1. Medical Genetics
Assoc. Prof. Ömer Faruk Bayrak Department of Medical Genetics Yeditepe University

2. Classical and Modern Genetics
Humans have long understood that offspring tend to resemble parents, and have selectively bred animals and plants for many centuries. The principles of heredity were first explained by Mendel in the mid nineteenth century, using defined crosses of pea plants.
2. In the last century, genetics has become an important biological tool, using mutants to gain an understanding of specific processes. This work has included:
a. Analyzing heredity in populations.
b. Analyzing evolutionary processes.
c. Identifying genes that control steps in processes.
d. Mapping genes.
e. Determining products of genes.
f. Analyzing molecular features of genes and regulation of gene expression.

3. 3. 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

4. Classical and Modern Genetics
4. Completion of genomic sequencing for an increasing number of organisms has spawned the new field of genomics. Knowledge of individual genes and their regulation will be important to basic biological research, as well as to specific applications such as medical genetics.
5. Powerful new techniques in genetics raise important ethical, legal and social issues that will need thoughtful solutions.

5. Human Genome Project Proposed in 1985
1988. Initiated and funded by NIH and US Dept. of Energy ($3 billion set aside)
1990. Work begins.
1998. Celera announces a 3-year plan to complete the project years early
Published in Science and Nature in February, 2001

6. What we’ve learned from our genome so far…
There are a relatively small number of human genes, less than 30,000, but they have a complex architecture that we are only beginning to understand and appreciate.
-We know where 85% of genes are in the sequence.
-We don’t know where the other 15% are because we haven’t seen them “on” (they may only be expressed during fetal development).
-We only know what about 20% of our genes do so far.
So it is relatively easy to locate genes in the genome, but it is hard to figure out what they do.

8. How much data make up the human genome?
3 pallets with 40 boxes per pallet x 5000 pages per box x 5000 bases per page = 3,000,000,000 bases!
To get accurate
sequence requires
6-fold coverage.
Now: Shred 18 pallets
and reassemble.

9. Human genome content 1-2 % codes for protein products
24% important for translation
75% “junk”
Repetitive elements
Satellites (regular, mini-, micro-)
Transposons
Retrotransposons
Parasites

10. Comparative Genomics

11. What Do Medical Geneticists Do
Diagnosis and treatment of genetic disease
Presymptomatic testing for genetic disease
Carrier testing, especially for high risk people
Genetic counseling during pregnancy

12. Genetic Evaluation Data gathering
History, especially family history
Physical examination - major and subtle findings
Pattern recognition
Laboratory testing – EMG, DNA

13. Medical genetics in the health service
A Medical Genetics Unit
Clinical
Genetics
Consultant
Molecular
Genetics
Lab
Cytogenetics
Lab
Clinical diagnosis
Genetic counselling
Risk assessment
Prenatal & presymptomatic diagnosis

14. What Should You Know? Basic understanding of clinical genetics
Be able to draw, and understand, a family tree
Have awareness of when you should be considering a genetic condition
Have a working knowledge of the most important genetic conditions
Know how & when to refer to local specialist genetics services

15. Genetic diseases traditionally - 3 types of diseases
1. genetically determined
2. environmentally determined
today - distinctions are blurred
up to 20% of pediatric in-patients have genetic abnormality
about 50% of spontaneous abortuses have chromosomal aberration
only mutations that are not lethal are reservoir of genetic diseases

16. Role of Genes in Human Disease
Most diseases / phenotypes result from the interaction between genes and the environment
Some phenotypes are primarily genetically determined
Achondroplasia
Other phenotypes require genetic and environmental factors
Mental retardation in persons with PKU
Some phenotypes result primarily from the environment or chance
Lead poisoning

17. Terminology hereditary = derived from parents
familial = transmitted in the gametes through generations
congenital = present at birth (not always genetically determined - e.g. congenital syphilis, toxoplasmosis)
! not all genetical diseases are congenital - e.g. Huntington disease - 3rd to 4th decade of life

18. Fig. 13.3 ©Scion Publishing Ltd
Etiology of diseases.
For any condition the overall balance of genetic and environmental determinants can be represented by a point somewhere within the triangle.
Fig ©Scion Publishing Ltd

20. Genetic Susceptibility Coronary Heart Disease
Genetic Variation
Genetic Disease
~80%
Genetic Susceptibility
Common Gene Variation
Gene + Environment
Delayed onset
(usually adult)
Coronary Heart Disease
Hypertension
Diabetes
Cancer
Vascular Disease
Classic
Medical Genetics
~20%
Single gene
Chromosome
Early onset
(usually pediatric)
Marfan Syndrome
PKU
Cystic Fibrosis
Neurofibromatosis
Down syndrome

21. Classification of genetic disorders
+ environment
Multifactorial
Single gene
Chromosomal
Mitochondrial
Somatic mutations (cancer)
Male

22. Fig. 1.15 ©Scion Publishing Ltd
Continuum of penetrance.
There is a continuum of penetrance from fully penetrant conditions, where other genes and environmental factors have no effect, through to low-penetrance genes that simply play a small part, along with other genetic and environmental factors, in determining a person’s susceptibility to a disease.
Multiple sclerosis is used as an example of a multifactorial condition where genetic factors play a major part in determining susceptibility, but current research suggests that each individual factor has a very low penetrance.
Fig ©Scion Publishing Ltd

23. Genetic factors
Male
Mutations in single genes (often causing loss of function)
Variants in genes causing alteration of function
Chromosomal imbalance causes alteration in gene dosage

24. Classification of genetic disorders
Single Gene Disorders
Male
Mutations in single genes
Multifactorial diseases
+ environment
Variants in genes
Chromosome disorders
Chromosomal imbalance

25. Heterozygotes with one copy of the altered gene are affected
Dominant
Heterozygotes with one copy of the altered gene are affected
Recessive
Homozygotes with two copies of the altered gene are affected
Male
X-linked recessive
Males with one copy of the altered gene on the X-chromosome are affected

26. Genetic disorders Multifactorial (common)
- “Environmental” influences act on a genetic predisposition to produce a liability to a disease.
- One organ system affected.
- Person affected if liability above a threshold.
Single gene (1% liveborn)
- Dominant/recessive pedigree patterns (Mendelian inheritance). - Can affect structural proteins, enzymes, receptors, transcription factors.
Chromosomal (0.6% liveborn)
- Thousands of genes may be involved. - Multiple organ systems affected at multiple stages in gestation. - Usually de novo (trisomies, deletions, duplications) but can be inherited (translocations).

27. The contributions of genetic and environmental
factors to human diseases
GENETIC ENVIRONMENTAL
Duchenne
muscular dystrophy
Haemophilia
Osteogenesis imperfecta
Club foot Pyloric stenosis Dislocation of hip
Peptic ulcer Diabetes
Tuberculosis
Phenylketonuria Galactosaemia
Spina bifida Ischaemic heart disease Ankylosing spondylitis
Scurvy
Rare Genetics simple Unifactorial High recurrence rate
Common Genetics complex Multifactorial Low recurrence rate

28. Multifactorial “Environmental” influences act on a genetic predisposition One organ system affected
Single gene Dominant/recessive pedigree patterns Structural proteins, enzymes, receptors, transcription factors
Chromosomal Multiple organ systems affected Inherited or de novo
Environmental Drugs, infections

29. The Family History The Family History is a powerful tool
for estimating genetic risk
Obtain information on children, sibs, and parents
Age/date of birth
Health status
Age at death
Cause of death
This is the ‘nuclear’ family
Expand as necessary to grandparents, uncles & aunts, etc.

30. Normal female
Normal male
Single bar indicates mating
Normal parents and normal offspring
Single parent means partner is not significant for the analysis

31. Double bar indicates consanguineous mating
Fraternal twins (not identical)
Identical twins
Number of children
Affected
Heterozygote
Female X-linked carrier
Dead Aborted or stillborn 2 6

32. Founders I 1 2 II 2 3 1 2 3 4 5 6
III 2 1 2 3 4 5 6 IV 1 2 3 4 5 6
Proband
IV - 2 V 1 2

33. Single gene disorders High risks to relatives
Dominant/recessive pedigree patterns
Some isolated cases due to new dominant mutations
Structural proteins, enzymes, receptors, transcription factors
I:1 AA
I:2 AB
II:1
II:2
II:3 BB ?
III:1
Tom
I:1
I:2
II:1
II:2
II:3
II:5
II:6
II:8
III:1
III:2
IV:1
I:2
I:1
I:3
II:1
II:2
II:3
II:4
II:5
II:6
II:7
II:8
II:9
II:10
II:11
II:12
II:13
II:14
II:15
III:1
III:2
III:3
IV:1
IV:2
IV:3
IV:4
III:4
III:5
IV:5
IV:6
IV:7
III:6
III:7
IV:8
IV:9
IV:10
III:8
III:9
III:10
III:11
III:12
III:14
III:13
III:15
III:16
III:17
IV:11
IV:12
IV:13

34. 1. Disorders with multifactorial inheritance (polygenic)
influence of multiple genes + environmental factors
relatively frequent
Diabetes mellitus (see Endocrine pathology)
Hypertension (see Circulation)
Gout (discussed here + see Crystals)
Schizophrenia (Psychiatry)
Congenital heart disease - certain forms (see Heart)
Some types of cancer (ovarian, breast, colon) (see Neoplasms)
often familial occurrence - probability of disease is in 1st degree relatives about 5-10%; 2nd degree relatives - 0,5-1%

35. 2. Monogenic (mendelian) disorders
mutation of 1 gene, mendelian type of inheritance
today about 5000 diseases
Autosomal dominant
Autosomal recessive
X-linked

36. Autosomal dominant disorders
both homozygotes and heterozygotes are affected
usually heterozygotes (inherited from one parent)
both males and females are affected
transmission from one generation to the other
50% of children are affected

37. 2. Autosomal recessive majority of mendelian disorders
only homozygotes are affected, heterozygotes (parents) are only carriers
25% of descendants are affected
if the mutant gene occurs with low frequency - high probability in consanguineous marriages
onset of symptoms often in childhood
frequently enzymatic defect
testing of parents and amnial cells

38. X-linked diseases transmitted by heterozygous mother to sons
daughters - 50% carriers, 50% healthy
sons - 50% diseased, 50% healthy
Children of diseased father - sons are healthy, all daughters are carriers
Hemophilia A (defect of Factor VIII)
Hemophilia B (defect of Factor IX)
Muscle dystrophy (Duchen disease)

39. 3. Chromosomal aberrations (cytogenetic disorders)
alternations in the number or structure of chromosomes
autosomes or sex chromosomes
studied by cytogenetics
cell cycle arrested in metaphase (colchicin) - staining by Giemsa method (G-bands) - photographing - karyotype
2 sets of 23 chromosomes
22 pairs of autosomes, 2 sex chromosomes (XX or XY)
cytogenetic disorders are relatively frequent! (1:160 newborns; 50% of spontaneous abortions)

40. Numerical abnormalities
euploidy - normal 46 (2n)
polyploidy (3n or 4n) - spontaneous abortion
aneuploidy
trisomy (2n+1) compatible with life
monosomy (2n-1) - autosomal - incompatible with life
- sex chromosomal compatible with life

41. Structural abnormalities
breakage followed by loss or rearrangement
deletion, translocation
Generally:
loss of chromosomal material is more dangerous than gain
abnormalities of sex chromosomes are better tolerated than autosomal
abnormalities of sex chromosomes sometimes symptomatic in adult age (e.g. infertility)
usually origin de novo (both parents and siblings are normal)

42. Prenatal diagnostics amniocentesis - analysis of amniotic fluid
cytogenetic analysis (karyotype - e.g. Down)
biochemical activity of various enzymes (e.g. Tay-Sachs)
analysis of various specific genes (CF gene - PCR)
sex of the fetus (X-linked disorders - hemophilia)

44. Recommended reading list - textbooks
Human Molecular Genetics 3
Strachan & Read
Garland Publishing, ISBN
Principles of Medical Genetics
Gelehrter, Collins & Ginsburg
Lippincott, Williams & Wilkins, ISBN
Genetics in Medicine
Nussbaum, McInnes & Willard
Elsevier, ISBN

45. Journals Nature Genetics Nature Reviews Genetics Trends in Genetics
Nature Reviews Genetics
Trends in Genetics