Human Genetics: is the science of biological variations in humans. Medical Genetics: is the science of human biologic variations as it relates to health.

Human Genetics: is the science of biological variations

in humans.

Medical Genetics: is the science of human biologic

variations as it relates to health and disease.

Clinical Genetics is the science and art of diagnosis,

prevention & treatment of genetic disease.

Definitions …

Genetic disorder: is a condition caused by

abnormalities in genes or chromosomes.

Genetic disease: refers to diseases present in

all cells of the body and present since conce-

ption (cancer excluded).

How to search for a genetic condition?

www.google.com (search text; ‘images’; ‘videos’, etc)

www.download.com (download software)

www.youtube.com (videos)

www.pubmed.com

OMIM from www.pubmed.com

List of Genetic disorders at Wikipedia (encyclopedia)

Center for Inherited Disease Research (CIDR)

National Organization for Rare Disorders

Genetic disorders…

Genetic Disorders

A. Chromosomal Abnormalities due toErrors in meiosis (DS; 45,X0; 47,XXY)

B. Genetic changes during production ofgerm cells by the parent (Fragile X, HD)

C. Defective genes inherited from intact parents (Hereditary disease)

1- Dominant 2- Recessive

Down syndrome (47,+21)

Turner syndrome (45,X0)

Klinefelter syndrome (47,XXY, …)

XYY syndrome (47,XYY; 48,XXYY)

(arise from meiotic non-disjunction in the father)

A- Chromosomal Abnormalities

Down Syndrome (DS)…

1.Down-slanting palpebral fissure

and a slightly protruding tongue.

2.The prominent epicanthal fold of a

child with DS is shown.

3.The pupil demonstrates a light

smudge opacity called a Brush-

field spot.4.A simian crease is seen on the

hand of this child with DS.

Typical Down’s syndrome hand Typical Down’s syndrome foot

Frontal (a) and lateral (b) appearance of a patient with DS

Down Syndrome…

Trisomy 21 FISH karyotype GTG-banding of a trisomy 21 patient

Cytogenetics of DS…

Maternal nondisjunction in DS

Hope … associated with Early Intervention

• Development of communication.

• Social development.

• Motor Development

Turner syndrome (45,X0) is characterized by a phenotypic female with gonadal dysgenesis & sexual immaturity:

- 1ry Amenorrhea & Infertility associated with:

- short stature (< 5 feet)

- webbing of the neck

- increased carrying angle at elbow

- cardiovascular abnormality.

- renal abnormality.

Turner Syndrome …

Turner Syndrome …

Klinefelter Syndrome…

Incidence 1/1000 male births

Karyotype with 47,XXY (with Barr body).

No. of Barr bodies inform of the no. of X-chromosomes.

Characterized by postpubertal testicular failure.

Phenotype male with small testes, hyalinized testicular

tubules, azoospermia (result in infertility)

Barr body: A condensed, inactivated X chromosome present in most female mammals in all somatic cells, but not in germ cells

The Barr, or sex chromatin, body is an inactive X-chromosome (Lyon’s hypothesis). It appears as a dense, dark-staining spot at the periphery of the nucleus of each somatic cell in the human female.

Karyotype with a male having Klinefelter syndrome (47,XXY)

Murray Barr(1948)

Genetic disorders…

Genetic Disorders

A. Chromosomal Abnormalities due toErrors in meiosis (DS; 45,X0; 47,XXY)

B. Genetic changes during production ofgerm cells by the parent (Fragile X, HD)

C. Defective genes inherited from intact parents (Hereditary disease)

1- Recessive 2- Dominant

B. Trinucleotide repeats

Refers to a specific DNA sequence of 3 nucleotides (e.g. CGG) that is repeated along the human genome

No. of the polymorphic repeats varies from one to another (two to several hundreds).

Trinucleotide repeat sequences are stable, and inherit from parents to children with the same no. of repeats.

Polymorphic repeat regions are the basis of

fingerprinting (forensics, … etc).

Fragile X Syndrome …

Most common form of inherited mental retardation.

Incidence of ~1/4000 male and ~1/8000 females.

Due to expansion of trinucleotide repeats (CGG)n at X27.3.

Mutation in the FMR1 gene due to expansion CGG repeats.

Large ears, prominent jaws, joint laxity and macroorchidism

It is AD neurodegenerative disease (incidence 1/10,000) that

affects muscle coordination and leads to cognitive decline

and dementia.

HD typically becomes noticeable in mid-adult life (35-44 y).

HD is the most common genetic cause of abnormal

involuntary writhing movements called chorea.

HD characterized by slowly progressive selective cell death in

the CNS.

no effective treatment or cure.

Huntington’s disease (H. chorea)…

George Huntington

(1872)

An expansion due to (CAG)n repeats located in

coding region of the Huntingtin gene (located at

chromosome 4p16.3) (1993).

In Huntington’s disease:

- N < 26 rpts → normal individual

- N = 27-35 rpts → mutable alleles don’t cause

disease, but show meiotic instability.

- N = 36-39 rpts → reduced pentrance (late-

onset) or non-pentrance.

- N ≥ 40-100 rpts → mutant

Huntington’s disease…

Genetic disorders…

Genetic Disorder

A. Chromosomal Abnormalities due toErrors in meiosis (DS; 45,X0; 47,XXY)

B. Genetic changes during production ofgerm cells by the parent (Fragile X; MD, HD)

C. Hereditary disease: Defective genesinherited from intact parents (carriers)

1- Recessive 2- Dominant

Dominant: if one parent can transmit the genetic

information (in genes) that causes a child’s disease

(Fam. hypercholestrolemia; Achondroplasia).

Recessive: if both parent lack the disorder (i.e.

homozygous for the mutant gene) and pass the

disease’s gene to a child (sickle-cell anemia, PKU,

lamellar ichthyosis, β-thalassemia, … etc).

Achondroplasia…

ACH describes short-limb dwarfism due to mutations of fibroblast growth factor receptor-3 gene (FGFR3- 4p16.3)

IQ is normal

PKU with mental retardation and neurological problems, lighter hair and skin color, enhanced reflexes, convulsive seizures,

LI patients suffer from palmoplantar keratoderma, often with painful fissures,digital contractures, and loss of pulp volume. A nail dystrophy including ridging,subugeal hyperkeratosis, or hypoplasia. Ectropion, eclabion (turning outward of the eye lids and lip, respectively), scalp involvement, and loss of eye brows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis.

Autosomal Recessive diseases

Lamellar Ichthyosisdue to a mutation in

TGM1 gene

Phenylketonuria diseasedue to a mutation of

PAH gene

Hereditary diseases…

X-linked: pass from mother (XX) to affect often males

(XY) (DMD, Hemophilia A, G6PD).

Y-linked: (Oligospermia, Azoospermia, …).

Mitochondrial: known as maternal inheritance. Only

egg cells contribute mitochondria to the developing

embryo, only female can pass on mitochondria

conditions to their children (Lebre’s hereditary Optic

Neuropathy ‘LHON’).

Duchenne Muscular Dystrophy…

Weakness proximal more than distal.

Weakness in lower limb than in upper limb

Pseudohypertrophy.

Hypotonia & Hyporeflexia.

Sensory system intact.

Mental impairment may occur.An 8-y-old boy with D/BMD with enlarged calves

WHAT IS MUSCULAR DYSTROPHIES?- DMD/BMD disease- Limb girdle MD- Spinal muscule atrophy- Myotonic MD (AR)- Facioscapulohumeral MD

A dystrophin patient (7 y) and his younger brothers (1.5 y) diagnosed in the preclinical stage as D/BMD by the +ve family history and raised CPK level (2845 IU/L).

Duchenne Muscular Dystrophy…

Biochemical Genetics

A) The Role of Proteins

B) Metabolic Pathways and Disease1- Defects in amino acid metabolism2- Defects in Carbohydrate metabolism3- Defects in Nucleic acid metabolism4- Defects in Lipid metabolism

C) Defects in Receptor Proteins1- Hemoglobin Variants2- Thalassemias

A) Role of Proteins

Greek Word “proteios” means ‘being of first importance.

Destroy invading microbes (antibodies)

Act as Enzymes,

Act as hormones (insulin), receptors (VDR), transport

molecules (hemoglobin),

Role in DNA replication (helicase, RNA primase, DNA

Ligase, …)

Enzymes …

Enzymes convert molecules (substrates) into products through a biochemical reaction.

Metabolism is the sum of all biochemical reactions in the cell.

Gene 1 Gene 2 Gene 3

Enzyme 1 Enzyme 2 Enzyme 3

Compound (A) (B) (C) (D)

B) Metabolic Pathways and Disease

In 1901, Garrod discovered “inborn errors of metabolism”

of Alkaptonuria (AKU).

Direct link between specific enzyme and genetic disease

was made in 1952 (G6PD & glycogen storage disease).

The major disorders for which dietary control is available

are:

- PKU - galactosemia - tyrosinemia

- Homocystinuria - MSUD.

Nine essential a.a.: His, isoleu, leu, lys, meth, phe, thr, try

and val. Phenylketonuria (PKU) first discovered by Følling.

- Jervis showed that the classical PKU was linked to PAH deficiency.

Alkaptonuria: excretion of homogentisic acid, dark pigment in cartilage areas (ears, tip of nose, whites of eyes, arthritis in later life).

Oculocutaneous albinism (OCA): lack of melanin (hair, skin, eyes) lack of tyrosinase in pigment cells (albino phenotype).

1-Defects in Amino acid…

Phenylketonuria Disease

Galactosemia: AR disease (1/57,000) results from the inability to metabolize galactose.

- Untreated galactosemia causes gastrointestinal

disturbance, dehydration, loss of appetite, and lately

cataracts and MR.

Fructosuria: AR in 1/130,000 due to lack of fructokinase in liver, kidney, intestine.

Pentosuria: AR in 1/2500-5000 (Ashkenazi Jewish).

2-Defects in Carbohydrates…

Lesch-Nyhan syndrome: XL-disease (1/10,000) associated with a defect in purine metabolism (cause overproduction of uric acid).

- Renal failure, spastic movement, MR, strong tendency

for self-mutilation?!!

The disease is caused by a lack of hypoxanthine guanine ribosyl transferase (HGPRT).

Allopurinol only may treat the uric acid level.

3-Defects in Nucleic acid…

Tay-Sachs disease (hz <1/100,000; het 1/300): AR-disease shows degeneration of cell structures and high conc of GM2-ganglioside due to lacking of ‘hexosaminidase A’ deposited in the nervous system.

Normal at birth, listless and weak, difficult to feed. Loss of motor function, delays in learning to sit and stand. A

characteristic cherry-red spot develops on retina. At age of 12 m, rapid decrease in mentality, motor function, onset of blindness, deafness, brain enlarge.

Death occurs around 3 y from pneumonia or lung infection. Sandhoff disease: def. in hexosaminidase A,B.

4-Defects in Lipid…

Proteins also play other roles including

signal receptors and transducers.

These functions usually takes place in the

plasma membrane of the cell.

Mutations in receptor function can have

drastic consequences.

C) Defects in Receptor Proteins

Fam. hypercholesterolemia (1/100,000).

It is AD (2p24.1) associated with a defect in cellular

receptors that function in cholesterol metabolism.

Affected individuals are susceptible to heart disease

and early death.

Cholesterol is ingested, and packaged into particles

(LDL) that project by receptors into the cells, and

cholesterol is used by the cell.

Defects in Receptor Proteins…

If the receptors are defective, the LDL builds up in the blood and deposited in the artery walls causing atherosclerotic plaque → heart disease.

Fam. hypercholesterolemia het. have ½ of the usual number of receptors and twice the normal level of LDL.

Heart attacks starts at early 30’s. 1/500 individuals is heterozygotes, and homozygotes

(no function of receptor) estimates 1/million (6-times of normal LDL, and heart attacks at early 2 y age.

Fam. Hypercholesterolemia…

Background:

- After 4-6 wk: presence of Y-chr → testis, while absence of Y-chr → ovary.

- Once testis development is initiated, two hormones are produced testosterone and MIH.

- Testosterone is converted to dihydrotestosterone (DHT) which develop the ex. genitalia.

- Absence of testis: → development of ovary.

Defects in Receptor Protein… Test. Feminization

Testicular feminization (XL-recessive). Genotype male (XY) & phenotype female. Testis formation is induced normally, and testosterone

and MIH production occurs normally → no internal genitalia of a female.

Mutation in X-chr blocks the ability of cells to respond to testosterone or DHT.

Hence, Wolffian duct degenerates and indifferent genitalia develops as female structures.

very attractive female, well-developed breast, very little pubic hair, lack of menstruation.

Testicular Feminization…

Disease Defective/Absent

Receptor

Inheritance

Phenotype

Fam. Hyper-cholesterolemia

LDL AD Elevated levels of cholesterol in blood, atherosclerosis, heart attacks; early death

Pseudohypo-parathyroidism

Parathormone (PTH)

XL-D Short stature, obesity, round face, MR

Diabetes insipidus Vasopressin XL-R Failure to concentrate urine, severe thrist, dehydration, MR in infants unless early diagnosed

Testicular feminization Testosterone XL-R Transformation of genotypic male into phenotypic female, malignancies often develop in intra-abdominal testes

Some heritable Traits associated with Defective Receptors

Transport Protein: The globin Model

Hemoglobin: an iron-containing protein molecule found in RBCs is involved in transfer of O2 and CO2.

Adult Hb is a tetramer composed of 2 types of polypeptides.

Quaternary structure of Hb A1 consists of 2a & 2β-chains. Hb A2 (2a- & 2d-chains).

- a-genes on 16p & b-gene on locus 11p- The globin gene is composed of 3 exons

and 2 introns (IVS).

1- Hemoglobin Variant…

• Hb S: Linus Pauling 1949: is an abnormal Hb

that becomes insoluble in deoxygenated state.

The insoluble molecules polymerize into tubular

structures that distort the membrane of RBCs

forming sickle shaped cells.

• Hb C: is slightly insoluble in the deoxygenated

state forming intracellular crystals that makes

the RBCs membrane rigid with reduced life

span → mild form of anemia. • Hb F (db-chains): there is a persistence of

production of fetal Hb into childhood and adult life. This is due to ∆ or point mutations in d and b.

A fatal (AR) genetic disorder associated with an abnormal type of Hb, a blood transport protein.

Common in US Black. Protein transports O2 from lungs to tissues. Under conditions of low O2 tension, the abnormal Hb in

SCA causes the sickle-shaped. The deformed cells are fragile and easily broken apart. Patients tire easily, develop heart failure because the

increased load on the Circulatory system.

Sickle cell anemia…

The deformed cells clog the blood vessels and capillaries, and hence reduces O2 transport and bringing sickling crisis.

As O2 concn. reduced more and more red blood cells become sickled, bringing on intense pain, causing ulcers and sores on the body surface.

Blood blockage in brain leads to strokes and hence partial paralysis.

Sickle cell anemia…

• Thalassemias are heritable group characterized by reduction or absence of ‘alpha’ and ‘beta’ globins.

• Common in Mediterranean basin and Southeast Asia. “Thalassa” Greek word means “for sea”.

• α-Thalassemia: α-globin is reduced or absent (α1, α2).

* α1→ mild to heterozygotes, α1→ fatal to homozygous (complete ∆ of α-genes).

* α2 → intact to het, α2 → mild anemia to homozygous.• β-Thalassemia: β-globin chain is affected éout ∆ (types,

βº, β+).

* βº gives very low β-globin protein due to splicing mutations during formation of mRNA (in splicing site).

2- Thalassemias…

II. Polygenic & Multifactorial Inheritance

Many disorders doesn’t conform to any recognized pattern of Mendelian InheritanceCongenital

MalformationsCommon acquired diseases

Cleft lip/palateCHDNTD’s (e.g. spina bifida, anencephaly)

AsthmaAutismDiabetes MellitusEpilepsyHypertensionPsoriasisRheumatoid arthritisSchizophrenia

Polygenic disorder: A phenotype that is dependent upon the interaction of a number of genes.

Traits showing ‘continuous variation’ that resemble ‘normal distribution’ are controlled by two or more genes are examples of ‘polygenic inheritance’.

Discontinuous variation: Phenotypes that fall into 2 or more distinct, non-overlapping classes.e.g. height, weight, skin color, intelligence, blood pressure, many forms of behaviors.

Multifactorial traits are those that involve 2 or more genes and strong interaction with the environment.

Heritability: It measures the degree of environmental or genetic effects or both on a trait.

Linkage Analysis: It is valuable in mapping single-gene disorders by studying the co-segregation of genetic markers with the disease.

In multifactorial disorders such MR, Epilepsy, Psychotic illness (manic depression, Schizophrenia).

Candidate genes: with Coronary heart disease (CHD), Alzheimer, Bronchial asthma, etc.

Multifactorial Disorders

Estimates of Heritability of various disorders

Disorder Frequency (%) Heritability

Schizophrenia 1 85

Asthma 4 80

Cleft lip + cleft palate 0.1 76

Coronary artery disease 3 65

Hypertension (essential) 5 62

Peptic ulcer 4 37

Congenital heart disease 0.5 35

Multifactorial Disorders…

Disease Models for multifactorial inheritance:• Autism (4-10/10,000)• Type 1 Diabetes Mellitus (IDDM) (0.4%)• Type 2 Diabetes Mellitus (non-IDDM) (10%)• Crohn disease

Linkage: Co-inheritance of 2 or more nonallelic genes bcuz their loci are in close proximity on the same chromosome, such that after meiosis they remain associated more often than the 50% expected for unlinked genes.

Linkage Disequilibrium: The preferential association of a particular allele, i.e. a mutant allele for a disease with a specific allele at a nearby locus more frequently than expected by chance.

LOD score: A statistical method that tests whether a set of linkage data indicates two loci are linked or unlinked {+3 (1000:1 odds) is taken of linkage; -2 (100:1 odds against) indicates no linkage}.

Multifacotrial inheritance …

Association Studies Odd ratio (OR): It gives an indication of

how much more frequently the disease occurs in individuals with a specific marker than in those without that marker.

Transmission disequilibrium test (TDT): requires a collection of an affected proband and both parents (regardless of affected status)

Allele 1

Allele 2

Parents a b

Controls c d

Odd ratio

= a/c b/d= ad/bc

Population/migrationFamily studies: Twin studies: Adoption studies:Polymorphism association studies:Biochemical studies