OVERVIEW OF MEDICAL

GENETICS

Prof. Dr. Mohamed Ali, M.Sc.. M.Phil., B.Ed., M.S (Sing)., Ph.D
(Sing)
Department of Clinical Biochemistry
Faculty of Medicine
University of Tabuk
 Course Objectives
• Principles of Medical Genetics
• Application to Clinical Practice
• Understand Ongoing Developments
NO. LECTURES
1 Medical Genetics: An Overview (Biochemistry) Dr. Ali (male & Female)
Mendelian and Non-Mendelian Modes of Inheritance
2
Biochemistry Dr. Mohammad Tarik (male & Female)

3 Structural and Numerical Autosomal Anomalies Biochemistry Dr. Mohammad Tarik (male & Female)

4 Structural and Numerical Sex Chromosomal Anomalies (Biochemistry) Dr. Ali (male & Female)

5 Clinical Features and Molecular Diagnosis of Most Common Hereditary Diseases (Biochemistry)Dr. Ali (Mmale & Female)

6
Genetic Principles and Clinical Features of Most Common Hereditary Disorders (Hemoglobinopathies, Sickle-Cell Anemia, Thalassemia, Hemophilia, Albinism, Duchenne Muscular
7 Dystrophy, Fibrocystic Diseases) (Biochemistry)Dr. Ashraf Male & Female

8 Genetic Basis of Common Hereditary Diseases of Inborn Errors of Metabolism (Biochemistry) Dr.Ashraf(Male),Dr. Eman (Female)

9 Immunogenetics (Biochemistry) Dr. Ashraf (Male & Female)

10 Genetics of Common Medical Diseases Biochemistry) (Dr. Ali (male & Female)
11 Prenatal and Pre-implantation Diagnosis (Biochemistry) Dr.Ashraf(Male),Dr. Eman (Female)
12 Cancer Genetics (pathology)

13 Forensic Genetics and Molecular Basis of Application of DNA Finger-Printing to Forensic Science as New Tools to Solve Criminal Dilemmas (Biochemistry) Dr. Eman (Male & Female)

14 Basic Principles of Application of Genetic Engineering as a New Modality of Treatment of Many Congenital Disorders and Cancer (Biochemistry) Dr. Ali (male & Female)

15 Genetic Counseling and Genetic Screening (Pediatrics)

NO. PRACTICAL

1 Standard Genetics Laboratory Report (Biochemistry) Dr.Ashraf(Male),Dr. Eman (Female)

2 Normal and Abnormal Human Karyotype (Biochemistry)

3 Pedigree Analysis and Risk Assessment (Family Medicine)

4 Family History: Constructing and Interpreting a Family Tree from a Verbal Description (Family Medicine)

5
Diagnosis of Most Common Hereditary Diseases (Pediatrics)
6

7 DNA Report and Chromosome Report (Biochemistry) Dr.Ashraf(Male),Dr. Eman (Female)

8 Practice of the Genetic Counselling Clinic Including Principles of Genetic Counselling and Impact of Genetic Diagnosis on the Extended Family (Pediatrics)

NO. TUTORIALS
1 Molecular Principles of Blood Groups (Biochemistry)
2 Genetic Screening and Risk Assessment (Pediatrics)
NO. SELF-DIRECTED LEARNING (SDL)

1 Applications of Genetic Engineering: Gene and Stem-Cell-Based Therapies (by students)

2 Molecular Basis of Diabetes Mellitus (by students)

NO. CLINICAL PRESENTATIONS
1 Mongolism, Turner Syndrome & Klinfilter Syndrome (Pediatrics)
Medicine Through a Genetic Lens
 What is Medical Genetics?
Medical genetics deals with human genetic
variation of medical significance.

Major recognized areas of specialization are

the study of chromosomes, and the structure
and function of individual genes.
 What is Medical Genetics?
Clinical Genetics
the application to diagnosis and
patient care
 What is Medical Genetics and why
need to be studied?

diagnosis

albinism
Sickle cell anemia
What is Medical Genetics?

Imagining
Diagnosis
 What is Medical Genetics?
Molecular incision enzyme
Diagnosis

Gel electrophoresis
 What is Medical Genetics?

Prevention phenylphruvic acid

prenatal diagnosis

PKU/PAH (Phenylalanine
hydroxylase)
 What is Medical Genetics?

Therapy
Consult
In the beginning,
There was
Mendel…
 A Conceptual History of Medical Genetics

1900 Mendel’s Laws rediscovered

1901 Dominant inheritance of brachydactyly
1902 Inborn errors of metabolism
1918 Anticipation described
1931 Cytoplasmic inheritance of mitochondrial DNA
1937 Linkage of color blindness and hemophilia
1955 Human diploid chromosome number is 46
1970 Amniocentesis for chromosomal disorders
1970 Tay-Sachs screening
1976 Human globin genes cloned
1987 Predictive genetic testing for Huntington disease
1991 Medical genetics became an ABMS specialty
2001 Draft sequence for the human genome
 What Do Medical Geneticists Do in 2017?

Diagnosis and treatment of genetic disease

Presymptomatic testing for genetic disease

Carrier testing, especially for high risk people

Genetic counseling during pregnancy

1178 board-certified medical geneticists

 BASIC MEDICAL
GENETICS CONCEPTS
 mutation effect on
protein function
 phenotypic expression
 classes of genetic disease
Mutations result in different alleles
An allele is an alternative form of a gene
(one member of a pair) that is located at a
specific position on a specific chromosome.
When the alleles of a pair are heterozygous,
the phenotype of one trait may be dominant
and the other recessive.
• alleles are classified as “dominant” or “recessive”
• dominant phenotypes – observable in heterozygotes
• recessive phenotypes – observable only in homozygotes
 Mutations are classified by effect
on protein function
• loss-of-function (most common)
e.g. Decreased amount normal protein:
Inborn errors of metabolism as in Tay-Sachs [recessive]
Haploinsufficiency as in FH [dominant]

• gain-of-function
e.g. Gene dosage effects as in trisomy 21 [dominant];
Dominant-negative effect as in OI [dominant]
Abnormal protein properties as in HD [dominant]

• novel property
e.g. HbS [recessive]

• inappropriate expression
e.g. Oncogenes in cancer
 Variations in phenotypic manifestation of
mutant alleles are due to:

• complementation as in XP, profound

hearing loss
• penetrance (100% - achondroplasia -
unusual)
• variable expression
Causes of variable expression:
• allelic heterogeneity: hemophilia variants
• locus heterogeneity: hyperphenylalanemias
• modifier loci: Waardenburg syndrome
(methylation); Alzheimer’s (multiple genes);
SNPs
• environment (XP, α-1 antitrypsin deficiency)
Common classes of genetic disease:
1. enzyme defects (PKU; Lesch-Nyhan;
Tay-Sachs; I-cell disease; XP)
• Almost always recessive.
• Pathophysiology due to substrate accumulation,
product deficiency, or both.
• When substrate is diffusible, the
pathophysiology is unpredictable; when
substrate can’t diffuse, the cell in which it
accumulates is damaged.
• Several enzyme functions can be affected.
Common classes of genetic disease (cont.):

2. Defects in receptor proteins (Familial

hypercholesterolemia)
3. Transport defects (Cystic fibrosis)
4. Disorders of structural proteins (Duchenne
muscular dystrophy; Osteogenesis imperfecta)
5. Neurodegenerative disorders (Alzheimer’s
disease; triplet repeat disorders)
6. Mitochondrial diseases (MELAS, MERRF)
7. Pharmacogenetic diseases (malignant
hyperthermia; G6DP)
 Triplet Repeat Disorders
• Dynamic expansion of DNA triplet repeats

• Normal alleles polymorphic

• Inheritance dominant or recessive
• Presymptomatic, symptomatic expansion size varies
• Base sequence, location of repeat varies
• Parent-of-origin effects on repeat expansion varies
(anticipation)
• Stability during meiosis and mitosis varies (variable
expression)
 Polyglutamine disorders
• Huntington Disease (autosomal dominant)

• Spinobulbar muscular atrophy (X-linked

recessive; androgen receptor)
• CAG repeat
• Anticipation: expansion occurs preferentially
during male gametogenesis
• Variable expression: mitotic instability low (limited
mosaicism)
• Protein aggregation, not loss-of-function
 Fragile X Syndrome
• X-linked recessive

• CGG repeat in 5’ untranslated region of FRA gene

(posttranscriptional regulator; methylation effects)
• Most common form of hereditary mental retardation
• Anticipation: expansion occurs preferentially in
female gametogenesis
• Variable expression: Mitotic instability high
• Disease caused by loss of function; very large
expansions needed
 Myotonic Dystrophy
• Autosomal dominant

• CTG repeat in 3’ untranslated region of protein

kinase gene; mechanism of pathophysiology
unknown.
• Anticipation: either parent can transmit
amplified copy; massive expansion occurs only
in maternal gametogenesis
• Variable expression: mitotic instability high
• Abnormal transcript processing, not deletions,
point mutations, etc.
 Freidreich ataxia
• Autosomal recessive

• GAA repeat in intron of mitochondrial gene frataxin

(involved in iron metabolism).
• Anticipation: no parent of origin effects
• Variable expression: mitotic instability low
• Loss of function
• 4% are compound heterozygotes (expansion/point
mutation)
 Mitochondrial Disorders
3 types of mutations
• missense mutations in coding regions of genes that alter
activity of OXPHOS proteins (Leigh disease-ATPase)
• point mutations in tRNA or rRNA genes that impair
mitochondrial protein synthesis (MELAS; MERRF)
• rearrangements that generate deletions/duplications in mtDNA
( not usually transmitted from affected mother to offspring;
disorders occur as sporadic new cases-Kearns-Sayre
syndrome)
Maternal inheritance
Usually heteroplasmic (phenotypic expression: reduced
penetrance, variable expression, pleiotropy)
 Pharmacogenetic Diseases
• Unanticipated reactions to medications largely/entirely
genetic (6.7% incidence in American hospitals; 0.3% fatal).
• Single gene defects or multifactorial
Examples:
• Malignant hyperthermia (autosomal dominant-Ca+ release
channel; other loci)
• Acute Intermittent Porphyria (autosomal dominant
disease: drug-related alteration in gene expression of heme
biosynthetic enzyme)
• G6PD (X-linked recessive; more than 400 variants; most
common disease-producing single gene enzyme defect of
humans)
• Acetylation polymorphism (slow or rapid drug inactivation)
 Traditional View of Disease
• The body as machine
• Disease: The machine is broken
• Medicine: Fix the machine

• Focus is on disease
– Patient: someone who develops “disease” before
consulting a physician
 Genetical View of Disease
• Disease is the result of mismatch between
integrated, but variable,homeostatic systems and
some experience(s) of an equally variable
environment.
• Incongruence may be potential (susceptibility) or
inevitable.
• Environment may be internal or external, physical or
social.
• Continuity of health and disease
 Genetical View of Disease II
• Disease is an (almost) inevitable consequence
of our diversity.
• Focus is on the Individual.
• Management is directed at whichever
component is most amenable.
• Care rather than cure
• Prevention of disease
 Genetical View of Disease III
• Why this disease ?
• Why this person ?
• Why now ?

• Three time scales at once

– Phylogenetic history of the genes
– Trajectory of the lifetime
– Experiences of the moment---Chance
 Impact of Genetic Disease
50% of conceptions
3% of live births
5% of individuals before age 25
 Types of Genetic Disease
• Chromosomal
• Single gene---Mendelian
• Multifactorial---common complex diseases
• Somatic cell ---cancers
Age of Expression of Genetic Disease
 The Human Genome
• What is it ?
– Picking the right metaphor
• What does it tell us ?
• How can we use the “Genome” medically ?
 Metaphors
• Rosetta Stone
• Book of Life
• Code of codes
• The periodic table
• Cook book
• Musical score…
Musical sequence
Musical sequence-2
Genotype
 What does the Genome tell us?
• Estimated number of genes ~30,000
– Humbling…C. elegans with <1000 cells has 19,000 genes
 What does the Genome tell us?
• Estimated number of genes ~30,000
• Only 1 to 1.5% of the genome encodes proteins
– 75% of the genome is not transcribed
– 50% is repetitive DNA
– JUNK DNA –the fodder/history of evolution
– Recombination
• Diversity
• “genomic” disease
 What does the Genome tell us?
• Estimated number of genes ~30,000
• Only 1 to 1.5% of the genome encodes proteins
• We humans are 99.9% identical at the DNA sequence
level
We humans are 99.9% identical at the
DNA sequence level
• We are a young species--~100,000 humans
came out of Africa <150,000 years ago
 We humans are 99.9% identical at
the DNA sequence level
• There are still ~3 million nucleotide
differences among us---that presumably
account for differences in disease
susceptibility, drug responses, etc.
• Polymorphic variation between and within
populations
• Implications for concepts of “race,”
“individuality”
• Text book
• Reference
Thompson & Thompson Genetics in Medicine, 7th
Principles of Medical Genetics (Williams & Wikins)
Introduction

46,XY karyotype
 Androgen insensitivity syndrome, AIS

• Mechanism
Caused by mutations of the gene encoding
the androgen receptor.
• symptoms
A person with complete androgen
insensitivity syndrome (CAIS) has a female
external appearance, and suppressed
menstruation.
androgen insensitivity syndrome， AISXR

46,XY karyotype
retained testis
Introduction

•Mechanism
47,XXY (extra chromosome )
Klinefelter sydrome

mania ??
 Introduction-Disease and Genetics

A. Disease caused by (or related to)

environmental stress.

SARS
Bird Flu

H1N1 Flu
Introduction-Disease and Genetics

Down syndrome

Many of the common physical features

Low IQ

B. Disease caused by (or related to)

genetic factors.
Introduction-Disease and Genetics

Duchenne muscular dystrophy

caused by a gene mutation
 Introduction-Disease and Genetics

connate rachitis

Conjoined Twins

C. diseases caused by the combined action of

gene and environment.
Genetic variations underlie
phenotypic differences
Wilt Chamberlain,
a famous NBA basketball player
(7 feet, 1 inch; 275 pounds)

Willie Shoemaker,
a famous horse racing jockey
(4 feet, 11 inches;
barely 100 pounds).
 Genetic variations cause
inherited diseases

Genetic Diseases Complex Diseases Environmental

Diseases

- Cystic fibrosis - Alzheimer disease - Influenza

- Down syndrome - Cardiovascular - Hepatitis

Disease - Measles
- Sickle cell disease
- Diabetes (type 2)
- Turner syndrome - Parkinson Disease

- Environment - Genes
 Basic terminology
 Locus – location of a gene/marker
on the chromosome.

 Allele – one variant form of a

gene/marker at a particular locus.

Locus1
Possible Alleles: A1,A2

Locus2
Possible Alleles: B1,B2,B3
 A little more basic terminology
Polymorphism:
- Variations in DNA sequence (substitutions, deletions,
insertion, etc) that are present at a frequency greater
than 1% in a population.
- Have a WEAK EFFECT or NO EFFECT at all.
- Ancient and COMMON.

Mutation:
- Variations in DNA sequence (substitutions, deletions,
etc) that are present at a frequency lower than 1% in a
population.
- Can produce a gain of function and a loss of function.
- Recent and RARE.
 Some Facts
 In human beings, 99.9% bases are same

 Remaining 0.1% makes a person unique

 Different attributes / characteristics / traits
• how a person looks
• diseases he or she develops

 These variations can be:

 Harmless (change in phenotype)
 Harmful (diabetes, cancer, heart disease, Huntington's
disease, and hemophilia )
 Latent (variations found in coding and regulatory regions, are
not harmful on their own, and the change in each gene only
becomes apparent under certain conditions e.g. susceptibility
to heart attack)
 Forms of genetic variations
Single nucleotide substitution: replacement of
one nucleotide with another
Microsatellites or minisatellites: these tandem
repeats often present high levels of inter- and
intra-specific polymorphism
Deletions or insertions: loss or addition of one
or more nucleotides
Changes in chromosome number, segmental
rearrangements and deletions
 Single base changes
 Transitions
 Purine to purine or pyrimidine to pyrimidine
 A to G or G to A T to C or C to T

 Transversions
 Purine to pyrimidine or pyrimidine to purine
Causes of gene mutations
 Consequences of mutations

 Most mutations are neutral

- 97% DNA neither codes for protein or RNA, nor indirectly
affects gene function
- A new variant in the 1.5% coding regions may not result
in a change in amino acid
- Variants that change amino acid may not affect function
 Certain mutations have functional effect
and even cause disease
- Gain-of-function mutations often produce dominant
disorders
- Loss-of-function mutations result in recessive disease
 Genetic disease
A. What is genetic disorder?
A genetic disorder is a disease that is caused by
an abnormality in an individual’s DNA.
Abnormalities can range from a small mutation in
a single gene to the addition or subtraction of
an entire chromosome or set of chromosomes.
 Genetic disease

B. Characteristics of genetic disorders

1. congenital
2. mode of inheritance
3. population distribution
4. familial
5. infectious
 Genetic disease

B. Characteristics of genetic disorders

1. congenital
2. mode of inheritance
3. population distribution
4. familial
5. infectious
 Down syndrome

albinism
 Genetic disease

B. Characteristics of genetic disorders

1. congenital
2. mode of inheritance
3. population distribution
4. familial
5. infectious
3 Pedigree of Genetic Disease
 Genetic disease

B. Characteristics of genetic disorders

1. congenital
2. mode of inheritance
3. population distribution
4. familial
5. infectious
 Genetic disease

B. Characteristics of genetic disorders

1. congenital
2. mode of inheritance
3. population distribution
4. familial
5. infectious
 Genetic disease

B. Characteristics of genetic disorders

1. congenital
2. mode of inheritance
3. population distribution
4. familial
5. infectious
 Genetic disease
human prion diseases
genetic and infectious

Neuron ： Vacuolar degeneration

• Creutzfeldt－Jakob disease

tribe
 Genetic disease
C. Classification of Genetic Disorders

1. single-gene disorders
2. chromosome disorders
3. multifactorial disorders
4. somatic cell genetic disorders
5. mitochondrial disorders
 Genetic disease
C. Classification of Genetic Disorders

1. single-gene disorders
2. chromosome disorders
3. multifactorial disorders
4. somatic cell genetic disorders
5. mitochondrial disorders
 Genetic disease

Single-gene disorders result when a

mutation causes the protein product of a
single gene to be altered or missing.
 Genetic disease
C. Classification of Genetic Disorders

1. single-gene disorders
2. chromosome disorders
3. multifactorial disorders
4. somatic cell genetic disorders
5. mitochondrial disorders
In chromosome disorders, entire
chromosomes, or large segments of them, are
missing, duplicated, or otherwise altered.
 Patau syndrome
Trisomy 13 -- the presence of an extra (third)
chromosome 13 in all of the cells.
 Symptoms

• Physical characteristics

• Organ defects

• Mental retardation
 physical characteristics

small eyes

cleft lip,cleft palate low-set ears

physical characteristics

rocker foot
 Organ defects

• heart defects

• spinal defects
• abnormal genitalia

• gastrointestinal hernias

• polycystic kidney disease

 mental retardation
• Incomplete brain development

• Low IQ
 99％do not survive gestation and are
spontaneously aborted

 82-85% do not survive past 1 month of age,

85% do not survive past 1 year of age
 Diagnosis &Treatment

• Diagnosis: chromosome analysis

• NO TREATMENT
 Genetic disease
C. Classification of Genetic Disorders

1. single-gene disorders
2. chromosome disorders
3. multifactorial disorders
4. somatic cell genetic disorders
5. mitochondrial disorders
Multiple genes are missing as a result of this
deletion, and each may contribute to the
symptoms of the disorder. One of the deleted
genes known to be involved is TERT
(telomerase reverse transcriptase). This gene
is important during cell division because it
helps to keep the tips of chromosomes
(telomeres) in tact.
 Genetic disease

Multifactorial disorders result from

mutations in multiple genes, often coupled
with environmental causes.
 Genetic disease
C. Classification of Genetic Disorders

1. single-gene disorders
2. chromosome disorders
3. multifactorial disorders
4. somatic cell genetic disorders
5. mitochondrial disorders
 Genetic disease
Somatic cell genetic diseases:

result from the altered genetic materials in

somatic cells.
 Genetic disease
C. Classification of Genetic Disorders

1. single-gene disorders
2. chromosome disorders
3. multifactorial disorders
4. somatic cell genetic disorders
5. mitochondrial disorders
 Genetic disease
Mitochondrial genetic diseases:

Due to the mutation of mitochondrial DNA.