genetics and internal medicine (1& 2)
TRANSCRIPT
Genetics Course:Mastering Medical Genetics
Dr. Ahmed Elshebiny , MDDr. Ahmed Elshebiny , MDLecturer of Internal MedicineLecturer of Internal Medicine
Faculty of Medicine, Menoufyia UniversityFaculty of Medicine, Menoufyia University
Former Clinical Research FellowFormer Clinical Research Fellow,,Joslin Diabetes Center, Harvard UniversityJoslin Diabetes Center, Harvard University
Course includes1. Basic Principles of Medical Genetics 2. Genetic basis of disease: How diseases could be
inherited? 3. Medical Genetics in Clinical Practice : What is the
impact of genetics on the present and future of Medicine?
Let us start with this introductory video about genes
Medical Genetics Any application of genetic principles
to medical practice. “Genetics – study of individual genes
and their effects”
Outline
The Genetics course
Basics Diseases ApplicationsStructure & Facts
Functions
Inherited disorders
Gene Therapy
Cloning
Stem Cell
Genetic Testing
1. The Human Genome 2. DNA structure and packaging3. Mitochondrial DNA4. Chromosomal Morphology
5. Chromosome Replication6. Gene Expression7. Meiosis , Mitosis and Gametogenesis8. Epigenetics
9. Population Genetics10. Consanguinity11. Family medical History12. Inherited disorders13. Mendelian inheritance14. Non Mendelian inheritance15. Cytogenetic abnormalities
Structure & Facts of the Human Genome
Functions& Physiology
Clinical Genetics
2 -Genetic basis of disease1. Chromosomal abnormalities
2. Genetics of Metabolism
3. Genetics of Hemoglobinopathies
4. Genetics of Bleeding disorders
5. Genetics of Development
6. Cancer Genetics
3-Medical Genetics in Clinical Practice
Genetic testing Genetic screening Molecular diagnostics Genetic engineering Gene Therapy Stem cell therapy Cloning
Genetics Course (1):Mastering Medical Genetics
The Human Nuclear Genome Genome = all of the DNA in an organism or
cell Size of human genome: 3.4 billion base pairs Number of human genes: ~30,000 Genes vary in length and can cover thousands of
bases average size: ~3,000 bp Only about 2% of the human genome contains
coding genes Action of much of the genome is unknown
DNA Structure
DNA Structure
Epigenetics 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.
These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations.
Chromosome Facts # of chromosomes per somatic cell: 22 pairs + 1 pair
sex-determining chromosomes = 46 # of chromosomes per gamete (egg/sperm): 23 One chromosome of each pair donated from each
parent’s egg or sperm Sex chromosomes: XY for males; XX for females Largest chromosome #1 = ~263 million base pairs
(bp) Smallest chromosome Y = ~59 million bp
Chromosomal morphology methods Chromosomal staning FISH
Chromosomal Banding
Chromosomes
Mitochondrial DNA
Circular Several copies No histones
Function of DNA
The Human genome functions
Gene Expression Transcription Translation
Meiosis , Mitosis and Gametogenesis Mitosis is the process by which a cell
separates its duplicated genome into two identical halves
Meiosis is the process that transforms one diploid into four haploid cells.
Where do your genes come from?
Genomic imprinting Most genes expressed equally from both alleles Small number of genes show differential expression
dependent on parent of origin (mainly on chromosomes 6,7,11,14,15)
‘Imprint’ is mediated by methylation transcriptional inactivation
Imprint persists through cell divisions in embryo Imprint removed at gametogenesis and then re-
established according to sex of transmitting parent
Population Genetics Is the study of distributions of genes in
populations Disease frequency Genotype frequencies from generation to
generation Genetic Polymorphisms
SNPs
Polymorphism Occurrence of 2 or more alleles at aspecific
genetic locus in frequencies greater than can be explained by mutations alone
Single nucleotide polymorphisms Restriction fragment length polymorphism
(RFLP) Variable number tandem repeat
polymorphism (VNTR)
Clinical genetics
Clinical genetics is the practice of clinical medicine with particular attention to hereditary disorders.
Inherited disorders Cytogenetic Single gene Polygenic Multifactorial
Clinical Genetics Genotype: An individual’s genetic makeup - forms of a
particular gene at a given locus
Phenotype: The observable expression of a genotype
Homozygous: Identical forms of a particular gene
Heterozygous: Different forms of a gene– CARRIER if one normal and one abnormal
Dominant: Condition phenotypically expressed in someone carrying one copy of a mutant gene
Recessive: Condition phenotypic ally expressed only in someone with two copies of the mutant gene
Autosomal dominance Vertical transmission
On average, 50% of offspring of affected parent will be affected
Unaffected individuals do not transmit trait
Males and females equally affected
Autosomal Dominant Conditions Marfan Syndrome Achondroplasia Familial (early-onset) Alzheimer
Disease Huntington Disease Familial Hypercholesterolemia Familial Breast Cancer (BRCA1 or
BRCA2 mutations)
Autosomal Recessive Inheritance Horizontal transmission; disease in siblings but usually not in earlier
generations (unaffected, carrier parents)
On average, 25% recurrence risk
Males and females equally affected
Increased consanguinity (relatedness) seen
Autosomal Recessive Conditions Sickle cell disease Cystic fibrosis Tay-Sachs disease Hemochromatosis Phenylketonuria Thalassemias
X-linked recessive inheritance Incidence of trait is much higher in males than
females No father-to-son transmission 100% of daughters of affected males are
(unaffected) carriers 50% of sons of carrier females are affected and
50% of daughters are carriers Trait may be transmitted through series of
carrier females
X-linked recessive conditions Haemophilia Duchenne and Becker muscular dystrophy Androgen insensitivity syndrome Hunter syndrome Glucose-6-phosphate-dehydrogenase
deficiency Bruton agammaglobulinaemia
Xplinked dominant Males and females affected, females usually less
severely affected than males 1 in 2 risk to children of affected female (M+F) All daughters of affected male affected but no male
to male transmission
X-linked dominant inheritance Males and females affected
Vitamin D resistant ricketsOTCDFragile X syndrome
Lethal in malesIncontinentia pigmentiRett syndromeXL chondrodysplasia
punctataGoltz syndrome
Mitochondrial inheritance Mitochondria are
exclusively maternally inherited
Males and females affected but only females will transmit to offspring
Risks to offspring of affected or carrier females are difficult to determine 0-100%
Family Medical Historyfamily medical history represents a “genomic
tool” that can capture the interactions of genetic susceptibility, shared environment and common behaviors in relation to disease risk.
References Merck manual : online textbook
E-medicine , online textbook , specialties,.
BRS series : Genetics 2010 Lecture notes : Genetics (2006) Kumar & Klark : Clinical Medicine 2009 Other Web Resources & books
Genetics Course (2):Mastering Medical Genetics
Genetic basis of disease1. Cytogenetic abnormalities2. Genetics of Metabolism3. Genetics of Development4. Genetics and CV disease5. Genetics and Respiratory disease6. Genetics of Hemoglobinopathies7. Genetics of Bleeding disorders8. Genetics and kidney9. Genetics and GIT10. Genetics and Rheumatic disease11. Genetics and Neurological disease12. Cancer & Genes
Cytogenetic
Single gene
Polygenic
Inherited disorders Cytogenetic Single gene Polygenic Multifactorial
Cytogenetic Single genePolygenic and multifactorial
MCQ 1 All are single gene disorders except:
a) Polyposis coli
b) Sickle cell anemia
c) Turner’s syndrome
d) Alport’s syndrome
MCQ 2 Point mutations are the cause of the
following except:
a) Sickle cell anemia
b) Cystic fibrosis
c) Diabetes Mellitus
d) Beta thalassemia
understanding genetic basis of diseasehelps guide therapy
Dietary restriction can eliminate compounds toxic to patients with certain genetic defects, such as phenylketonuria or homocystinuria.
Supplementation: folic acid reduces homocysteine levels in people with 5,10-methylene tetrahydrofolate reductase polymorphism.
Cytogenetic abnormalities Numerical Chromosomal abnormalities Structural chromosomal abnormalities
Deletions Micro-deletions Translocations Ring Chromosomes Breakage Isochromosomes
Numerical Structural
Numerical Chromosomal abnormalities Polyploidy ( e.g Vesicular mole) Aneuploidy ( Sex chromosomes, Autosomal)
Monosomy Triosomy
Mixploidy Mosaicism Chimerism
Turner Syndrome ( Monosomy X) a female does not have the usual pair of two X
chromosomes. Commonly (Mosaic) Turner syndrome occurs in about 1 out of 2,000 live
births. Short stature (142-152 cm) Absent menstruation Infertility Physical features
Turner syndrome
Turner’s associated complications Heart defects Hypothyroidism Kidney problems Arthritis Diabetes Cataract
Treatment of Turner syndrome GH Estrogen: start at 12 or 13 years Cardiac surgery when needed IVF ( to achieve pregnancy) Psychological support
Is Turner Syndrome “hereditary?” Although it is a genetic
disorder, it is not usually hereditary
There are no known environmental causes of the syndrome
Women with Turner Syndrome are usually infertile
Klinfilter syndrome
47,XXY
Klinefelter Syndrome
Clinical Features Hypogonadism Reduced testosterone levels Infertility Tall stature Gynaecomastia Educational difficulties – Intelligence can be 10-15
points lower than siblings but usually in normal range Behavioural problems.Ttt: testosterone therapy may help
Other sex Chromosomal aneuploidies Triple X ( 47, XXX) 47, XYY males
Autosomal Aneuploidies Triosomy 21 (Dawn) Triosomy 13 (Patau) Triosomy 18(Edward)
Dawn syndrome
Microdeletion Syndromes DiGeorge Williams
Genetics and metabolism
Carbohydrate
Lipids
Amino acid
DegradationUrea cycle
Transport
Genetics of Carbohydrate Metabolism Carbohydrate Galactosemia Fructosuria Lactose intolerance Glycogen storage diseases
Genetics of Lipid Metabolism Familial hypercholesterolemia (AD)
(LDLR gene)
Genetic diseases involving degradation pathways Mucopolysacharoidosis Hexoaminidase difficiency
Tay –Sach’s disease
Hunter syndrome video
Tay-Sachs disease Single gene Hexaminidase enzyme
difficiency Accumulation of
ganglioside GM2
Genetics of transport pathways
Menke’s disease Wilson Hemochromatosis
Trinucleotide repeat disorders Fragile X syndrome, Xplinked Huntington’s disease, AD Myotonic Dtstrophy, AD Fridreich’s ataxia
Fragile X syndrome learning disabilities and mental retardation. Usually males are more severely affected by this
disorder than females. In addition to learning difficulties, affected males
tend to be restless, fidgety, and inattentive. Affected males also have characteristic physical
features that become more apparent with age.
Fragile x video
Fragile X syndrome
4-Genetics and CV disease Long Q-T syndromes Marfan Atherosclerosis Brugada
Marfan Syndrome Fibrilin 1 gene on chromosome 15 Intilligence is usually normal Tall stature with disproportionate long limbs Muscloskletal, Heart, eye, skin, pulmonary Ghent criteria
Marfan syndrome video
5-Cystic fibrosis
Cystic fibrosis
6-Genetics in Hematology Hereditary and congenital Anemias Porphyrias Bleeding disorders Inherited thrombophilia
Sickle cell disease
7 -Genetics and Rheumatology FMF
Genetics and Renal diseas PKD Alport Genetic heterogenicity
8 -Genetics and Neurology Hereditary Ataxias Huntington Charcot-Marie-Tooth disease Alzheimer Mental Retardation Neurocutaneous
9-Tumors, Cancer and Genes Polyposis syndromes Heriditary non polyposis CC MEN Cancer vaccines
Neurofibromatosis Tuberous sclerosis
Jewish Heritage Screening Tay-Sachs disease (TSD) Niemann pick disease Mucolipidosis type IV (MLIV) Gaucher disease Familial dysautonomia Fanconi anemia Bloom syndrome Canavan syndrome
Multifactorial and Polygenic disorders1. Asthma2. Autism3. Multiple Sclerosis and other such diseases which are
Autoimmune in nature4. Cancers5. Ciliopathies6. Cleft Palate7. Diabetes8. Heart Disease9. Hypertension10. Inflammatory Bowel Disease11. Mental Retardation12. Obesity
References Merck manual : online textbook
E-medicine , online textbook , specialties,.
BRS series : Genetics 2010 Lecture notes : Genetics (2006) Kumar & Klark : Clinical Medicine 2009 Other Web Resources & books