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Medical Genetics

Medical Genetics. Mohammed El- Khateeb Dental Postgraduate MG - Lec . 1 3 ed July 2013. OBJECTIVES. Basic understanding of clinical genetics Be able to draw, and understand, a family tree Have awareness of when you should be considering a genetic condition

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Medical Genetics

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  1. Medical Genetics Mohammed El-Khateeb Dental Postgraduate MG - Lec. 1 3ed July 2013

  2. OBJECTIVES • Basic understanding of clinical genetics • Be able to draw, and understand, a family tree • Have awareness of when you should be considering a genetic condition • Have a working knowledge of the most important genetic conditions • Know how & when to refer to local specialist genetics services

  3. What’s a ___? • Genetics : Is the branch of biology that deals with heredity and variation in all living organisms • The subfields of genetics : • Human genetics, • Animal genetics, • Plant genetics • Medical genetics

  4. What’s a ___? • Medical Genetics : Is the science or study of biological variation as it pertains to health and disease in human beings. Any application of genetic principles to medical practice. “Genetics – study of individual genes and their effects” Includes studies of inheritance, mapping disease genes, diagnosis, treatment, and genetic counseling

  5. History of Medical Genetics Early Genetics - Biblical, Talmud Mendel - 1860s Modern Experimental Genetics - 1900s Maize, drosophila, mouse Medical Genetics - 1960s to the present

  6. Foundations of Heredity Science • Variable traits are inherited • Gene – trait-specific unit of heredity • Alternative versionsof a gene (alleles)determine the trait • Each parent transmitsan allele to the offspring Gregor Mendel Charles Darwin

  7. Mendel studies seven characteristics in the garden pea

  8. Mendel deduced the underlying principles of genetics from these patterns • Segregation • Dominance • Independent assortment

  9. Alleles: alternative versions of a gene. The gene for a particular inherited character resides at a specific locus (position) on homologous chromosome. For each character, an organism inherits two alleles, one from each parent

  10. Prenatal Genetics 1970s - Prenatal Ultrasound & Amniocentesis Inheritance of Genetically Complex Disorders Non-Mendelian Genetics Genomic Imprinting Triple Nucleotide Repeats Mitochondrial Inheritance 1990s - Neuropsychiatric Disorders, Diabetes, Cardiovascular Interaction of genes with environmental triggers Medical Genetics: 1960s to the present • DNA Genetics • 1953 - Watson and Crick’s Double Helix • 1992 –2003 Human Genome Project • 2003 -> the future of medical dx & tx

  11. C19th:Mendel discovers basis of inheritance Darwin’s theory of natural selection 1953:Watson and Crick discover structure of DNA 1985: PCR 1986:Duchenne muscular dystrophy gene 1989:Cystic Fibrosis gene 1998:Decision to sequence entire human genome 2001:Human genome sequence completed

  12. What is DNA Day? April 1953 Drs. James Watson and Francis Crick determined the structure of DNA(double helix)

  13. What is DNA Day? April 1953 Drs. James Watson and Francis Crick determined the structure of DNA(double helix) April 2003 Human Genome Project determined the entire DNA sequence of a human(3 billion letters)

  14. What is DNA? • It's a history book - a narrative of the journey of our species through time. • It's a shop manual, with an incredibly detailed blueprint for building every human cell. • And it's a transformative textbook of medicine, with insights that will give health care providers immense new powers to treat, prevent and cure disease." Francis Collins

  15. Importance of Genetics to Medicine • >12 million Americans with genetic disorders (GD) • 80% of MR due to genetic component • 2-3% background population risk for a major birth defect (BD) • 15% overall miscarriage risk for any pregnancy • 25-50% first trimester miscarriage risk • 30-50% first trimester losses due to chromosome anomalies • >30% pediatric hospital admissions due to GD • GD affect all major systems, any age, any race, male or female

  16. Importance of Genetics to Medicine • Changing focus of medicine: • primary care physicians vs specialists • prevention vs treatment • genetic causation for both rare and common diseases • Human Genome Project • designer drugs • Problem based approach taken in medical schools • Genetics as the link between basic research & clinical observation

  17. Importance of Genetics to Medicine Triple theme: • Genetic traits as they segregate through families allows insights into health of the population • Flow of information from DNA to RNA to protein links genetics to physiology • Ethical issues linked to treatment, therapy options, research, decision-making and quality of life

  18. What are Genetic Variations? • Variations are simply differences in genetic sequence • Variation can be seen at every genetic level: • In the DNA • In the genes • In the chromosomes • In the proteins • In the function of proteins

  19. Classification of genetic disorders • Single gene • Chromosomal • Mitochondrial • Multifactorial • Somatic mutations (cancer)

  20. Single Gene Defects • Autosomal recessive • Autosomal dominant • X-linked recessive • X-linked dominant

  21. Exons Polyadenylation signal Start of transcription Termination codon UAA UAG UGA Initiation codon ATG Introns 5’ untranslated region 3’ untranslated region Basic Gene Structure Promoter

  22. Sickle Cell Anemia

  23. Inheritance R D X

  24. Single-Gene “Mendelian” Disorders • Structural proteins • Osteogenesisimperfecta and Ehlers-Danlos (collagens); Marfan syndrome (fibrillin); Duchenne and Becker muscular dystrophies (dystrophin) • Enzymes and inhibitors • Lysosomal storage diseases; SCID (adenosine deaminase); PKU (phenylalanine hydroxylase); Alpha-1 antitrypsin deficiency • Receptors • Familial hypercholesterolemia (LDL receptor) • Cell growth regulation • Neurofibromatosis type I (neurofibromin); Hereditary retinoblastoma (Rb) • Transporters • Cystic fibrosis (CFTR); Sickle cell disease (Hb); Thalassemias

  25. Single gene disorders • Single mutant gene has a large effect on the patient • Transmitted in a Mendelian fashion • Autosomal dominant, autosomal recessive, X-linked, Y-linked • Osteogenesisimperfecta - autosomal dominant • Sickle cell anaemia - autosomal recessive • Haemophilia - X-linked

  26. Fertilization: Diploid Genome • Each parent contributes one genome copy • Offspring cells have two near-identical copies

  27. Genes & chromosomes Chromosomes • Linear agglomeratesof proteins & DNAin the cell’s nucleus • Distributed evenlyupon division • Morgan (1910):Genes reside alongthe chromosomes

  28. Mitosis vs. meiosis Meiosis KM

  29. Cell Cycle

  30. Chromosomes Homologous chromosome: one of a matching pair of chromosomes, one inherited from each parent. Sister chromatids are identical

  31. Chromosome Number Constancy in Different Species • Buffalo 60 • Cat 38 • Dog 78 • Donkey 62 • Goat 60 • Horse 64 • Human beings 46 • Pig 38 • Sheep54

  32. Genetic Material (chromosomes pairs) Pair of homologous chromosomes Sister chromatids Centromere

  33. ISCN 1995 International System for Human Cytogenetic Nomenclature Group A (1-3) Group B (4-5) Group C (6-12, X) Group D (13-15) Group E (16-18) Group F (19-20) Group G (21-22)

  34. Numerical chromosome changes/aneuploidy • Result from errors occurring during meiotic or mitotic segregation • Structural chromosome changes Chromosomal Rearrangements

  35. Multifactorial inheritance • Familial clustering which does not conform to any recognized pattern of Mendelian inheritance • Determined by the additive effects of many genes at different loci together with the effect of environment • Examples include congenital malformations, asthma, schizophrenia, diabetes , hypertension

  36. Etiology of diseases. For any condition the overall balance of genetic and environmental determinants can be represented by a point somewhere within the triangle.

  37. Haemophilia Osteogenesis imperfecta Peptic ulcerDiabetes Club footPyloric stenosisDislocation of hip Duchenne muscular dystrophy Tuberculosis Scurvy Spina bifidaIschaemic heart diseaseAnkylosing spondylitis PhenylketonuriaGalactosaemia GENETICENVIRONMENTAL The contributions of genetic and environmental factors to human diseases RareGenetics simpleUnifactorialHigh recurrence rate CommonGenetics complexMultifactorialLow recurrence rate

  38. Polygenic diseases • The most common yet still the least understood of human genetic diseases • Result from an interaction of multiple genes, each with a minor effect • The susceptibility alleles are common • Type I and type II diabetes, autism, osteoarthritis

  39. Population Genetics • Identifies how much genetic variation exists in populations • Investigates factors, such as migration, population size, and natural selection, that change the frequency of a specific gene over time • Coupled with DNA technology, investigates evolutionary history and DNA identification techniques

  40. Non-Traditional Inheritence • Mitochondrial genes • Trinucleotide repeats • Genetic imprinting

  41. Mitochondrial Inheritance • Matrilineal mode of inheritance: only mother passes mitochondrial DNA to offspring • Higher spontaneous mutations than nuclear DNA • affects both males and females , but transmitted only through females • range of phenotypic severity due to heteroplasmy • Example: diabetes mellitus with sensorineuronal deafness

  42. Human Genome Project (HGP)

  43. Human Genome Project • Initiated by the same laboratories that brought you thermonuclear devices • 1990 taken over by NIH • Actually involved sequencing many genomes • First draft sequence in 2001, “completed” in 2003 (public effort and Celera Corp.) • DNA sequence in any two human beings is 99.9% identical only 0.1% is unique

  44. The human Genome project GoalsThe study of the genome • To determine the DNA sequence (exact order of A,T,G,C,) For all the DNA in human • To determine which segment of DNA represent individual genes (Protein Coding Unit

  45. Model organisms

  46. Mapping Human Genetic-based Diseases • Thousands known • Most genes mapped and sequenced

  47. OMIM Synopsis of the Human Gene Map (Updated 8 June 2012)

  48. OMIM Entry Statistics: Number of Entries in OMIM (Updated 7 June 2013)

  49. Applications of the Human Genome Project • Genetic testing ( diagnostic, presymptomatic screening, prenatal) • Gene therapy • Pharmacogenomics: Moving Away from “One-Size-Fits-All” Therapeutics

  50. Diagnosis and Prevention of Genetic Diseases • Diagnosis • Chromosomal Abberations • Single Gene Disorders • Preventions • Genetic Counseling • Prenatal Dignosis • Preimplantation Diagnosis

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