Genetics of publich health
Inhoudsopgave
College 1 - meet and greet mendel..................................................................................... 2
College 2 - genes and diseases.......................................................................................... 3
College 3 - Genetic testing.................................................................................................. 4
College 4 - more than mendel............................................................................................. 5
College 5 - Public health and genetics............................................................................... 7
College 6 - clinical genetics.................................................................................................7
College 7 - translation of genomics into healthcare......................................................... 8
College 8 - preconception care......................................................................................... 10
College 9 - consanguinity.................................................................................................. 11
College 10 - prenatal screening........................................................................................ 12
College 11 - Whole genome sequencing.......................................................................... 14
College 12 - Ethical, legal and social aspects of WGS................................................... 14
College 13 - from genetics to genomics and further.......................................................16
College 14 - Epigenetics.................................................................................................... 17
College 15 - new developments in gene editing..............................................................19
Working lecture: Dilemma’s in decision making............................................................. 20
College 16 - (in)equality and genetics.............................................................................. 22
College 17 - Psychological and behavioural implications of genetic testing...............23
College 18 - the shadow of eugenics................................................................................24
College 19 - pharmacogenomics...................................................................................... 25
College 20 - clinical validity...............................................................................................26
College 21 - Clinical utility................................................................................................. 28
College 22 - potential use of polygenic risk scores........................................................ 29
College 23 - new possibilities outside clinical genetics................................................. 30
Working lecture: Population genetics.............................................................................. 31
Working lecture: Genetic screening................................................................................. 33
Working lecture: Calculating interactions between genes and environment...............33
,College 1 - meet and greet mendel
- Explain the principles of monogenetic (mendelian) inheritance and illustrate them
- Create a pedigree using information about a family and calculate teh risk of suffering
from or passing an inheritend disorder, in the case of autosomal dominant,
autosomal recessive and X-linked recessive transmission.
Pedigree symbols
Children in order of birth > First-born at the left
Autosomaal dominant inheritance pattern
● Several generations
● one mutated copy needed for disorder
● men and females equally affected
● One parent affected > 50% chance
● Two parents affected > 75% chance
● Huntington, BRCA1&2, Lynch syndrome,
anchodroplasia.
Autosomal recessive inheritance pattern
● Two mutated copies needed
● Men and females equally affected
● Both parents carrier, ¼ children affected
● Sometimes parents are consanguineous
● Usually one generation
● CF, phenylketonuria (PKU), hemoglobinopathies
(sickle cell anemia, thalassemia)
Typical X-linked (sex-linked) recessive inheritance pattern
● Sons are affected
● Women usually only carrier (1X mutated), when 2X mutated than affected
● No inheritance from man to man
● No increased risk on X-linked disorder if there is a healthy male in between
● Fathers (if fertile!) can have daughters how are carriers
● Duchenne, Hemophilia A and B (impaired blood clotting), color blindness.
,College 2 - genes and diseases
- What is meant by genetic variation
- What is meant by chromosomal disorder, monogenic disorder, Mendelian subsets of
common diseases, multifactorial and complex disorders.
Gene = functional unit that is regulated by transcription + encodes a product (protein/ RNA).
Genes are located at chromosomes (23 pairs). Only 2% codes for protein (exons). Exons
translate to proteins and determine hereditary traits. 98% non-coding DNA (introns).
Human genetic variation = the genetic differences in and among populations. One gene
codes for multiple proteins or complexes and that determines complexity of species.
Genetic variation
Differences in DNA sequence between individuals within populations, phenotypic variation.
Two individuals each differ 1 base in 1000 base pairs. Relevance: forensic or paternity test.
Types of variations:
1. Polymorphisms: DNA variants with frequency higher than 1% in population.
Examples are SNPs (one base differs in individuals). Most are benign (no effect)
2. Pathogenic mutations: rare and deleterious changes in DNA causing disease.
a. Somatic mutations: not inherited.
b. Germ/ sex mutations: in sperm/ egg, sometimes inherited
Mechanisms: DNA replication, chemical damage or ionizing radiation > DNA changes.
Gene mutation: alterations at gene level (point mutation, single base, insertion, deletions).
Hereditary = inherited (usually genetic, but not always inherited, acquired mutations).
Congenital = apparent at birth, not all congenital disorders are genetically determined.
40-60% unknown cause. No all hereditary diseases are congenital (BRCA).
Classification of genetic disorders
1. Chromosomal disorders
a. Numerical (aneuploidy)
- Loss (monosomy, turner)
- Gain (trisomy 21, down)
b. Structural changes = translocations, deletions etc.
Loss chromosomal material more dangerous than gain. Sex chromosome abnormalities are
better tolerated than autosomal (= other than sex chromosomes, down). Example: sex
chromosome abnormalities -> Klinefelter: males extra X (lower development + not infertile).
2. Monogenic disorder
Results from mutations in 1 single gene, 1% liveborn. Often follows a Mendelian
inheritance pattern. Like Tay-sachs (enzyme defects) or Familial hypercholesterolaemia
(defects in membrane receptors/ transport). Other mechanisms are Alteration in
structure or function of non-enzyme proteins or genetic variants leading to unusual
drug reactions.
3. Mendelian subset of common disease
Some single-gene mutations predispose individuals to common disease (BRCA1/2).
, 4. Multifactorial and complex disorders
Results from interaction of multiple genetic and environmental factors. Most common
disorders are multifactorial (asthma, dementia, depression etc.). Key characteristics:
a. Polygenic (multigenic): involving multiple genes, each low risk (add up)
b. Environmental influences: diet, lifestyle (significant rate).
Individually chromosomal + monogenic disorders > rare: together common (1-2% liveborn).
Genetic effect vs. environmental effect
College 3 - Genetic testing
- Different types of genetic testing
Before DNA testing, diagnostic genetic testing relied on the detection of phenotypes
(physical examination) and/ or metabolites. Taste test: baby salty tasting skin (CF) etc.
Genetic test analyzes:
1. Genotype: DNA, RNA and chromosomes
2. Metabolites: proteins, enzymes
3. Phenotype: appearance, characteristics
Outcome genetic test results
- Positive: identified variant is likely pathogenic
- Negative: no Pathogenic variant is found
- Variants of unknown significance (VUS): functional effect (currently) unknown
Diagnostic testing = confirms and rules out suspected genetic disorder in a symptomatic
individual. Monogenic diseases have 100% penetration. Example: patient with colon cancer
+ affected family: testing Lynch. Succes varies by condition > incomplete knowledge of the
genetic basis of the disease, genetic heterogeneity (many variants), non genetic factors.
Predictive genetic testing = identifies likelihood of developing genetic condition in
asymptomatic individuals with familiy history of a genetic disorder. Types:
1. Presymptomatic: complete penetrance (HD)
2. Predisposition: identifies mutations with variable (higher) risk (BRCA1/2)
Carrier testing = carrier of autosomaal recessive + X-linked identification. It helps to
determine the risk of passing it of to offspring (CF)
Inhoudsopgave
College 1 - meet and greet mendel..................................................................................... 2
College 2 - genes and diseases.......................................................................................... 3
College 3 - Genetic testing.................................................................................................. 4
College 4 - more than mendel............................................................................................. 5
College 5 - Public health and genetics............................................................................... 7
College 6 - clinical genetics.................................................................................................7
College 7 - translation of genomics into healthcare......................................................... 8
College 8 - preconception care......................................................................................... 10
College 9 - consanguinity.................................................................................................. 11
College 10 - prenatal screening........................................................................................ 12
College 11 - Whole genome sequencing.......................................................................... 14
College 12 - Ethical, legal and social aspects of WGS................................................... 14
College 13 - from genetics to genomics and further.......................................................16
College 14 - Epigenetics.................................................................................................... 17
College 15 - new developments in gene editing..............................................................19
Working lecture: Dilemma’s in decision making............................................................. 20
College 16 - (in)equality and genetics.............................................................................. 22
College 17 - Psychological and behavioural implications of genetic testing...............23
College 18 - the shadow of eugenics................................................................................24
College 19 - pharmacogenomics...................................................................................... 25
College 20 - clinical validity...............................................................................................26
College 21 - Clinical utility................................................................................................. 28
College 22 - potential use of polygenic risk scores........................................................ 29
College 23 - new possibilities outside clinical genetics................................................. 30
Working lecture: Population genetics.............................................................................. 31
Working lecture: Genetic screening................................................................................. 33
Working lecture: Calculating interactions between genes and environment...............33
,College 1 - meet and greet mendel
- Explain the principles of monogenetic (mendelian) inheritance and illustrate them
- Create a pedigree using information about a family and calculate teh risk of suffering
from or passing an inheritend disorder, in the case of autosomal dominant,
autosomal recessive and X-linked recessive transmission.
Pedigree symbols
Children in order of birth > First-born at the left
Autosomaal dominant inheritance pattern
● Several generations
● one mutated copy needed for disorder
● men and females equally affected
● One parent affected > 50% chance
● Two parents affected > 75% chance
● Huntington, BRCA1&2, Lynch syndrome,
anchodroplasia.
Autosomal recessive inheritance pattern
● Two mutated copies needed
● Men and females equally affected
● Both parents carrier, ¼ children affected
● Sometimes parents are consanguineous
● Usually one generation
● CF, phenylketonuria (PKU), hemoglobinopathies
(sickle cell anemia, thalassemia)
Typical X-linked (sex-linked) recessive inheritance pattern
● Sons are affected
● Women usually only carrier (1X mutated), when 2X mutated than affected
● No inheritance from man to man
● No increased risk on X-linked disorder if there is a healthy male in between
● Fathers (if fertile!) can have daughters how are carriers
● Duchenne, Hemophilia A and B (impaired blood clotting), color blindness.
,College 2 - genes and diseases
- What is meant by genetic variation
- What is meant by chromosomal disorder, monogenic disorder, Mendelian subsets of
common diseases, multifactorial and complex disorders.
Gene = functional unit that is regulated by transcription + encodes a product (protein/ RNA).
Genes are located at chromosomes (23 pairs). Only 2% codes for protein (exons). Exons
translate to proteins and determine hereditary traits. 98% non-coding DNA (introns).
Human genetic variation = the genetic differences in and among populations. One gene
codes for multiple proteins or complexes and that determines complexity of species.
Genetic variation
Differences in DNA sequence between individuals within populations, phenotypic variation.
Two individuals each differ 1 base in 1000 base pairs. Relevance: forensic or paternity test.
Types of variations:
1. Polymorphisms: DNA variants with frequency higher than 1% in population.
Examples are SNPs (one base differs in individuals). Most are benign (no effect)
2. Pathogenic mutations: rare and deleterious changes in DNA causing disease.
a. Somatic mutations: not inherited.
b. Germ/ sex mutations: in sperm/ egg, sometimes inherited
Mechanisms: DNA replication, chemical damage or ionizing radiation > DNA changes.
Gene mutation: alterations at gene level (point mutation, single base, insertion, deletions).
Hereditary = inherited (usually genetic, but not always inherited, acquired mutations).
Congenital = apparent at birth, not all congenital disorders are genetically determined.
40-60% unknown cause. No all hereditary diseases are congenital (BRCA).
Classification of genetic disorders
1. Chromosomal disorders
a. Numerical (aneuploidy)
- Loss (monosomy, turner)
- Gain (trisomy 21, down)
b. Structural changes = translocations, deletions etc.
Loss chromosomal material more dangerous than gain. Sex chromosome abnormalities are
better tolerated than autosomal (= other than sex chromosomes, down). Example: sex
chromosome abnormalities -> Klinefelter: males extra X (lower development + not infertile).
2. Monogenic disorder
Results from mutations in 1 single gene, 1% liveborn. Often follows a Mendelian
inheritance pattern. Like Tay-sachs (enzyme defects) or Familial hypercholesterolaemia
(defects in membrane receptors/ transport). Other mechanisms are Alteration in
structure or function of non-enzyme proteins or genetic variants leading to unusual
drug reactions.
3. Mendelian subset of common disease
Some single-gene mutations predispose individuals to common disease (BRCA1/2).
, 4. Multifactorial and complex disorders
Results from interaction of multiple genetic and environmental factors. Most common
disorders are multifactorial (asthma, dementia, depression etc.). Key characteristics:
a. Polygenic (multigenic): involving multiple genes, each low risk (add up)
b. Environmental influences: diet, lifestyle (significant rate).
Individually chromosomal + monogenic disorders > rare: together common (1-2% liveborn).
Genetic effect vs. environmental effect
College 3 - Genetic testing
- Different types of genetic testing
Before DNA testing, diagnostic genetic testing relied on the detection of phenotypes
(physical examination) and/ or metabolites. Taste test: baby salty tasting skin (CF) etc.
Genetic test analyzes:
1. Genotype: DNA, RNA and chromosomes
2. Metabolites: proteins, enzymes
3. Phenotype: appearance, characteristics
Outcome genetic test results
- Positive: identified variant is likely pathogenic
- Negative: no Pathogenic variant is found
- Variants of unknown significance (VUS): functional effect (currently) unknown
Diagnostic testing = confirms and rules out suspected genetic disorder in a symptomatic
individual. Monogenic diseases have 100% penetration. Example: patient with colon cancer
+ affected family: testing Lynch. Succes varies by condition > incomplete knowledge of the
genetic basis of the disease, genetic heterogeneity (many variants), non genetic factors.
Predictive genetic testing = identifies likelihood of developing genetic condition in
asymptomatic individuals with familiy history of a genetic disorder. Types:
1. Presymptomatic: complete penetrance (HD)
2. Predisposition: identifies mutations with variable (higher) risk (BRCA1/2)
Carrier testing = carrier of autosomaal recessive + X-linked identification. It helps to
determine the risk of passing it of to offspring (CF)
