 1236 Cardiovascular Disorders......Page 1250 46.2 THE EVALUATION OF THE PATIENT WITH CONGENITAL HEART DEFECT......Page 1252 46.3 SPECIFIC SYNDROMES WITH CONGENITAL HEART DEFECT......Page 1260 46.4 CHROMOSOMAL DISORDERS......Page 1261 46.5 MICRODELETIONS/ MICRODUPLICATION SYNDROMES......Page 1262 46.6 SINGLE-GENE DISORDERS......Page 1264 46.8 CHARGE SYNDROME......Page 1265 46.10 SMITH–LEMLI–OPITZ SYNDROME......Page 1266 46.13 MATERNAL DRUG INGESTION......Page 1268 46.14 FOLIC ACID SUPPLEMENTATION......Page 1269 46.16 EMPIRICAL RISKS FOR OFFSPRING......Page 1270 APPENDIX......Page 1273 REFERENCES......Page 1297 WEBSITES......Page 1301 47.2 HYPERTROPHIC CARDIOMYOPATHY......Page 1303 47.3 DILATED CARDIOMYOPATHY......Page 1319 47.4 ATYPICAL CARDIOMYOPATHIES......Page 1326 REFERENCES......Page 1330 RELEVANT WEBSITES......Page 1339 48.1 HISTORICAL PERSPECTIVES AND INTRODUCTION......Page 1341 48.4 PHENOTYPE AND NATURAL HISTORY OF HPAH AND IPAH......Page 1342 48.5 INHERITANCE AND GENETICS OF PAH IN FAMILIES......Page 1343 TO PAH......Page 1346 48.7 MOLECULAR AND CELLULAR PATHOGENESIS......Page 1348 48.8 DIAGNOSIS......Page 1350 48.9 MANAGEMENT......Page 1351 48.10 COUNSELING......Page 1354 REFERENCES......Page 1355 RELEVANT WEBSITES......Page 1359 49.1 INTRODUCTION......Page 1361 49.2 PHENOTYPE AND NATURAL HISTORY......Page 1362 49.3 ETIOLOGY......Page 1367 49.4 PATHOGENESIS......Page 1368 49.5 DIAGNOSIS......Page 1369 49.6 MANAGEMENT......Page 1370 REFERENCES......Page 1374 50.1 DEVELOPMENT OF THE LYMPHATIC SYSTEM......Page 1379 50.2 DISORDERS OF THE LYMPHATIC SYSTEM......Page 1380 50.3 MENDELIAN DISORDERS AFFECTING BOTH THE LYMPHATIC AND VENOUS SYSTEM......Page 1383 50.4 VARICOSE VEINS......Page 1384 REFERENCES......Page 1385 CROSS REFERENCES......Page 1386 51.3 PRIMARY ABNORMALITIES IN CARDIAC RHYTHM: VENTRICULAR TACHYDYSRHYTHMIAS......Page 1387 51.4 PRIMARY ABNORMALITIES IN CARDIAC RHYTHM: SUPRAVENTRICULAR DYSRHYTHMIAS......Page 1402 51.5 PRIMARY CONDUCTION ABNORMALITIES......Page 1404 51.6 FAMILIAL DYSRHYTHMIAS ASSOCIATED WITH MYOCARDIAL DISEASE......Page 1406 51.7 NEUROLOGIC DISORDERS ASSOCIATED WITH DYSRHYTHMIAS AND CONDUCTION DISEASE......Page 1418 51.8 CONGENITAL HEART DISEASE AND DYSRHYTHMIAS OR CONDUCTION DISEASE......Page 1427 REFERENCES......Page 1429 FURTHER READING......Page 1447 52.1 INTRODUCTION......Page 1449 52.2 MENDELIAN FORMS OF HYPERTENSION......Page 1451 52.3 CANDIDATE GENES......Page 1453 52.4 GENOME-WIDE ASSOCIATION STUDIES......Page 1460 REFERENCES......Page 1462 53.2 CLASSIFICATION......Page 1471 53.3 PATHOLOGIC AND MOLECULAR BASIS......Page 1474 53.4 GENETIC BASIS OF PREECLAMPSIA......Page 1478 53.5 ANIMAL MODELS......Page 1479 REFERENCES......Page 1480 RELEVANT WEB PAGES......Page 1484 54.1 INTRODUCTION......Page 1485 54.2 GENETIC VARIANTS INFLUENCING COMPONENTS OF THE COAGULATION CASCADE......Page 1487 54.3 GENETIC VARIANTS INFLUENCING NATURAL ANTICOAGULANTS......Page 1491 54.5 GENETIC VARIANTS INFLUENCING PLATELET FUNCTION......Page 1493 54.6 GENOME-WIDE ASSOCIATION ANALYSIS FOR THROMBOSIS......Page 1494 54.7 HOW DO WE ACCOUNT FOR THE MISSING HERITABILITY?......Page 1495 REFERENCES......Page 1497 55.1 INTRODUCTION......Page 1505 55.2 CHALLENGES TO GENETIC STUDIES OF CHD......Page 1506 55.3 MOUSE MODELS OF ATHEROSCLEROSIS......Page 1507 55.4 CANDIDATE GENE STUDIES IN HUMANS......Page 1510 55.5 GENOME WIDE ASSOCIATION STUDIES......Page 1515 55.6 GWAS FINDINGS FOR CVD RISK FACTORS......Page 1520 55.7 GENETIC RISK SCORES AND PREDICTION ALGORITHMS FOR PERSONALIZED MEDICINE......Page 1524 55.8 SUMMARY AND FUTURE DIRECTIONS......Page 1525 REFERENCES......Page 1526 FURTHER READING......Page 1540 56.2 THE VENOUS SYSTEM......Page 1542 56.3 DISORDERS OF THE VENOUS SYSTEM......Page 1543 56.4 CONCLUSION......Page 1546 REFERENCES......Page 1547 RELEVANT WEBSITES......Page 1549 57.2 CAPILLARY MALFORMATION......Page 1551 57.3 STURGE–WEBER SYNDROME......Page 1552 57.4 CAPILLARY MALFORMATION– ARTERIOVENOUS MALFORMATION......Page 1553 57.5 CEREBRAL CAVERNOUS MALFORMATION......Page 1554 REFERENCES......Page 1555 RELEVANT WEBSITES......Page 1556 Respiratory Disorders......Page 1558 58.1 INCIDENCE OF CYSTIC FIBROSIS......Page 1560 58.2 CLINICAL FEATURES......Page 1562 58.3 GENETICS......Page 1566 58.4 DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS......Page 1581 58.5 MANAGEMENT......Page 1584 REFERENCES......Page 1588 59.1 INTRODUCTION......Page 1614 59.2 THE GENETICS OF ASTHMA AND ALLERGIC DISEASES......Page 1616 REFERENCES......Page 1624 RELEVANT WEB PAGES......Page 1629 60.2 DISEASES WITH AIRFLOW LIMITATION: DEFINITIONS......Page 1631 60.3 PHENOTYPIC EVALUATION IN COPD......Page 1632 60.4 CIGARETTE SMOKING AND COPD......Page 1636 60.5 SEVERE AAT DEFICIENCY......Page 1637 60.6 RISK OF COPD IN Z ALLELE HETEROZYGOTES......Page 1646 60.7 COPD AND COPD-RELATED PHENOTYPES IN OTHER GENETIC SYNDROMES......Page 1647 60.8 RISK TO RELATIVES FOR NON-AAT COPD......Page 1648 60.10 LINKAGE ANALYSIS......Page 1650 60.11 GENETIC ASSOCIATION STUDIES......Page 1651 60.12 ANIMAL MODELS OF COPD......Page 1653 REFERENCES......Page 1654 RELEVANT WEBSITES......Page 1662 61.2 IDIOPATHIC INTERSTITIAL PNEUMONIA AND FAMILIAL INTERSTITIAL PNEUMONIA......Page 1664 61.3 ASSOCIATED POLYMORPHISMS IN OTHER COMMON FORMS OF ILD......Page 1670 61.4 GENETIC SYNDROMES WITH ILD MANIFESTATIONS......Page 1671 REFERENCES......Page 1676 Renal Disorders......Page 1686 62.1 INTRODUCTION......Page 1688 62.2 CLINICAL FEATURES......Page 1689 62.4 ERRORS OF ORGANOGENESIS......Page 1690 62.5 ERRORS OF MIGRATION AND POSITION......Page 1716 62.6 ERRORS RESULTING IN OBSTRUCTION......Page 1719 REFERENCES......Page 1721 FURTHER READING......Page 1724 63.2 AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE (MIM 173900)......Page 1726 63.3 AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (MIM 263200)......Page 1732 63.4 FAMILIAL NEPHRONOPHTHISIS......Page 1735 63.5 MEDULLARY CYSTIC KIDNEY DISEASE......Page 1743 63.7 GENETIC SYNDROMES WITH CYSTIC RENAL DISEASE AS A MAJOR COMPONENT......Page 1745 63.8 MECHANISMS OF CYSTOGENESIS......Page 1747 REFERENCES......Page 1751 RELEVANT WEB PAGES......Page 1757 64.2 GLOMERULAR FILTRATION BARRIER......Page 1759 MUTATIONS......Page 1760 MUTATIONS......Page 1761 MUTATIONS......Page 1762 MUTATIONS......Page 1763 MUTATIONS......Page 1764 MUTATIONS......Page 1765 64.13 DIAGNOSIS OF NS......Page 1766 64.15 CONCLUSIONS......Page 1767 REFERENCES......Page 1768 CROSS REFERENCE......Page 1771 65.2 GENERALIZED DISORDERS OF TUBULAR FUNCTION (FANCONI SYNDROME)......Page 1772 65.3 DISORDERS OF AMINO ACID TRANSPORT......Page 1773 65.4 RENAL TUBULAR ACIDOSIS......Page 1775 REFERENCES......Page 1776 CROSS REFERENCES......Page 1778 66.1 TUMORS OF THE KIDNEY......Page 1780 66.2 BLADDER NEOPLASMS......Page 1787 66.4 TESTICULAR NEOPLASMS......Page 1788 REFERENCES......Page 1790 CROSS REFERENCES......Page 1796 Gastrointestinal Disorders......Page 1797 67.2 EMBRYOLOGICAL BACKGROUND......Page 1799 67.3 CLASSIFICATION OF GASTROINTESTINAL DISORDERS......Page 1800 REFERENCES......Page 1811 RELEVANT WEB PAGES......Page 1814 68.1 INTRODUCTION AND DISEASE DEFINITION......Page 1816 68.2 PHENOTYPIC HETEROGENEITY......Page 1818 68.3 RACIAL AND ETHNIC DIFFERENCES......Page 1820 68.4 FAMILIAL AGGREGATION......Page 1821 68.6 INFERENCES REGARDING MODE OF INHERITANCE......Page 1822 68.7 ASSOCIATION OF IBD WITH RARE GENETIC SYNDROMES......Page 1824 68.8 ASSOCIATIONS WITH OTHER DISEASES......Page 1826 68.9 GENE AND ENVIRONMENTAL INTERACTIONS......Page 1827 68.10 GENE IDENTIFICATION......Page 1830 68.11 CANDIDATE GENE STUDIES......Page 1833 68.12 CLINICAL APPLICATION OF GENETIC INFORMATION......Page 1839 REFERENCES......Page 1840 FURTHER READING......Page 1852 69.2 FORMATION OF BILIRUBIN......Page 1854 69.3 STRUCTURE OF BILIRUBIN......Page 1856 69.5 TOXIC EFFECTS OF BILIRUBIN......Page 1857 69.6 DISPOSITION OF BILIRUBIN......Page 1858 69.7 BILIRUBIN MEASUREMENT......Page 1862 69.9 DISORDERS OF BILIRUBIN METABOLISM......Page 1863 REFERENCES......Page 1876 70.1 INTRODUCTION......Page 1888 70.2 THE GENETICS OF COLORECTAL CANCER......Page 1889 70.3 FAMILIAL COLORECTAL CANCER......Page 1893 70.4 OTHER FAMILIAL GASTROINTESTINAL POLYPOSIS SYNDROMES......Page 1905 70.5 GENETICS OF GASTRIC CANCER......Page 1910 REFERENCES......Page 1911 Hematologic Disorders......Page 1923 71.2 NORMAL HUMAN HEMOGLOBIN......Page 1925 71.3 HEMOGLOBIN BIOSYNTHESIS......Page 1928 71.4 HUMAN HEMOGLOBIN VARIANTS......Page 1931 71.5 SICKLE-CELL ANEMIA AND RELATED DISORDERS......Page 1935 71.7 HEMOGLOBIN VARIANTS WITH ALTERED OXYGEN AFFINITY......Page 1939 71.9 THALASSEMIAS......Page 1941 REFERENCES......Page 1966 72.1 HEMOLYSIS DUE TO HEREDITARY RED BLOOD CELL ENZYME DISORDERS......Page 1969 72.3 HEMOLYSIS DUE TO HEREDITARY RED BLOOD CELL MEMBRANE DISORDERS......Page 1978 72.4 MEGALOBLASTIC ANEMIAS......Page 1984 72.5 DYSERYTHROPOIETIC ANEMIAS......Page 1986 72.6 SIDEROBLASTIC ANEMIAS......Page 1987 72.7 METHEMOGLOBINEMIA......Page 1988 REFERENCES......Page 1989 73.2 THE COAGULATION CASCADE......Page 1994 73.3 INHERITED DISORDERS PREDISPOSING TO THROMBOSIS......Page 2013 REFERENCES......Page 2020 74.3 DETECTION OF FETOMATERNAL HEMORRHAGE......Page 2027 74.4 RH BLOOD GROUP SYSTEM......Page 2028 74.5 ALLOIMMUNE THROMBOCYTOPENIA......Page 2034 74.6 MANAGEMENT OF ALLOIMMUNIZATION......Page 2035 REFERENCES......Page 2037 FURTHER READING......Page 2040 75.2 GENERAL PATTERNS OF CHROMOSOME ABERRATIONS AND GENOMIC ABNORMALITIES IN LEUKEMIA AND LYMPHOMA......Page 2041 75.3 SIGNIFICANCE OF DETECTING ACQUIRED CHROMOSOME AND GENE ABNORMALITIES IN LEUKEMIA AND LYMPHOMA......Page 2042 75.4 APPLICATION OF CYTOGENETIC, FISH, AND MICROARRAY TECHNIQUES IN DIAGNOSIS OF LEUKEMIA AND LYMPHOMA......Page 2043 75.5 MYELOPROLIFERATIVE NEOPLASM......Page 2044 75.6 MYELODYSPLASTIC SYNDROMES......Page 2046 75.7 ACUTE MYELOID LEUKEMIA DE NOVO......Page 2050 75.8 AML AND MDS ASSOCIATED WITH PRIOR CYTOTOXIC TREATMENT......Page 2055 75.9 B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA......Page 2056 75.10 RECURRING CHROMOSOME AND GENOMIC ABNORMALITIES IN T-CELL ALL......Page 2059 75.13 NON-HODGKIN LYMPHOMAS......Page 2061 75.14 MOLECULAR ANALYSIS OF RECURRENT CHROMOSOME ABNORMALITIES......Page 2068 REFERENCES......Page 2070 76.2 THE IMMUNE RESPONSE......Page 2085 76.3 AUTOIMMUNE PATHOLOGY......Page 2086 76.4 AUTOREACTIVE T CELLS AND THE FAILURE OF TOLERANCE......Page 2087 76.5 GENETICS OF AUTOIMMUNE DISEASES......Page 2089 76.7 GENETIC SUSCEPTIBILITY TO AUTOIMMUNE DISEASE......Page 2090 REFERENCES......Page 2096 77.3 PATHOGENIC AUTOANTIBODIES AND IMMUNE COMPLEXES......Page 2101 77.4 THE GENETICS OF HUMAN SLE......Page 2102 77.6 PREGNANCY COUNSELING OF SLE PATIENTS......Page 2112 REFERENCES......Page 2113 FURTHER READING......Page 2121 78.1 INTRODUCTION......Page 2123 78.2 RHEUMATOID ARTHRITIS......Page 2124 78.3 SERONEGATIVE SPONDYLOARTHROPATHIES......Page 2133 78.4 JUVENILE IDIOPATHIC ARTHRITIS......Page 2142 REFERENCES......Page 2145 79.1 INTRODUCTION......Page 2152 79.2 HEREDITARY SYSTEMIC AMYLOIDOSIS......Page 2153 79.3 HEREDITARY LOCALIZED AMYLOIDOSIS......Page 2161 79.4 HEREDITARY NON-AMYLOID PROTEIN DEPOSITION DISEASE......Page 2162 REFERENCES......Page 2163 80.2 SPECIFIC INHERITED IMMUNODEFICIENCY DISORDERS......Page 2170 80.3 PRIMARY B-CELL DEFICIENCIES (HUMORAL IMMUNE DEFECTS)......Page 2179 80.4 IMMUNODEFICIENCIES WITH IMMUNE DYSREGULATION......Page 2182 80.5 IMMUNODEFICIENCY SYNDROMES......Page 2184 REFERENCES......Page 2188 81.3 THE CLASSICAL PATHWAY......Page 2200 81.7 REGULATION OF COMPLEMENT ACTIVATION......Page 2201 81.8 INHERITED COMPLEMENT DEFICIENCIES......Page 2202 81.9 MANAGEMENT OF COMPLEMENT DEFICIENCIES......Page 2206 REFERENCES......Page 2207 FURTHER READING......Page 2211 Endocrinologic Disorders......Page 2213 82.2 HISTORICAL BACKGROUND......Page 2215 82.3 PHAGOCYTE DEVELOPMENT, KINETICS, AND FUNCTIONS......Page 2216 82.4 GRANULOCYTE FUNCTION DISORDERS......Page 2219 82.5 MONOCYTES/MACROPHAGES FUNCTION DISORDERS......Page 2229 CROSS REFERENCES......Page 2232 REFERENCES......Page 2233 83.2 ANTERIOR PITUITARY......Page 2244 83.3 POSTERIOR PITUITARY: GENETIC DISORDERS OF AVP DEFICIENCY......Page 2271 REFERENCES......Page 2275 84.1 INTRODUCTION......Page 2281 84.2 CONGENITAL HYPOTHYROIDISM......Page 2284 84.5 GENETIC BASIS OF AUTOIMMUNE THYROID DISEASE......Page 2292 84.6 GENETIC BASIS OF THYROID CARCINOMA......Page 2293 REFERENCES......Page 2295 85.2 PRIMARY HYPERPARATHYROIDISM......Page 2305 85.3 FAMILIAL HYPOCALCIURIC HYPERCALCEMIA......Page 2307 85.4 NEONATAL SEVERE HYPERPARATHYROIDISM......Page 2308 MUTATIONS IN FAMILIAL HYPOCALCIURIC HYPERCALCEMIA AND NEONATAL SEVERE HYPERPARATHYROIDISM......Page 2309 85.8 MULTIPLE ENDOCRINE NEOPLASIA TYPE 1......Page 2311 85.9 MULTIPLE ENDOCRINE NEOPLASIA TYPE 2......Page 2313 85.11 HYPERPARATHYROIDISM-JAW TUMOR SYNDROME......Page 2314 85.13 DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS OF HYPERCALCEMIA......Page 2316 85.15 PRIMARY HYPOPARATHYROIDISM......Page 2317 85.16 FAMILIAL ISOLATED HYPOPARATHYROIDISM......Page 2319 85.17 HYPOPARATHYROIDISM WITH MULTIPLE MALFORMATIONS......Page 2320 85.19 AUTOIMMUNE HYPOPARATHYROIDISM: ACQUIRED AND INHERITED DISORDERS......Page 2321 85.20 PSEUDOHYPOPARATHYROIDISM......Page 2322 MUTATIONS......Page 2327 85.25 MANAGEMENT OF HYPOPARATHYROIDISM......Page 2328 REFERENCES......Page 2330 WEBSITES......Page 2338 86.2 DIFFICULTIES IN GENETIC STUDIES OF DIABETES......Page 2339 86.4 GENETIC HETEROGENEITY IN DIABETES......Page 2340 86.5 TYPE 2 DIABETES MELLITUS......Page 2362 86.6 FINAL CONSIDERATIONS AND SPECULATIONS......Page 2377 REFERENCES......Page 2378 RELEVANT WEB PAGES......Page 2395 87.1 CLINICAL ASPECTS: NORMAL AND ABNORMAL ADRENAL FUNCTION......Page 2397 87.2 STEROID 21-HYDROXYLASE DEFICIENCY......Page 2401 87.3 STEROID 11ß-HYDROXYLASE DEFICIENCY......Page 2407 87.4 3ß-HYDROXYSTEROID DEHYDROGENASE DEFICIENCY......Page 2416 87.5 STEROID 17a-HYDROXYLASE/17,20-LYASE DEFICIENCY......Page 2417 87.6 CONGENITAL LIPOID ADRENAL HYPERPLASIA......Page 2418 87.7 TREATMENT......Page 2419 87.8 CONGENITAL ADRENAL HYPERPLASIA: PRENATAL DIAGNOSIS AND TREATMENT......Page 2421 REFERENCES......Page 2423 FURTHER READING......Page 2432 88.2 46,XX DISORDERS OF SEXUAL DEVELOPMENT......Page 2434 REFERENCES......Page 2467 FURTHER READING......Page 2478 89.2 DISCOVERY OF BRCA1......Page 2479 89.3 DISCOVERY OF BRCA2......Page 2481 89.4 PATHOLOGY OF FAMILIAL BREAST CANCERS......Page 2482 89.5 BRCA1 AND BRCA2 MUTATION ANALYSIS......Page 2483 89.6 RARE FAMILIAL SYNDROM