Medical Genetics

Assoc. Prof. Ömer Faruk BayrakDepartment of Medical GeneticsYeditepe University

Classical and Modern Genetics1. 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.

1900

1901

1902

1918

1931

19551937

Mendel’s Laws rediscovered

Anticipation described

Dominant inheritance of brachydactyly

Cytoplasmic inheritance of mitochondrial DNA

Linkage of color blindness and hemophiliaHuman diploid chromosome number is 46

Amniocentesis for chromosomal disorders

Tay-Sachs screening

Predictive genetic testing for Huntington disease

1970

1987

1970

3. A Conceptual History of Medical Genetics

Inborn errors of metabolism

Human globin genes cloned1976

Draft sequence for the human genome2001

1991 Medical genetics became an ABMS specialty

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.

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

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.

How much data make up the human genome?

3 pallets with 40 boxes per pallet x 5000 3 pallets with 40 boxes per pallet x 5000 pages per box x 5000 bases per page = pages per box x 5000 bases per page = 3,000,000,000 bases!3,000,000,000 bases!

To get accurate To get accurate sequence requires sequence requires 6-fold coverage. 6-fold coverage.

Now: Shred 18 pallets Now: Shred 18 pallets and reassemble.and reassemble.

Human genome content

• 1-2 % codes for protein products• 24% important for translation• 75% “junk”• Repetitive elements

– Satellites (regular, mini-, micro-)– Transposons– Retrotransposons– Parasites

Comparative Genomics

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

Genetic Evaluation Data gathering

History, especially family history

Physical examination - major and subtle findings

Pattern recognition

Laboratory testing – EMG, DNA

ClinicalGenetics

Consultant

CytogeneticsLab

Molecular Genetics

Lab

A Medical Genetics UnitA Medical Genetics Unit

• Clinical diagnosisClinical diagnosis• Genetic counsellingGenetic counselling• Risk assessmentRisk assessment• Prenatal & presymptomatic diagnosisPrenatal & presymptomatic diagnosis

Medical genetics in the health serviceMedical genetics in the health service

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

Genetic diseases

• traditionally - 3 types of diseases• 1. genetically determined• 2. environmentally determined• 3. 1. + 2.• 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

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

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

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.

~20%

ClassicMedical Genetics

Single geneChromosome

Early onset(usually pediatric)

Marfan SyndromePKU

Cystic FibrosisNeurofibromatosis

Down syndrome

Genetic Disease

Genetic Variation

~80%

Genetic Susceptibility

Common Gene VariationGene + Environment

Delayed onset(usually adult)

Coronary Heart DiseaseHypertension

DiabetesCancer

Vascular Disease

Classification of genetic disorders

• Multifactorial

• Single gene

• Chromosomal

• Mitochondrial

• Somatic mutations (cancer)

Male

+ environment

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.

Genetic factors

Male

Mutations in singlegenes (often causing

loss of function)

Variants in genes causing alteration of

function

Chromosomal imbalance causes alteration in gene

dosage

Classification of genetic disorders

Male

Mutations in single genes

Variants in genes

Chromosomal imbalance

Single Gene Disorders

Multifactorial diseases

Chromosome disorders

+ environment

Recessive

Homozygotes with two copies of the altered gene are affected

Dominant

Heterozygotes with one copy of the altered gene are affected

X-linked recessive

Males with one copy of the altered gene on the X-chromosome are affected

Male

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).

GENETIC ENVIRONMENTAL

Duchenne muscular dystrophy

HaemophiliaOsteogenesis imperfecta

Club footPyloric stenosisDislocation of hip

Peptic ulcerDiabetes

Tuberculosis

PhenylketonuriaGalactosaemia

Spina bifidaIschaemic heart diseaseAnkylosing spondylitis

Scurvy

The contributions of genetic and environmental factors to human diseases

RareGenetics simple

UnifactorialHigh recurrence rate

CommonGenetics complexMultifactorialLow recurrence rate

• Multifactorial“Environmental” influences act on a genetic predispositionOne organ system affected

• Single geneDominant/recessive pedigree patternsStructural proteins, enzymes, receptors, transcription

factors

• ChromosomalMultiple organ systems affectedInherited or de novo

• EnvironmentalDrugs, infections

The Family History is a powerful toolfor estimating genetic risk

Obtain information on children, sibs, and parentsAge/date of birth

Health statusAge at death

Cause of death

This is the ‘nuclear’ family

Expand as necessary to grandparents, uncles & aunts, etc.

The Family History

Normal female

Normal male

Single bar indicates mating

Normal parents and normal offspring

Single parent means partner is not significant for the analysis

Double bar indicates consanguineous mating

Fraternal twins (not identical)

Identical twins

Number of children

Affected

Heterozygote

Female X-linked carrier

Dead Aborted or stillborn

62

2 3

I

II

III

IV

2

1 2

1 2 3 4 5 6

1 2 3 4 5 6

1 2 3 4 5 6

Founders

ProbandIV - 2V

1 2

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:1AA

I:2AB

II:1AA

II:2AB

II:3BB

?

III:1BB

Tom

I:2I: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:14III:13 III:15 III:16 III:17

IV:11 IV:12 IV:13

I:1 I:2

II:1 II:2 II:3 II:5 II:6 II:8

III:1 III:2

IV:1

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%

2. Monogenic (mendelian) disorders

• mutation of 1 gene, mendelian type of inheritance

• today about 5000 diseases

• Autosomal dominant

• Autosomal recessive

• X-linked

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

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

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)

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)

Numerical abnormalities

• euploidy - normal 46 (2n)• polyploidy (3n or 4n) - spontaneous abortion• aneuploidy• trisomy (2n+1) - 47 - compatible with life• monosomy (2n-1) - autosomal - incompatible

with life• - sex chromosomal -

compatible with life

Structural abnormalities

• breakage followed by loss or rearrangement• deletion, translocationGenerally: • 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)

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)

Recommended reading list - textbooks

• Human Molecular Genetics 3– Strachan & Read

• Garland Publishing, ISBN 0-8153-4182-2

• Principles of Medical Genetics– Gelehrter, Collins & Ginsburg

• Lippincott, Williams & Wilkins, ISBN 0683034456

• Genetics in Medicine– Nussbaum, McInnes & Willard

• Elsevier, ISBN 0721602444

Journals

• Nature Genetics– http://www.nature.com/ng/index.html

• Nature Reviews Genetics– http://www.nature.com/nrg/index.html

• Trends in Genetics– http://www.trends.com/tig/default.htm