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

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

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. 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

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 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.

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

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

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. Fig. 13.3 ©Scion Publishing Ltd

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

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

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. 1.15 ©Scion Publishing Ltd

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

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

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

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).

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

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

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.

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 2 6

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

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

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, 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)

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 Nature Reviews Genetics Trends in 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