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Professor and Chair, Department of Medical Biochemistry and ... Professor and Chair, Department of Medical Biochemistry and ... Document Transcript

  • American University of Antigua College of Medicine Medical Genetics Andreas Lück, D.N.Sc. Professor and Chair, Department of Medical Biochemistry and Genetics Course Description and Purpose Medical genetics is one of the most rapidly advancing areas of modern medicine, and molecular genetics is now integral to all aspects of biomedical sciences. In order to be able to successfully practice medicine nowadays, in-depth knowledge of the principles of human genetics and their application to a wide array of clinical problems is paramount. During the course we will discuss the following topics: principles, mechanisms and patterns of inheritance (including genetic diseases), genetic diversity, population genetics, cytogenetics, molecular basis of genetic diseases (including application of recombinant DNA techniques), pharmacogenetics, immunogenetics, molecular biology and genetics of cancer, and genetic counselling. Goal The goal of this course is to provide a solid understanding and foundation of the principles of human genetics relevant to clinical medicine, with emphasis on disease mechanisms, diagnosis and treatment.. Course Objectives Upon completion of this course, you should • Understand and be able to explain how genetic factors predispose to genetic diseases and their implications on diagnosis, treatment/disease management, and prevention; • Understand and be able to explain the clinical manifestations of common genetic diseases; • Understand and be able to explain how knowledge of a patient’s genotype can be used to develop effective approaches to diagnosis and treatment for that individual; • Understand and be able to explain the indications for prenatal diagnosis and the procedures that are employed for such testing; • Understand and be able to explain the existence of and justification for screening programs and the difference between screening and individualized testing; • Understand and be able to explain the differences in goals and approaches regarding screening programs in newborns, pregnant women, and other groups; • Understand and be able to explain treatment of genetic diseases and the present state of gene-based therapies;
  • 2 • Understand and be able to explain indications and methods for referral of individuals to medical geneticists; • Understand and be able to explain how medical practice is affected by legal and ethical issues; and • Be able to deal with genetics questions on the USMLE Step I Exam with ease, confidence, and competence Format Course material will be presented in a lecture and discussion format. Required Texts Nussbaum, R.L., McInnes, R.R., and Huntington, F.W.: Thompson & Thompson – Genetics in Medicine, 6th edition (2001), WB Saunders Company, ISBN: 0-7216-6902-6 Recommended Texts • Gelehrter, T.D., Collins, F.S., and Ginsburg, D.: Principles of Medical Genetics, 2nd edition (1998), Lippincott Wiiliams & Wilkins, ISBN 0683034456 • Strachan, T., and Read, A.: Human Molecular Genetics, 3rd edition (2004), Garland Press, ISBN 0815341849 • Mueller, R.F., Ian, D., and Young, M.D.: Emery’s Elements of Medical Genetics, 11th edition (2001), WB Saunders, ISBN 044307125X Examinations and Grading System • Four “mini” exams and the final exam will assess your ability to master the course material. • Material to be covered in exams and weight of the individual exams: see below. • The exams are in multiple choice format. Each question will be assigned 72 seconds. The “mini” exams will have 30 to 40 questions; the final exam may have up to 100 questions. Thus, the allocated time for the mid-term exam will be 35 to 50 minutes for the final exam up to 120 minutes. • Every attempt possible will be made to phrase exam questions clear and unambiguous. • Exams will focus on but may not be limited to the material that has been covered in class. Note: All material covered by the reading assignments plus all of the additional material supplied during the course is testable! • Exams will not be curved. • Performance grades from each exam will be directly communicated to you on an individual and confidential basis. The grades for the final exam and the final course grades will be communicated after the final exam. • Exam reviews will be held on day after the exam. • Note: During exam reviews students are NOT permitted to have personal belongings (bags, notebooks, etc) in the classroom. Any attempt to audiotape and/or copy down the correct answers in any way will be regarded as
  • 3 cheating and will automatically lead to failure of the exam and disciplinary action. • The final exam will be comprehensive • A failing grade (“zero”) will be assigned for a missed exam. The only accepted exceptions are documented emergencies. Make-up exams may be granted on an individual basis under exceptional circumstances. A make-up exam for a missed final exam will not be possible. Exam Content Exam 1 Concepts of Mendelian Genetics; Cell Cycle, Mitosis, Meiosis, Apoptosis; Autosomal Dominant, Autosomal Recessive and X-linked Inheritance and Disorders; Mutations, Polymorphisms Exam 2 Genetic Variation in Populations, Mapping and Linkage Analysis, Principles of Cytogenetics and Clinical Cytogenetics: Autosomal and Sex Chromosome Disorders, Immunogenetics Exam 3 Molecular Genetics: Hemoglobinopathies, Biochemical Genetics Exam 4 Biochemical Genetics (topics covered after Exam 3), Treatment of Genetic Disease, Disorders with complex inheritance, Cancer Genetics Final Exam Comprehensive Weight of exams: Exam 1 10% Exam 2 10% Exam 3 10% Exam 4 10% Final Comprehensive Exam (Shelf): 60% Grading: A: > 90.0% B: 80.0% – 89.9% C: 70.0% – 79.9% F: <70.0% Note: A score of 64 or better on the Final Exam (Shelf) will result in passing the course. Course Policy on Attendance • The general University policy regarding absences applies. American University of Antigua - College of Medicine - allows 20% absences (14 days) per semester during the basic science program. The ‘twenty percent rule’ specifically includes unanticipated emergency leaves, for any reason, from the basic science campus. • Students who have a persistent tendency to come late and thus disrupt the teaching process may be subject to notification to administration. Rules of Conduct See Student Handbook for University policy. University policy will be enforced Recording of Lectures
  • 4 You are allowed to audiotape lectures. University policy prohibits video taping of lectures. DETAILED OUTLINE OF COURSE Week 1, Monday Orientation Week 1, Tuesday Review of Course Outline General discussion of the course and the expectations. Questions from the students about the course are entertained. Week 1, Wednesday Principles of Mendelian Genetics This lecture outlines the principles of Mendelian genetics, which are important even today in the post-genomic area. Fundamental genetic principles and laws will be discussed. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 1 - 3 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand and learn: • The implications of Memdelian genetics • The importance of Mendelian genetics for inheritance of single gene defects • The distribution pattern of genes in offspring generations Be proficient at the integration of the learned material into the greater concept of genetics in medicine Understand the importance of mendelian genetics in clinical settings Contents of Lecture • Genotype and Phenotype • Homozygous and heterozygous • Dominant and recessive • Monohybrid cross o Law of Uniformity o Law of Segregation • Dihybrid cross o Law of Independent Assortment • Punnett Squares • Incomplete Dominance • Codominance
  • 5 Week 1, Thursday, Friday Cell Cycle, Mitosis, Meiosis, and Week 2, Monday Apoptosis At the beginning of this lecture we will discuss the cell cycle and its control with particular emphasis on checkpoints (G1 to S phase transition and G2 to M phase transition) and cell cycle controlling proteins: cyclins, cyclin dependent kinases, and tumor suppressor proteins like RB and p53. We then continue with a brief review of mitosis and meiosis. Here the focus is on the similarities and differences between mitosis and meiosis. Genome mutations like nondysjunctions will be discussed. The last section of this lecture will focus on apoptosis, its characteristics and biological importance. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 4 - 16 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand and learn: • The phases of the cell cycle and how the cell cycle is controlled • The importance of various checkpoints of the cell cycle • Cell cycle promoting proteins and tumor suppressors • The cellular response to DNA damage or misalignment of metaphase chromosomes • The phases and events in mitosis and meiosis • How crossovers between chromosomes in prophase of meiosis I create genetic diversity • The importance of apoptosis in normal development • The differences between apoptosis and necrosis • How apotosis can be triggered • The molecular components involved in apoptosis Be proficient at the integration of the learned material into the greater concept of genetics in medicine Understand the importance of (1) the cell cycle, its control, and cell division, (2) mitosis and meiosis and (3) apoptosis in clinical settings Contents of Lecture: Cell Cycle and its Control • Phases of the Cell Cycle • Checkpoints • Cyclin-dependent kinases and cyclins • Maturation promoting factor (MPF) o Activation o Targets • Spindle Assembly Checkpoint
  • 6 • G1 to S progression and control • Role of retinoblastoma and p53 proteins • Cellular response to DNA damage Mitosis • Phases and events of mitosis • Restriction of DNA replication Meiosis • Difference: mitosis and meiosis • Phases and events • Crossovers in prophase of Meiosis I • Chromosome segregation in Meiosis I • Meiosis in spermatogenesis and oogenesis • MPF during oocyte meiosis • Metaphase I and metaphase II arrest • Fertilization and completion of meiosis II Apoptosis • Definition and importance • Apoptosis vs. necrosis • Characteristics of apoptosis • Biochemical characteristics • Caspases: initiator vs. effector caspases • Molecular mechanisms • Transmembrane stimuli • Intracellular stimuli • Apoptosis and DNA damage Week 2, Tuesday, Wednesday: Autosomal Dominant Inheritance In autosomal inheritance, heterozygous individuals manifest traits. It is frequently possible to trace dominantly inherited traits or disorders through many generations of a family. Characteristic pedigree patterns of autosomal dominant inheritance and selected diseases will be discussed. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 51-78 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • Family pedigrees, symbols • Different types of inheritance • Characteristics of AD inheritance • Factors that complicate the determination of AD inheritance • The risk assessment for future generations
  • 7 Know: • Autosomal dominant diseases and their clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture Types of inheritance • Introduction to pedigrees • Mendelian disorders • Chromosomal disorders • Multifactorial disorders • Mitochondrial disorders • Definitions:locus, allele, proband, consultand, • Sibs, kindred, relatives, consanguineous, isolated cases, sporadic cases • Pedigree symbols • Autosomal dominant inheritance and disorders • Autosonal recessive inheritance and disorders • Haploinsufficiency • Dominant negative effect • Gain-of-function • Inherited dysfunction • Age of Onset • Genetic heterogeneity: locus, allele Autosomal dominant inheritance • Male-to-male transmission • Vertical transmission • AD diseases • Pedigree patterns • New mutations • Mosaicism: somatic, germline • Punnett square • Incomplete (reduced) penetrance • Variable expressivity • Pleiotropy • Delayed age of onset • Anticipation • Sex-limited phenotype in AD disease • Genomic imprinting • Uniparental disomy Clinical correlations • NF type I • Achondroplasia • Familail hypercholesterolemia • Osteogenesis imperfecta • DMD • OTC deficiency • Huntington’s Disease • Split hand deformity • Marfan Syndrome • Male-limited precocious puberty (familial testotoxicosis)
  • 8 • Prader-Willi Syndrome • Angelman Syndrome • Beckwith-Wiedeman Syndrome Week 2, Thursday, Friday Autosomal Recessive Inheritance Recessive traits and disorders are manifested only in the homozygous state. Heterozygous individuals normally show no features of the trait or disease. As we will discuss, the family tree for AR inheritance differs significantly from those of AD or X- linked inheritance. Unlike in AD inheritance it is not possible to trace a trait or disease through the family. Instead, affected individuals are typically iin a single sibship, which is referred to as “horizontal” transmission. Certain factors that are of importance in AR inheritance, such as consanguinity, will be discussed. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 51-78 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The characteristics of autosomal recessive inheritance • Risk assessment for future generations • The concept of consanguinity • The importance of the coefficient of inbreeding • Why genetically isolated populations have a high incidence and prevalence of AR disorders Know: • Autosomal recessive diseases and their clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lectures: • Definitions: carrier status • Risk determination to offspring • Horizontal transmission • Male-to-male transmission • Genetic isolates • Consanguinity • Coefficient of inbreeding • Sex-influenced expression of phenotype • Segregation analysis and binomial theorem • Bias of ascertainment Clinical correlations • Albinism • Alkaptonuria • Cystic fibrosis
  • 9 • Gaucher’s disease • Tay-Sachs disease • Mucopolysaccaridoses • Nieman-Pick diseasae • PKU • Hemochromatosis Week 3, Monday, Tuesday X-linked Inheritance Sex-linked inheritance refers to the pattern of inheritance shown by genes that are located on either of the sex chromosomes. In most instances, this will be an X-linked pattern of inheritance as only very few genes are located on the Y chromosome. This lecture will focus on X-linked inheritance and the implications that result from this particular type of inheritance. Both X-linked dominant and X-linked recessive patterns of inhertitance including selected disease examples will be discussed. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 51-78 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: The role of the X chromosome and the implications for males and females Characteristics of X-linked inheritance The concept of X-chromosome inactivation and mosaicism That some regions escape inactivation The concept of variable expressiviry in females and manifesting heterozygotes That some X-linked diseases are embryonic lethal for males The differences between X-linked dominant and X-linked recessive inheritance Know: X-linked dominant and recessive diseases and their clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture • Sex chromosomes • Pseudoautosomal region • Hemizygosity • Lion Hypothesis: X-chromosome inactivation • X-chromosome inactivation and mosaicism • Manifesting heterozygotes • Escape from inactivation • Variable expression in female heterozygotes • X-linked dominant inheritance: pedigree patterns • X-linked recessive inheritance: pedigree patterns
  • 10 • Risk determination to offspring • Absence of male-to-male transmission: exception for pseudoautosomal region • Consanguinity in X-linked recessive inheritance • Sex-limited expression in X-linked dominant disorders Clinical Correlations • Color blindness • Hemophilia A and B • DMD • Wiskott-Aldrich Syndrome • Fragile X syndrome • Viamin D-resistant rickets • Ornithine transcarbamylaase deficiency • Rett syndrome • Incontinentia pigmenti type 2 Week 3, Wednesday, Thursday Mutations and Polymorphisms The generation of mutations in DNA is a continuous process. Most of the mutations are recognized and corrected; however, some mutations escape the multiple layers of repair systems in the human body. Mutations in intergenic regions or in most areas of introns are tolerated. Mutations in essential control regions or in the coding regions of genes may lead to genetic diseases. The identification of a gene that is responsible for an inherited single-gene disorder in addition to having clinical diagnostic application allows for an understanding of the developmental basis of the pathology with the long-term prospect of potential therapeutic interventions. Genes between individuals are quite variable, and certain variations of genes are present in the gene pool of a population. These variations are called polymorphisms and may occur intragenic and in non-coding regions. Recombinant DNA technology allows for early detection of certain mutated and disease-causeing alleles by using RFLP analysis, while other polymorphisms can be used in paternal disputes and forensic medicine. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 79 - 94 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: The nature and implications of point mutations as well as genome and chromosome mutations The implications of failure to repair damaged DNA The implications of germline mutations The nature and applications of DNA polymorphisms Techniques used in mutation analysis and gene mapping
  • 11 Know: The diseases and polymorphisms discussed and their clinical, biochemical and physiological features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture Mutations • Definition and types of mutations • Genetic variation • Pathogenic mutations • Nomenclature of mutation effects on alleles • Genome mutations • Chromosome mutations • Gene mutations • Point mutations • Deletions, insertions, inversions, duplications • RNA splicing mutations • Replication errors (RER) • Failure of DNA repair • Germ line mutations • Rate of gene mutation Polymorphisms • Definition • Coding region polymorphisms • Non-coding region polymorphisms • Methods of detection • RFLP analysis • DNA fingerprinting and applications • Southern blot and hybridization • Genetic mechanism that result in sequence exchange between repeats • VNTR polymorphisms • Slipped mispairing • Unequal crossing over • Detection and analysis of polymorphisms by PCR Clinical correlations • Xeroderma pigmentosum • Ataxia telangiectasia • Bloom syndrome • Fanconi syndrome (anemia) • Hereditary nonpolyposis colon cancer • ABO blood group system • Rh blood group • Galactosemia • Alpha-1 antitrypsin
  • 12 Week 3, Friday Review Learning Objectives for Examination 1 • Learn and understand the terminologies discussed making sure all the keywords and terms are completely understood. • Be proficient in application of the knowledge acquired in this section. • Be able to integrate and understand the fundamental scientific and clinical importance of the topics discussed. Week 4, Monday Examination 1 Week 4, Tuesday Review Examination 1 Week 4, Wednesday - Friday Population Genetics This lecture will illuminate some of the mathematical aspects of the ways in which genes are inherited, together with how genes are distributed and maintained in particular frequencies in a given population. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 05 - 109 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The basic concepts and definitions of population genetics • The Hardy-Weinberg principle and its applications • How genotype frequencies are maintained over multiple generations • The importance of population genetics in different modes of inheritance • How small populations and isolated populations lead to changes in the gene pool and genotype frequencies • The meaning and consequences of “founder effect” • How mutations and selection influence and shift the Hardy-Weinberg equilibrium Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine.
  • 13 Contents of Lecture • Brief overview of history of Population Genetics • What is population genetics • Definitions: population, gene pool • Ethnic groups • Gene frequencies • Genetic differences between subpopulations • Hardy-Weinberg Principle • Mathematical deductions • Genotype frequencies in the first generation • Second generation • Three alleles • Applications of the Hardy-Weinberg principle • In autosomal dominant inheritance • In autosomal recessive inhereitance • In X-linked recessive inheritance • In X-linked dominant inheritance • Equilibrium genotype frequencies • Hardy-Weinberg equilibrium • Exceptions to random mating • Disturbance of Hardy-Weinberg equilibrium • Stratification • Coefficient of inbreeding • Small populations and genetic drift • Founder effect • Gene flow • Mutation and selection Week 5, Monday - Wednesday Mapping and Linkage Analysis Mapping of human genes is one of the most important foundations of modern medical genetics. With the completion of the Human Genome Project in 2001, the locations of the approximately 35,000 to 50,000 human genes are known. Such information is of great importance for two reasons: (1) application to disease diagnosis and (2) identification of the genes responsible for genetic diseases. However, having this information at hand does not necessarily imply that mapping will be obsolete in the future. Although the sequence of many genes has been determined, there are still huge gaps when it comes to the encoded gene products and their functions. There are two fundamentally different approaches for assembling gene maps of human chromosomes: physical mapping and genetic mapping. Both techniques will be discussed in detail with respect to their execution and the information gained.
  • 14 Reading Assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 51-78 Learning Objectives Learn the terminology discussed and be proficient at its application Understand: The different ways of obtaining maps of genes and chromosomes The techniques used in physical mapping Mapping using linkage analysis The concept of recombination and non-recombination between a gene of interest and a polymorphic marker The importance of “phase” in genetic mapping The relationship between theta and genetic distance The relationship between LOD scores and linkage The limitations of genetic mapping How to obtain high-resolution mapping Know: The diseases discussed and their clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Content of Lecture • Physical mapping vs. genetic mapping • Somatic cell hybridization • Interspecies somatic cell hybridization scheme • Somatic cell hybridization mapping panels • Mapping to chromosomal regions • Radiation hybrid mapping • Mapping by gene dosage analysis • FISH • Fiber FISH • Linkage analysis • Homologous recombination in meiosis • Genetic markers • Recombination vs. non-recombination • Theta (recombination frequency) • Centi Morgan as measure of recombination frequency and genetic distance • LOD scores • Phase in linkage analysis
  • 15 • Determining phase in autosomal and X-linked inheritance • Linkage equilibrium vs. disequilibrium • Genetic linkage maps • Multipoint analysis • Relationship between genetic and physical distance • Mapping disease genes by linkage analysis • LOD scores and inherent problems • The 10 cM limit • High resolution mapping • Contigs of artificial chromosomes’ • Positional cloning • Candidate gene approach • Expressed sequence tags (ESTs) Clinical correlations • Tay-Sachs disease • Karyotype anomalies (extra X chromosomes) • DMD • Cystic fibrosis • Retinitis pigmentosa • Hereditary nonpolyposis colon cancer Week 5, Thursday, Friday Cytogenetics: Principles and Week 6, Monday, Tuesday Disorders Clinical cytogenetics is the study of chromosomes, their structure, and their inheritance, pertaining to clinical medicine. It has been known for a long time that microscopically visible changes in the banding pattern of metaphase chromosomes or in the number of chromosomes account for a large number of clinical conditions and diseases. This lecture addresses the general principles of cytogenetics, the various types of numerical and structural abnormalities observed in human karyotypes, as well as more detailed accounts of several specific chromosomal disorders and their consequences. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 135 - 179 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The circumstances for referral to cytogenetic and karyotype analysis • The different techniques employed in clinical cytogenetics • The nature and consequences of the numerous types of structural chromosomal abnormalities
  • 16 • The origins and consequences of the numerical chromosome aberrations • Incidence of chromosomal abnormalities in populations • The importance of parent-of-origin effects • The importance of the sex chromosomes for the development of the reproductive tract and the genes involved • The implications of structural or numerical chromosome mutations of the sex chromosomes Know: • Autosomal disorders, sex-chromosome-linked disorders, and their basic, biochemical, and clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture Cytogenetic principles • Applications and Indications of cytogenetics and chromosome analysis • Chromosome nomenclature and classification of chromosome based on centromere location • Staining methods: o G-banding o Q-banding o R-banding o T-banding o C-banding o High-resolution banding o FISH • Chromosome sources • Chromosomal nondysjunction in meiosis and mitosis • Chromosome mutations • Aneuploidy: Trisomies and monosomies • Triploidy and tetraploidy • Translocations: balanced, unbalanced, reciprocal • Marker and ring chromosomes • Isochromosomes • Dicentric chromosomes • Robertsonian translocation • Deletions, insertions • Inversions: paracentric, pericentric • Fragile sites • Mosaicism: generalized and confined • Population incidence of chrmomsomal abnormalities • Parent-of-origin effects: imprinting, hydatiform moles, ovarian teratomas • Cytogenetics and mendelian disorders Cytogenetic Disorders Autosomal disorders • Down Syndrome: o Phenotype, features,
  • 17 o Nondysjunction vs. Robertsonain translocation o Isochromosome 21q21q o Mosaic Down syndrome and partial trisomy 21 o Recurrence risk • Edward syndrome o Phenotype and features, recurrence risk • Pateau Syndrome • Autosomal deletion syndromes: o Cri du chat syndrome, phenotype • Microdeletion syndromes: segmental aneusomy • Contiguous gene syndrome • Single gene deletions • Unequal crossing over • DiGeorge syndrome Sex chromosomes and abnormalities • Y chromosome • Embryology of the reproductive system • Sex determining region on the Y chromosome • Y linked genes in spermatogenesis • X chromosome inactivation • XIST and XIC • Nonrandom inactivation of the X chromosome • X linked mental retardation • Klinefelter syndrome: phenotype and features • 47,XXY syundrome: features and phenotype • Trisomy X: features and phenotype • Turner syndrome (45,X and variants): features and phenotype • Disorders of gonadal and sexual development • Camptomelic dysplasia • Sex reversed 46, XY • Denys-Drash syndrome • Female pseudohermaphroditism • Congenital adrenal hyperplasia • Male pseudohermaphroditism Week 6, Wednesday, Thursday Immunogenetics The genes that contribute to the immune system are of great importance in the clinical areas of transplantation, autoimmune diseases, and infection. It is well known that the humoral immune system is prepared to combat a tremendous number of antigens, most of which it has never encountered. This is due to several unusual genetic phenomena that are different from other systems: extensive polymorphism of expressed proteins and especially the ability to generate great diversity from a very limited number of genetic loci by somatic recombination of genes. This lecture introduces some of the gene systems that govern immune function, including the MHC, the T-cell receptor (TCR), and immunoglobulins.
  • 18 Reading Assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 277 - 288 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The general organization of the immune system and the genes involved • The structure and function of the T-cell receptor • The different classes and functions of the MHC • The importance and implications of the different HLA haplotypes • Structure, diversity and function of immunoglobulins • The process of somatic gene rearrangements to generate diversity Know: • Disorders of the immune system Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture • Organization of the Iimmune system • Self and non-self • Key families of genes • Immune responses • Antigen presentation • The MHC • Classes of MHC • MHC locus on chromosome 6 • Antigen processing • Products of class I MHC genes • Class II genes • Class III genes • Polymorphisms and inheritance of HLA haplotypes • HLA and disease association • Odds ratio correction • Immunoglobulins: structure and diversity • Somatic rearrangements of DNA • Germline genes • Somatic genes • Other sources of diversity • Molecular mechanism of antibody diversity • T-cell antigen receptor • TCR diversity
  • 19 • Disorders of the immune system: single gene disorders Week 6, Friday Review Learning Objectives for Examination 2 • Learn and understand the terminologies discussed making sure all the keywords and terms are completely understood. • Be proficient in application of the knowledge acquired in this section. • Be able to integrate and understand the fundamental scientific and clinical importance of the topics discussed. Week 7, Monday Examination 2 Week 7, Tuesday Review Examination 2 Week 7, Wednesday – Friday Hemoglobinopathies This lecture addresses the basic genetic and biochemical mechanisms of disorders of hemoglobin, hemoglobinopathies. The first part of this lecture focuses on the effect of mutations on protein function and the structure/function relationship of hemoglobin. In the following segments we will discuss structural variation of hemoglobin that lead to abnormal function, such as reduced or increased oxygen affinity. The last part of this lecture focuses on another type of hemoglobinemias, thalassemias. We will discuss the mechanisms leading to alpha, beta, and complex thalassemias, their clinical features, and treatment strategies.. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 181 -202 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The consequences of mutations on protein function • The structure/function relationship of hemoglobin • The organization and expression pattern of globin genes • The importance of the locus control region • The type of mutation leading to structural variations of hemoglobin • The mechanisms leading to thalassemias Know: • The structural variations of hemoglobindiscussed
  • 20 • The mutations, modes of inheritance, and biochemical/functional consequences for the discussed structural variations of hemoglobin • Clinical features of the discussed structural hemoglobin variants • The clinical features of the different thalassemias • Treatment options for alpha and beta thalassemia Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture • Effect of mutation on protein function • Primary abmormalities • Secondary abnormalities • Hemoglobin structural variants • Thalassemias • Structure and function of hemoglobin • Globin gene families • Normal Hemoglobins: A, A2, F, Gower 1, 2, Portland • Development and globin expression • Globin genes • Locus control region • Various structural variations of hemoglobin: causes, effects, clinical features o HbS o HbC o Hb Hammersmith o Hb Gun Hill o Hb Kempsey o Hb Kansas o Hb electrophoresis Thalassemias • Alpha and beta • Inclusion bodies: Heinz bodies • Null and “plus” thalassemias • Alpha thalassemia: loss of alpha globin genes o Unequal crossing over o HbH and hydrops fetalis • Beta thalassemia o Minor and major o Beta null and beta “plus” o Beta intermedia o Locations and types of mutation in beta thalassemia • HPFH and possible causes • Hb Lepore and antilepore • Complex thalassemias • Clinical heterogeneity
  • 21 Week 8, Monday - Friday Biochemical Genetics Week 9, Monday – Wednesday Biochemical Genetics This lecture is divided into several smaller presentations, illuminating selected examples that are of great medical importance and their molecular causes. The focus is on how mutations impair the synthesis, processing, cleavage or molecular associations of proteins and enzymes and thus disrupt biochemical pathways or structural functions. The relationship between a molecular defect and the locations and nature of its clinical pathology is examined. The importance of biochemical genetics and its understanding is underscored by the fact that more than 1,000 genes are associated with single-gene disorders. Moreover, there are several thousand single-gene diseases in which the biochemical defect remains to be determined. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 203 - 254 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The general concept of inborn errors of metabolism and their genetic causes and consequences • How certain mutations can disrupt biochemical pathways and lead to clinical symptoms • That organ involvement is dependent on the tissue-specific expression of the genes in question • Depending on the location of a mutation in the gene and the gene product the clinical symptoms may display great variability • The function of the normal gene products and how abnormal gene products impair or interfere with normal function • Available testing and treatment strategies for the diseases discussed • Risk factors for late-onset genetic diseases Know: • The diseases discussed, their biochemical and clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture General concepts Aminoacidopathies • Alcaptonuria
  • 22 o Pathology, biochemical and clinical features • MSUD o Biochemical features o Pathology and clinical features o Treatment • Homocystinuria o Pathology, biochemical and clinical features o Types of homocystinuria o Interface with folate metabolism • Albinism o Pathology and clinical features o PKU Lysosomal Storage Diseases o Basic concepts and common clinical features o Sphingolipidoses • Tay Sachs and Sandhoff’s o Hex A and Hex B genes and enzymes o Mechaniosm of mutation in Hex A gene o Hex A alleles in populations o Clinical features and phenotype • Fabry’s disease • Gaucher’s disease o Biochedmical features o Genetic isolates o Treatment • Nieman-Pick disease o Types A and B o Types C and D • Metachromatic leukodystrophy • Farber’s disease • Krabbe’s disease Mucopolysaccharidoses • Basic concepts • Hurler • Scheie • Hurler/Scheie o Biochemical features o Allelic heterogeneity o Clinincal features • Hunter o Biochemical features o Inheritance and gene location o Clinical features • Sanfilippo A – D o Biochemical features I cell Disease • Biochemical features • Clinical features
  • 23 • Targeting of lysosomal enzymes Glycogen Storage Diseases • Basic concepts • Type I – von Gierke’s o Biochemical features o Clinical features • Type II – Pompe’s o Biochemical and clinical features • Type III – Cori’s o Biochemical and clinical features • Type IV – Anderson’s o Biochemical and clinical features • Type V – McArdle’s o Biochemical and clinical features • Type VI – Hers’ o Biochemical and clinical features Lesh-Nyhan Syndrome • Biochemical features • Phenotype • Salvage pathway of purine nucleotides • Development of gout Cystic Fibrosis • General information • Clinical features • Molecular genetics • Role of CFTR • CFTR gene and mutations • Detection of the ΔF508 deletion by PCR Triplet Repeat Disorders • Basic concepts • Types of repeats and their locations • Fragile X syndrome o Genes involves o Clinical features o Biochemical features o Fragile X in females o Normal gene product: FMR protein o Abnormal gene products o FMRP and its function o Genetic testing strategy • Huntington’s Disease o Mode of inheritance o Clinical features o Age of onset o Mutation, pre-mutations o Incomplete penetrance o Normal and abnormal gene product and their biochemical properties
  • 24 • Other CAG repeat disorders: o Spinobulbar Muscular Atrophy (Kennedy disease) • Friedreich Ataxia o Mode of inheritance o Clinical features o Type and location of expansion • Myotonic dystrophy o Mode of inheritance o Clinical features o Reduced penetrance and variable expressivity o Biochemical and genetic features o Affected organ systems o Normal gene product o Abnormal gene product • Anticipation • Parent-of origin effects Muscular Dystrophies • Types of MD • Modes of inheritance • Less common MD • Limb girdle MD o Types o Affected muscles o Molecular biology of muscle cell membranes o Sarcolemmal complex o Sarcoglycans • Facioscapulohumeral MD o General features o Affected muscles o Clinical features • Other MD o Congenital, distal, Emery-Dreifus • Oculopharyngeal MD o Affected muscles o Clinical features • Duchenne and Becker MD o Mode of inheritance o DMD clinical features o Biochemical characteristics o Affected muscles o Dystrophin o Pseudohypertrophy of calves o Gower’s sign o Becker MD: clinical features
  • 25 o Molecular genetics of DMD and BMD o Diagnosis of DMD using multiplex PCR Familial Hypercholesterolemia • General features • Mode of inheritance and incidence • Biochemical features • Heterozygotes and homozygotes • Biochemistry of lipids and lipoprotein particles • Metabolism of chylomicrons, VLDL, IDL HDL and LDL • Apoproteins • Electrophoretic profiling of lipids • Hyperlipoproteinemias: Fredrickson classification • Standing chylomicron test • Type IIa hypercholesterolemia • Lipid depositions: xanthomas, xanthelasmas • LDL receptor, the gene and mutations in the gene for the LDL receptor • Class of mutations and disrupted events in lipoprotein metabolism • Risk for CHD • Atherogenesis Collagen disorders • Collagen structure and biosynthesis • Types of collagen and locations • Hydroxylation, glycosylation, and vitamin C dependency • Cross-linking • Assembly to fibrils and fibers • Disorders of collagen biosynthesis • Scurvy, OI, ED, Menke’s • Menke’s syndrome o General features o Phenotype and clinical features • Osteogenesis Imperfecta o Classification o Clinical feature: blue sclera o Variable expressivity o Types of OI: I to IV: phenotypes and clinical features o Effect of null mutations o Effect of mutations in the α1 chain on stoichiometry of normal and defective α chains in the triple helix o Effects of mutations in the α2 chain o Effect of substitutions of glycine residues in collagen chains • Ehlers Danlos syndrome o Types and genetic heterogeneity Alzheimer Disease • General features and implications • Phenotype
  • 26 • Disease characteristics • Histopathologic lesions • APP cleavage • Secretase enzymes • Presenilin 1 and 2 genes • ApoE Phenylketonuria • General features • Enzyme deficiency and metabolic defect • Types of PKU • Etiology • Clinincal features and neonatal screening • Biochemical effects • Treatment • Maternal PKU • Locus heterogeneity • Non-classic PKU • Benign hyperphenylalaninemias • Mutations of the PAH gene Week 9, Thursday, Friday Review Learning Objectives for Examination 3 • Learn and understand the terminologies discussed making sure all the keywords and terms are completely understood. • Be proficient in application of the knowledge acquired in this section. • Be able to integrate and understand the fundamental scientific and clinical importance of the topics discussed. Week 10, Monday Examination 3 Week 10 Tuesday Review Examination 3 Week 10, Wednesday – Friday Biochemical Genetics This lecture is divided into several smaller presentations, illuminating selected examples that are of great medical importance and their molecular causes. The focus is on how mutations impair the synthesis, processing, cleavage or molecular associations of proteins and enzymes and thus disrupt biochemical pathways or structural functions. The relationship between a molecular defect and the locations and nature of its clinical pathology is examined. The importance of biochemical genetics and its understanding is underscored by the fact that more than 1,000 genes are associated with single-gene disorders. Moreover, there are several thousand single-gene diseases in which the biochemical defect remains to be determined.
  • 27 Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 203 - 254 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The general concept of inborn errors of metabolism and their genetic causes and consequences • How certain mutations can disrupt biochemical pathways and lead to clinical symptoms • That organ involvement is dependent on the tissue-specific expression of the genes in question • Depending on the location of a mutation in the gene and the gene product the clinical symptoms may display great variability • The function of the normal gene products and how abnormal gene products impair or interfere with normal function • Available testing and treatment strategies for the diseases discussed • How individuals metabolize drugs and toxins in different ways Know: • The diseases and conditions discussed, their biochemical and clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture Pharmacogenetics • Definition • Drug metabolism • Genetic variation in response to drugs • Glucose 6-phosphatase deficiency o Function of G6PD and pathway location o Effects of G6PD deficiency on RBCs o Genetics of G6PD deficiency • N-acetyltransferase variants o Inactivation of drugs by acetylation • Succinylcholine sensitivity • Malignant hyperthermia • Acute Intermittent Porphyria o Heme biosynthesis o Porphyrias o Drugs implicated in AIP attacks
  • 28 Other disorders • Zellweger syndrome o Phenotype o Molecular genetics • Wilson’s disease o General features o Clinical features and phenotype o Genetics o Treatment • Menke’s syndrome • Hereditary hemochromatosis o Phenotype o General features o Genetics o Normal and abnormal gene products o Clinincal symptoms o Progression of disease • Refsum disease • Williams syndrome Week 11, Monday – Wednesday Treatment of Genetic Disease; Recombinant DNA and Gene Therapy In the first part of this lecture an overview of traditional ways to treat genetic diseases, such as avoidance, restriction, removal, and replacement is provided, followed by an overview of current and future ways of treating genetic diseases on the molecular level. Particular emphasis is on technical and ethical aspects of gene therapy. Certain experimental and in vitro methods are introduced. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 255 - 276 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The required consideration for the treatment of genetic diseases • The different traditional approaches of treatment, depending on the actual disease • The basic concept of gene therapy and practical difficulties • Techniques used to accomplish gene therapy • The role of animal models for the understanding of human diseases
  • 29 • Various approaches of recombinant DNA technology to manipulate the genome of cells and animals with the prospect of treating human diseases in the future • The necessary considerations for gene therapy • The value of experimental in vitro and in vivo procedures for modulation of gene expression and gene therapy Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture: • Current state of treatment of multifactorial diseases • Single gene disorders • Considerations for treatment of genetic diseases • Long-term assessment • Side effects • Genetic heterogeneity • Treatment strategies • Avoidance: G6PD • Dietary restriction: PKU • Replacement: homozygous FH, SCID, Sickle Cell disease, cystinosis • Removal: Wilson’s disease, hemochromatosis, fam. Polyposis of coli • Diversion: urea cycle disorders, FH • Inhibition: hypercholesterolemia • Depletion: hypercholesterolemia • Treatment at protein level: hemophilia, alpha1 AT, ADA,glucocerebrosidase • Treatment with excessive substrate of coenzyme • Modulation of gene expression: butyrate therapy, transplantation Recombinant DNA Technology • Transgenic and cloned animals • Embryonic stem cells • Germline transmission • Introduction of genes into mice via ES cells • Isolation of mouse ES cells: positive and negative selection • Gene targeting and homologous recombination • Knock-in strategy • Double replacement • Generation of gene-targeted knock-out mice • Conditional gene knock-outs: the Cre-lox system • Humanized and genetically engineered antibodies • Somatic animal cloning • Gene therapy: considerations o Target cell o Gene transfer strategy o Minimal requirements for gene therapy o DNA transfer into cells o Risks of gene therapy and ethical considerations o Feasibility of gene therapy for single gene disorders • Candidate diseases for gene therapy o SCID o Hemophilia B
  • 30 o DMD o SCID X1 • Examples for gene therapy trials • Approaches to gene therapy • Targeted inhibition of gene expression in vivo • Use of ribozymes • Use of antisense RNA or DNA • Direct inhibition of protein function • Ex-vivo gene augmentation: SCID • Genetic modification of cultured tumor-infiltrating lymphocytes • In vivo gene therapy for brain tumors Week 11, Thursday, Friday Mitochondrial and Complex Inheritance In this lecture we will discuss the genetics of mitochondrial inheritance and diseases as well as disorders with complex inheritance. Mitochondrial DNA mutates at a much higher rate than nuclear DNA and is therefore much more prone to developing diseases that follow a characteristic pattern of strict maternal inheritance. Common mitochondrial diseases and their biochemical and clinical features will be addressed. Disorders with complex or multifactorial inheritance have received a great deal of attention in the past decade. These diseases result from complex interactions between a number of predisposing genetic factors and a variety of environmental exposures that ultimately trigger, accelerate, or exacerbate the disease. Such diseases cluster in families, however, they do not follow simple mendelian patterns of inheritance. Reading Assignments Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 289 - 310 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The function and genetics of mitochondria • The genetics of mitochondrial diseases • Variable expressivity and broad organ involvement in mitochondrial diseases • The complex nature of multifactorial disorders • The concept of concordance and discordance and the importance of twin studies • The concept of case control studies Know:
  • 31 • How to identify mitochondrial and multifactorial patterns of inheritance in family trees • The diseases discussed and their clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Content of Lecture • Characteristics of multifactorial disorders • Characteristics of mitochondrial inheritance • Mitochondria o Oxidative phosphorylation and mitochondrial diseases o Genetics of mitochondrial diseases o Organ involvement and phenotype of mitochondrial diseases o Maternal inheritance o Pedigree patterns of mitochondrial diseases o Homoplasmy and heteroplasmy o Mitochondrial function and nuclear gene involvement o Multifactorial aspects of mitochondrial diseases • Multifactortial inheritance o Genetic analysis of qualitative traits o Familial aggregation: measured in lambda r o Concordance and discordance o Case control studies o Relative contributions of genes and environment to complex disease traits o Twin studies o Genetic analysis of quantitative traits o Familial aggregation of quantitative traits o Heritability (h2) o Characteristics of inheritance of complex diseases • Diseases with complex inheritance o Digenic retinitis pigmentosa o Cerebral venous thrombosis o Hirschsprung Diseasae o Type 1 DM o Alzheimer diseaseq o Neural tube defects o Cleft lip and palate o Coronary Artery disease • Genetic counseling of families if patients with multifactorial diseases • Patterns of multifactorial inheritance Week 12, Monday - Thursday Genetics of Cancer Cancer is one of the most common and most severe diseases seen in modern medicine. It is a genetic disease of somatic cells resulting from a variety of causes such as aberrant cell division, evasion of apoptosis, or by genetic predisposition through inheritance. In this lecture we will discuss the type of genes that have been
  • 32 implicated in initiating cancer and the mechanisms by which dysfunction of such genes can result in the disease. A number of heritable cancer syndromes is described, allowing insight into their pathogenesis and into cancer in general. Reading assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 311 - 333 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The biology and molecular changes underlying the development of cancer • That the development of cancer is a slow process that involves a number of steps • Not all tumors and neoplasms are automatically cancers • That some cancers run in families • The concept of oncogenes and tumor suppressor genes and proteins • Basic features of malignantly transformed cells • The concept of “loss of heterozygosity” • That cytogenetically visible chromosome translocations cause certain cancers • That failure of repair of damaged DNA may lead to cancer • The differences between malignant and benign tumors • The various approaches for the treatment of cancer • The difficulties in the treatment of chromosome instability syndromes • The importance of disrupted or constitutively active signal transduction pathways for the development of cancer Know: • The cancers discussed, their molecular causes, etiology, and clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Contents of Lecture • Cancers in the US • Cancer as function of age • Cancer biology • Progress of metastasis • Main forms of cancer • Genetic basis of cancer • Cancer in families • Oncogenes • Multiple endocrine adenomatosis type 2 • Hereditary papillary renal carcinoma • Activation of oncogenes in sporadic cancer • Loss of contact inhibition • Mutations in Ras • Growth factors and signal transduction pathways • Oncogenes and signal transduction • Oncogenes and cell survival • Chromosomal translocations and activation of oncogenes
  • 33 • Chronic myeloid leukemia • Burkitt lymphoma • Follicular B-cell lymphoma • Telomerase as oncogene • Tumor suppressor genes and proteins • Tumor suppressor genes in AD cancer syndromes • Retinoblastoma • Li Fraumeni syndrome • NF type 1 • Familail breast cancer: BRCA 1 and 2 • Familial colon cancer: HNPCC; FAP • Herefitary lymphoma with loss of expression of pro-apoptotic tumor suppressor genes • Loss of heterozygosity • Li Fraumeni syndrome and p53 • Ras activation downstream of receptor proteion tyrosine kinases • Homologous recombination-directerd DNA repair • Double strand break repair • PTEN hamartoma tumor syndrome • PTEN tumor suppressor • Von Hippel-Lindau syndrome • Wilms tumor • Familial Polyposis of coli • FPP and APC (adenomatous polyposis of coli) • HNPCC • DNA mismatch repair pathway • HNPCC and replication error positive (RER+) phenotype • Hereditary lymphoma • ALPS • Chromosome Instability Syndromes • Ataxia telangiectasia • Fanconi anemia • Bloom syndrome • Nucleotide excision repair • Cockayne syndrome • Xeroderma pigmentosum • Loss of tumor suppressor genes in sporadic cancers • Tumor progression by clonal evolution and cytogenetic changes • Gene amplification • Cancer and environment • Chemical carcinogens Week 12, Friday Review Learning Objectives for Examination 4 • Learn and understand the terminologies discussed making sure all the keywords and terms are completely understood. • Be proficient in application of the knowledge acquired in this section.
  • 34 • Be able to integrate and understand the fundamental scientific and clinical importance of the topics discussed. Week 13, Monday Examination 4 Week 13, Tuesday Review Examination 4 Week 13, Wednesday - Friday Developmental Genetics The development of a human being from a single undifferentiated cell (zygote) is an extraordinarily complex process. In this lecture we first review the basic principles of developmental biology, followed by a thorough discussion of the genes and hierarchies involved in human development. Developmental problems and malformations will be addressed and discussed. Reading Assignment: Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 335 - 358 Learning Objectives: Learn the terminology discussed and be proficient at its application Understand: • The basics of developmental biology • The different stages of development • The concept of regulative and mosaic development • The involvement of “master regulator” genes in development • The process of morphogenesis • The importance of PAX and HOX genes • How paracrine signaling influences development • The importance of somatic and embryonic stem cells and potential ethical dilemmas • What may cause birth defects and congenital syndromes • The importance of teratogens for developmental problems
  • 35 Know: • The diseases and conditions discussed and their clinical features Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Content of Lecture • Introduction to Developmental Biology • Concepts, Terms and Definitions • Importance of Model Organisms • PAX6 gene • Fertilization to Gastrulation • Regulative and mosaic development • Gastrulation and developmental abnormalities • Gene expression during development o Rubestein-Taybi syndrome • Stability of differentiated phenotype and cell lineage • Stem cells and regeneration • Hierarchy of developmental programs and progressive restrictions of cell fate o Waardenburg syndrome • Neural crest formation: PAX3 and MITF involvement o Piebaldism and KIT gene • Morphogenesis • HOX genes: transcription factors and developmental Identity o HOX13 mutations and synpolydactyl • Paracrine Signals in development o Sonic Hedhehog (SHH) o Sonic Hedgehog morphogen and holoprosencephaly o Werner syndrome (progeria) • Developmental Genetics in Cliinical Practice • Isolated birth defects, syndromes and sequences o Cornelia de Lange syndrome o Robin sequence • Malformations and deformations • Disruptions • Teratology • Teratogens o Thalidomide and its effects o Fetal alcohol syndrome • Reproductive genetics • Genetic determination and stochastic processes in development • Recent advances in developmental genetics Week 14, Monday, Tuesday Genetic Screening and Prenatal Diagnosis Genetic disease affects individuals and their families dramatically but every person and every couple having children is at some risk of having a disorder with a genetic component suddenly appearing. Several screening approaches and the inherent advantages but also problems will be discussed.
  • 36 Over the past three decades prenatal diagnosis has been widely accepted and used. Prenatal diagnosis is a frequently chosen option for couples who are at high risk of having a child with a serious hereditary disorder. This lecture introduces the available techniques for prenatal diagnosis and the insights and information they provide. Reading Assignments Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 359 - 374 Learning Objectives Learn the terminology discussed and be proficient at its application Understand: • What information prenatal diagnosis can provide • The limitations of prenatal diagnosis • Invasive vs. noninvasive testing • The tests available and how and when they are performed • The pros and cons of screening programs Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine. Content of Lecture • Goals of prenatal diagnosis • Indications • Invasive and noninvasive testing • Indications for invasive testing • Genetic counseling for prenatal diagnosis • Amniocentesis • Chorionic villus sampling • Cordocentesis • Maternal serum screen for alpha fetoprotein • Triple screen • Ultrasonography • Emerging technologies for prenatal diagnosis o Preimplantation genetic diagnosis o Fetal cells in maternal blood • Cytogenetics in prenatal diagnosis
  • 37 • Mosaics • Biochemical assays for metabolic diseases • DNA analysis • Case discussions: o Spinal muscular atrophy type I o Achondrogenesis type II o Trisomy 13 o Pallister-Killian syndrome Week 14, Wednesday – Friday Genetic Counseling and Risk Determination: Baye’s Theorem This lecture addresses the process of genetic counseling in providing information and risk assessment. Reading Assignments Nussbaum, R.L., McInnes, R.R., and Huntington, F.W. Thompson & Thompson – Genetics in Medicine 6th edition (2001) Pages 375 - 389 Learning Objectives Learn the terminology discussed and be proficient at its application Understand: • The principle of genetic counseling • Indications and considerations for • Ethical considerations • How to approach risk assessment in the absence of certain information • How to apply Baye’s theorem in a variety of cases Know: • The essential steps in genetic counseling Be proficient at integration of the learned material into the greater concept of medical genetics and clinical medicine.
  • 38 Content of Lecture • Ethical Principles of counseling • Indications for referral • Counseling case management • Legal and ethical considerations • Common problems • Critical ethical issues • Essential steps in Genetic Counseling • Genetics and Society • Criteria for newborn screening programs • Criteria for heterozygote screening programs • Risk assessment • Laws of addition and multiplication • Use of Mendelian and Hardy-Weinberg principles in risk assessment • Baye’s Theorem • Sequential steps in Bayesian assessment of risk • Linkage and pedigree analysis data in risk assessment • Isolated cases of X-linked disorders • Disorders with incomplete penetrance • Familial form of Parkinson’s disease • Application of molecular genetics to determine recurrence risk Week 15, Monday – Friday Review and Clinical Case Discussions A number of clinical cases will be presented and discussed in-depth. The emphasis of these discussions is to integrate selected diseases and/or metabolic states. Learning Objectives: 1. Develop or improve the ability to think laterally with a complete or a limited amount of information available (i.e. all or only a few clinical symptoms of a particular condition/disease are present in a patient) using clinical cases 2. Understand the clinical importance of genetic defects and the resulting pathophysiologic consequences Week 16 Final Exam Week Learning objectives for the final exam • Learn and understand the terminologies discussed in this course, making sure all the keywords and terms are completely understood. • Be proficient in application of the knowledge acquired in this course • Be able to integrate and understand the fundamental scientific and clinical importance of human metabolism in health and disease.
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