Genetics and internal medicine (1& 2)


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Genetics and internal medicine (1& 2)

  1. 2. Genetics Course: Mastering Medical Genetics Dr. Ahmed Elshebiny , MD Lecturer of Internal Medicine Faculty of Medicine, Menoufyia University Former Clinical Research Fellow, Joslin Diabetes Center, Harvard University
  2. 3. Course includes <ul><li>Basic Principles of Medical Genetics </li></ul><ul><li>Genetic basis of disease: How diseases could be inherited? </li></ul><ul><li>Medical Genetics in Clinical Practice : What is the impact of genetics on the present and future of Medicine? </li></ul><ul><li>Let us start with this introductory video about genes </li></ul>
  3. 4. Medical Genetics <ul><li>Any application of genetic principles </li></ul><ul><li>to medical practice. </li></ul><ul><li>“ Genetics – study of individual genes and their effects” </li></ul>
  4. 5. Outline The Genetics course Basics Diseases Applications Structure & Facts Functions Inherited disorders Gene Therapy Cloning Stem Cell Genetic Testing
  5. 6. <ul><li>The Human Genome </li></ul><ul><li>DNA structure and packaging </li></ul><ul><li>Mitochondrial DNA </li></ul><ul><li>Chromosomal Morphology </li></ul><ul><li>Chromosome Replication </li></ul><ul><li>Gene Expression </li></ul><ul><li>Meiosis , Mitosis and Gametogenesis </li></ul><ul><li>Epigenetics </li></ul><ul><li>Population Genetics </li></ul><ul><li>Consanguinity </li></ul><ul><li>Family medical History </li></ul><ul><li>Inherited disorders </li></ul><ul><li>Mendelian inheritance </li></ul><ul><li>Non Mendelian inheritance </li></ul><ul><li>Cytogenetic abnormalities </li></ul>Basic Principles of Medical Genetics Structure & Facts of the Human Genome Functions & Physiology Clinical Genetics
  6. 7. 2- Genetic basis of disease <ul><li>Chromosomal abnormalities </li></ul><ul><li>Genetics of Metabolism </li></ul><ul><li>Genetics of Hemoglobinopathies </li></ul><ul><li>Genetics of Bleeding disorders </li></ul><ul><li>Genetics of Development </li></ul><ul><li>Cancer Genetics </li></ul>
  7. 8. 3-Medical Genetics in Clinical Practice <ul><li>Genetic testing </li></ul><ul><li>Genetic screening </li></ul><ul><li>Molecular diagnostics </li></ul><ul><li>Genetic engineering </li></ul><ul><li>Gene Therapy </li></ul><ul><li>Stem cell therapy </li></ul><ul><li>Cloning </li></ul>
  8. 9. Genetics Course (1): Mastering Medical Genetics Basic Principles of Medical Genetics
  9. 10. The Human Nuclear Genome <ul><li>Genome = all of the DNA in an organism or cell </li></ul><ul><li>Size of human genome: 3.4 billion base pairs </li></ul><ul><li>Number of human genes: ~30,000 </li></ul><ul><li>Genes vary in length and can cover thousands of bases average size: ~3,000 bp </li></ul><ul><li>Only about 2% of the human genome contains coding genes </li></ul><ul><li>Action of much of the genome is unknown </li></ul>
  10. 11. DNA Structure
  11. 12. DNA Structure
  12. 13. Epigenetics <ul><li>Epigenetics is the study of heritable changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: επί - over, above) -genetics . </li></ul><ul><li>These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. </li></ul>
  13. 14. Chromosome Facts <ul><li># of chromosomes per somatic cell: 22 pairs + 1 pair sex-determining chromosomes = 46 </li></ul><ul><li># of chromosomes per gamete (egg/sperm): 23 </li></ul><ul><li>One chromosome of each pair donated from each parent’s egg or sperm </li></ul><ul><li>Sex chromosomes: XY for males; XX for females </li></ul><ul><li>Largest chromosome #1 = ~263 million base pairs (bp) </li></ul><ul><li>Smallest chromosome Y = ~59 million bp </li></ul>
  14. 15. Chromosomal morphology methods <ul><li>Chromosomal staning </li></ul><ul><li>FISH </li></ul>
  15. 16. Chromosomal Banding
  16. 17. Chromosomes
  17. 18. Mitochondrial DNA <ul><li>Circular </li></ul><ul><li>Several copies </li></ul><ul><li>No histones </li></ul>
  18. 19. Function of DNA The Human genome functions
  19. 20. Gene Expression <ul><li>Transcription </li></ul><ul><li>Translation </li></ul>
  20. 21. Meiosis , Mitosis and Gametogenesis <ul><li>Mitosis is the process by which a cell separates its duplicated genome into two identical halves </li></ul><ul><li>Meiosis is the process that transforms one diploid into four haploid cells. </li></ul>Where do your genes come from?
  21. 22. Genomic imprinting <ul><li>Most genes expressed equally from both alleles </li></ul><ul><li>Small number of genes show differential expression dependent on parent of origin (mainly on chromosomes 6,7,11,14,15) </li></ul><ul><li>‘ Imprint’ is mediated by methylation  transcriptional inactivation </li></ul><ul><li>Imprint persists through cell divisions in embryo </li></ul><ul><li>Imprint removed at gametogenesis and then re-established according to sex of transmitting parent </li></ul>
  22. 23. Population Genetics <ul><li>Is the study of distributions of genes in populations </li></ul><ul><li>Disease frequency </li></ul><ul><li>Genotype frequencies from generation to generation </li></ul><ul><li>Genetic Polymorphisms </li></ul>SNPs
  23. 24. Polymorphism <ul><li>Occurrence of 2 or more alleles at aspecific genetic locus in frequencies greater than can be explained by mutations alone </li></ul><ul><li>Single nucleotide polymorphisms </li></ul><ul><li>Restriction fragment length polymorphism (RFLP) </li></ul><ul><li>Variable number tandem repeat polymorphism (VNTR) </li></ul>
  24. 25. Clinical genetics <ul><li>Clinical genetics is the practice of clinical medicine with particular attention to hereditary disorders. </li></ul>
  25. 26. Inherited disorders <ul><li>Cytogenetic </li></ul><ul><li>Single gene </li></ul><ul><li>Polygenic </li></ul><ul><li>Multifactorial </li></ul>
  26. 27. Clinical Genetics <ul><li>Genotype: An individual’s genetic makeup - forms of a particular gene at a given locus </li></ul><ul><li>Phenotype: The observable expression of a genotype </li></ul><ul><li>Homozygous: Identical forms of a particular gene </li></ul><ul><li>Heterozygous: Different forms of a gene– CARRIER if one normal and one abnormal </li></ul><ul><li>Dominant: Condition phenotypically expressed in someone carrying one copy of a mutant gene </li></ul><ul><li>Recessive: Condition phenotypic ally expressed only in someone with two copies of the mutant gene </li></ul>
  27. 28. Autosomal dominance <ul><li>Vertical transmission </li></ul><ul><li>On average, 50% of offspring of affected parent will be affected </li></ul><ul><li>Unaffected individuals do not transmit trait </li></ul><ul><li>Males and females equally affected </li></ul>
  28. 29. Autosomal Dominant Conditions <ul><li>Marfan Syndrome </li></ul><ul><li>Achondroplasia </li></ul><ul><li>Familial (early-onset) Alzheimer Disease </li></ul><ul><li>Huntington Disease </li></ul><ul><li>Familial Hypercholesterolemia </li></ul><ul><li>Familial Breast Cancer (BRCA1 or BRCA2 mutations) </li></ul>
  29. 30. Autosomal Recessive Inheritance <ul><li>Horizontal transmission; disease in siblings but usually not in earlier generations (unaffected, carrier parents) </li></ul><ul><li>On average, 25% recurrence risk </li></ul><ul><li>Males and females equally affected </li></ul><ul><li>Increased consanguinity (relatedness) seen </li></ul>
  30. 31. Autosomal Recessive Conditions <ul><li>Sickle cell disease </li></ul><ul><li>Cystic fibrosis </li></ul><ul><li>Tay-Sachs disease </li></ul><ul><li>Hemochromatosis </li></ul><ul><li>Phenylketonuria </li></ul><ul><li>Thalassemias </li></ul>
  31. 32. X-linked recessive inheritance <ul><li>Incidence of trait is much higher in males than females </li></ul><ul><li>No father-to-son transmission </li></ul><ul><li>100% of daughters of affected males are (unaffected) carriers </li></ul><ul><li>50% of sons of carrier females are affected and 50% of daughters are carriers </li></ul><ul><li>Trait may be transmitted through series of carrier females </li></ul>
  32. 33. X-linked recessive conditions <ul><li>Haemophilia </li></ul><ul><li>Duchenne and Becker muscular dystrophy </li></ul><ul><li>Androgen insensitivity syndrome </li></ul><ul><li>Hunter syndrome </li></ul><ul><li>Glucose-6-phosphate-dehydrogenase deficiency </li></ul><ul><li>Bruton agammaglobulinaemia </li></ul>
  33. 34. Xplinked dominant <ul><li>Males and females affected, females usually less severely affected than males </li></ul><ul><li>1 in 2 risk to children of affected female (M+F) </li></ul><ul><li>All daughters of affected male affected but no male to male transmission </li></ul>
  34. 35. X-linked dominant inheritance <ul><li>Males and females affected </li></ul><ul><li>Vitamin D resistant rickets </li></ul><ul><li>OTCD </li></ul><ul><li>Fragile X syndrome </li></ul><ul><li>Lethal in males </li></ul><ul><li>Incontinentia pigmenti </li></ul><ul><li>Rett syndrome </li></ul><ul><li>XL chondrodysplasia punctata </li></ul><ul><li>Goltz syndrome </li></ul>
  35. 36. Mitochondrial inheritance <ul><li>Mitochondria are exclusively maternally inherited </li></ul><ul><li>Males and females affected but only females will transmit to offspring </li></ul><ul><li>Risks to offspring of affected or carrier females are difficult to determine 0-100% </li></ul>
  36. 37. Family Medical History <ul><li>family medical history represents a “genomic tool” that can capture the interactions of genetic susceptibility, shared environment and common behaviors in relation to disease risk. </li></ul>
  37. 38. References <ul><li>Merck manual : online textbook </li></ul><ul><li>E-medicine , online textbook , </li></ul><ul><li>specialties,. </li></ul><ul><li>BRS series : Genetics 2010 </li></ul><ul><li>Lecture notes : Genetics (2006) </li></ul><ul><li>Kumar & Klark : Clinical Medicine 2009 </li></ul><ul><li>Other Web Resources & books </li></ul>
  38. 39. THANK YOU
  39. 40. Genetics Course (2): Mastering Medical Genetics Genetic Basis of Disease
  40. 41. Genetic basis of disease <ul><li>Cytogenetic abnormalities </li></ul><ul><li>Genetics of Metabolism </li></ul><ul><li>Genetics of Development </li></ul><ul><li>Genetics and CV disease </li></ul><ul><li>Genetics and Respiratory disease </li></ul><ul><li>Genetics of Hemoglobinopathies </li></ul><ul><li>Genetics of Bleeding disorders </li></ul><ul><li>Genetics and kidney </li></ul><ul><li>Genetics and GIT </li></ul><ul><li>Genetics and Rheumatic disease </li></ul><ul><li>Genetics and Neurological disease </li></ul><ul><li>Cancer & Genes </li></ul>Cytogenetic Single gene Polygenic
  41. 42. Inherited disorders <ul><li>Cytogenetic </li></ul><ul><li>Single gene </li></ul><ul><li>Polygenic </li></ul><ul><li>Multifactorial </li></ul>Cytogenetic Single gene Polygenic and multifactorial
  42. 43. MCQ 1 <ul><li>All are single gene disorders except: </li></ul><ul><li>Polyposis coli </li></ul><ul><li>Sickle cell anemia </li></ul><ul><li>Turner’s syndrome </li></ul><ul><li>Alport’s syndrome </li></ul>
  43. 44. MCQ 2 <ul><li>Point mutations are the cause of the following except: </li></ul><ul><li>Sickle cell anemia </li></ul><ul><li>Cystic fibrosis </li></ul><ul><li>Diabetes Mellitus </li></ul><ul><li>Beta thalassemia </li></ul>
  44. 45. understanding genetic basis of disease helps guide therapy <ul><li>Dietary restriction can eliminate compounds toxic to patients with certain genetic defects, such as phenylketonuria or homocystinuria. </li></ul><ul><li>Supplementation: folic acid reduces homocysteine levels in people with 5,10-methylene tetrahydrofolate reductase polymorphism. </li></ul>
  45. 46. Cytogenetic abnormalities <ul><li>Numerical Chromosomal abnormalities </li></ul><ul><li>Structural chromosomal abnormalities </li></ul><ul><ul><ul><li>Deletions </li></ul></ul></ul><ul><ul><ul><li>Micro-deletions </li></ul></ul></ul><ul><ul><ul><li>Translocations </li></ul></ul></ul><ul><ul><ul><li>Ring Chromosomes </li></ul></ul></ul><ul><ul><ul><li>Breakage </li></ul></ul></ul><ul><ul><ul><li>Isochromosomes </li></ul></ul></ul>Numerical Structural
  46. 47. Numerical Chromosomal abnormalities <ul><li>Polyploidy ( e.g Vesicular mole) </li></ul><ul><li>Aneuploidy ( Sex chromosomes, Autosomal) </li></ul><ul><ul><ul><li>Monosomy </li></ul></ul></ul><ul><ul><ul><li>Triosomy </li></ul></ul></ul><ul><li>Mixploidy </li></ul><ul><ul><ul><li>Mosaicism </li></ul></ul></ul><ul><ul><ul><li>Chimerism </li></ul></ul></ul>
  47. 49. Turner Syndrome ( Monosomy X) <ul><li>a female does not have the usual pair of two X chromosomes. </li></ul><ul><li>Commonly (Mosaic) </li></ul><ul><li>Turner syndrome occurs in about 1 out of 2,000 live births. </li></ul><ul><li>Short stature (142-152 cm) </li></ul><ul><li>Absent menstruation </li></ul><ul><li>Infertility </li></ul><ul><li>Physical features </li></ul>
  48. 50. Turner syndrome
  49. 51. Turner’s associated complications <ul><li>Heart defects </li></ul><ul><li>Hypothyroidism </li></ul><ul><li>Kidney problems </li></ul><ul><li>Arthritis </li></ul><ul><li>Diabetes </li></ul><ul><li>Cataract </li></ul>
  50. 52. Treatment of Turner syndrome <ul><li>GH </li></ul><ul><li>Estrogen: start at 12 or 13 years </li></ul><ul><li>Cardiac surgery when needed </li></ul><ul><li>IVF ( to achieve pregnancy) </li></ul><ul><li>Psychological support </li></ul>
  51. 53. Is Turner Syndrome “hereditary”? <ul><li>Although it is a genetic disorder, it is not usually hereditary </li></ul><ul><li>There are no known environmental causes of the syndrome </li></ul><ul><li>Women with Turner Syndrome are usually infertile </li></ul>
  52. 54. Klinfilter syndrome
  53. 55. 47,XXY
  54. 56. Klinefelter Syndrome <ul><li>Clinical Features </li></ul><ul><li>Hypogonadism </li></ul><ul><li>Reduced testosterone levels </li></ul><ul><li>Infertility </li></ul><ul><li>Tall stature </li></ul><ul><li>Gynaecomastia </li></ul><ul><li>Educational difficulties – Intelligence can be 10-15 points lower than siblings but usually in normal range </li></ul><ul><li>Behavioural problems. </li></ul><ul><li>Ttt: </li></ul><ul><li>testosterone therapy may help </li></ul>
  55. 57. Other sex Chromosomal aneuploidies <ul><li>Triple X ( 47, XXX) </li></ul><ul><li>47, XYY males </li></ul>
  56. 58. Autosomal Aneuploidies <ul><li>Triosomy 21 (Dawn) </li></ul><ul><li>Triosomy 13 (Patau) </li></ul><ul><li>Triosomy 18(Edward) </li></ul>
  57. 59. Dawn syndrome
  58. 60. Microdeletion Syndromes <ul><li>DiGeorge </li></ul><ul><li>Williams </li></ul>
  59. 61. 2-Genetics and Metabolism
  60. 62. Genetics and metabolism Carbohydrate Lipids Amino acid Degradation Urea cycle Transport
  61. 63. Genetics of Carbohydrate Metabolism <ul><li>Carbohydrate </li></ul><ul><li>Galactosemia </li></ul><ul><li>Fructosuria </li></ul><ul><li>Lactose intolerance </li></ul><ul><li>Glycogen storage diseases </li></ul>
  62. 64. Genetics of Lipid Metabolism <ul><li>Familial hypercholesterolemia (AD) </li></ul><ul><li>(LDLR gene) </li></ul>
  63. 65. Genetic diseases involving degradation pathways <ul><li>Mucopolysacharoidosis </li></ul><ul><li>Hexoaminidase difficiency </li></ul>Tay –Sach’s disease Hunter syndrome video
  64. 66. Tay-Sachs disease <ul><li>Single gene </li></ul><ul><li>Hexaminidase enzyme difficiency </li></ul><ul><li>Accumulation of ganglioside GM2 </li></ul>
  65. 67. Genetics of transport pathways <ul><li>Menke’s disease </li></ul><ul><li>Wilson </li></ul><ul><li>Hemochromatosis </li></ul>
  66. 68. Trinucleotide repeat disorders <ul><li>Fragile X syndrome, Xplinked </li></ul><ul><li>Huntington’s disease, AD </li></ul><ul><li>Myotonic Dtstrophy, AD </li></ul><ul><li>Fridreich’s ataxia </li></ul>
  67. 69. Fragile X syndrome <ul><li>learning disabilities and mental retardation. </li></ul><ul><li>Usually males are more severely affected by this disorder than females. </li></ul><ul><li>In addition to learning difficulties, affected males tend to be restless, fidgety, and inattentive. </li></ul><ul><li>Affected males also have characteristic physical features that become more apparent with age. </li></ul>Fragile x video
  68. 70. Fragile X syndrome
  69. 71. 4-Genetics and CV disease <ul><li>Long Q-T syndromes </li></ul><ul><li>Marfan </li></ul><ul><li>Atherosclerosis </li></ul><ul><li>Brugada </li></ul>
  70. 72. Marfan Syndrome <ul><li>Fibrilin 1 gene on chromosome 15 </li></ul><ul><li>Intilligence is usually normal </li></ul><ul><li>Tall stature with disproportionate long limbs </li></ul><ul><li>Muscloskletal, Heart, eye, skin, pulmonary </li></ul><ul><li>Ghent criteria </li></ul>Marfan syndrome video
  71. 73. 5-Cystic fibrosis
  72. 74. Cystic fibrosis
  73. 75. 6-Genetics in Hematology <ul><li>Hereditary and congenital Anemias </li></ul><ul><li>Porphyrias </li></ul><ul><li>Bleeding disorders </li></ul><ul><li>Inherited thrombophilia </li></ul>
  74. 76. Sickle cell disease
  75. 77. 7- Genetics and Rheumatology <ul><li>FMF </li></ul>
  76. 78. Genetics and Renal diseas <ul><li>PKD </li></ul><ul><li>Alport </li></ul><ul><li>Genetic heterogenicity </li></ul>
  77. 79. 8- Genetics and Neurology <ul><li>Hereditary Ataxias </li></ul><ul><li>Huntington </li></ul><ul><li>Charcot-Marie-Tooth disease </li></ul><ul><li>Alzheimer </li></ul><ul><li>Mental Retardation </li></ul><ul><li>Neurocutaneous </li></ul>
  78. 80. 9-Tumors, Cancer and Genes <ul><li>Polyposis syndromes </li></ul><ul><li>Heriditary non polyposis CC </li></ul><ul><li>MEN </li></ul><ul><li>Cancer vaccines </li></ul>
  79. 81. <ul><li>Neurofibromatosis </li></ul><ul><li>Tuberous sclerosis </li></ul>
  80. 82. Jewish Heritage Screening <ul><li>Tay-Sachs disease (TSD) </li></ul><ul><li>Niemann pick disease </li></ul><ul><li>Mucolipidosis type IV (MLIV) </li></ul><ul><li>Gaucher disease </li></ul><ul><li>Familial dysautonomia   </li></ul><ul><li>Fanconi anemia </li></ul><ul><li>Bloom syndrome </li></ul><ul><li>Canavan syndrome </li></ul>
  81. 83. Multifactorial and Polygenic disorders <ul><li>Asthma </li></ul><ul><li>Autism </li></ul><ul><li>Multiple Sclerosis and other such diseases which are Autoimmune in nature </li></ul><ul><li>Cancers </li></ul><ul><li>Ciliopathies </li></ul><ul><li>Cleft Palate </li></ul><ul><li>Diabetes </li></ul><ul><li>Heart Disease </li></ul><ul><li>Hypertension </li></ul><ul><li>Inflammatory Bowel Disease </li></ul><ul><li>Mental Retardation </li></ul><ul><li>Obesity </li></ul>
  82. 84. References <ul><li>Merck manual : online textbook </li></ul><ul><li>E-medicine , online textbook , </li></ul><ul><li>specialties,. </li></ul><ul><li>BRS series : Genetics 2010 </li></ul><ul><li>Lecture notes : Genetics (2006) </li></ul><ul><li>Kumar & Klark : Clinical Medicine 2009 </li></ul><ul><li>Other Web Resources & books </li></ul>
  83. 85. THANK YOU