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