Lectures Genetics & Public Health
Course of the minor Biomedical Topics in Health Care (VU)
Content
Introduction to the course ................................................................................................................................................ 1
Meet & Greet: Mendel...................................................................................................................................................... 1
Genes & diseases .............................................................................................................................................................. 3
Public health & genetics.................................................................................................................................................... 7
More than Mendel .......................................................................................................................................................... 11
Translation of genomics into healthcare ........................................................................................................................ 16
Genetic testing ................................................................................................................................................................ 20
Genetic screening ........................................................................................................................................................... 21
Clinical genetics............................................................................................................................................................... 24
Prenatal screening .......................................................................................................................................................... 28
Consanguinity.................................................................................................................................................................. 33
Preconception care ......................................................................................................................................................... 37
Epigenetics ...................................................................................................................................................................... 40
From genetics to genomics and further.......................................................................................................................... 46
Whole genome sequencing ............................................................................................................................................ 52
Ethical, legal and social aspects ...................................................................................................................................... 57
Analytic and clinical validity ............................................................................................................................................ 60
Clinical utility ................................................................................................................................................................... 64
New possibilities outside clinical genetics ...................................................................................................................... 68
The shadow of eugenics.................................................................................................................................................. 73
New developments in gene editing ................................................................................................................................ 77
Psychological and behavioural aspects of genetic testing .............................................................................................. 79
(In)equality in genetics.................................................................................................................................................... 83
Pharmacogenomics ......................................................................................................................................................... 87
Working lectures ............................................................................................................................................................. 92
Assignment: screening criteria and parameters ......................................................................................................... 92
Assignment: population genetics................................................................................................................................ 94
Assignment: calculating interactions between genes and environment.................................................................. 102
Assignment: dilemmas in decision making ............................................................................................................... 107
Assignment: direct-to-consumer genetic testing ..................................................................................................... 113
,Introduction to the course
Genetics and public health
- How to use genetic knowledge in public health?
- How to convert genetic research findings into clinical developments of use to actual patients?
Practical issues
Assignments
- Assignment: From bench to bedside
- Self enrollment in group
- Assignment: Dilemmas in decision making (23 nov)
- Watch video & answer questions about this video
- Read 3 cases on genetic testing
- Assignment: DTC genetic testing (30 nov)
- View 1 website offering direct-to-consumer genetic testing with subgroup
- Present findings on 30 nov
- Same subgroups as assignment ‘from bench to bedside’
Final mark
- 70% exam: multiple choice and open questions
- 30% assignment ‘from bench to bedside’
- Oral presentation (10%)
- Written report, including peer review (20%)
- Exam, oral presentation and written report should all be passed
Study material
- List of study material on Canvas
- PACITA-document
- Articles
- Lecture slides
- Assignments
- Literature used for assignments that are not on the literature list, are not study material
Meet & Greet: Mendel
Learning goals
The student is able to:
- Explain the principles of monogenetic (Mendelian) inheritance and illustrate them with examples
- Draw a family tree using information about a family and calculate the risks of suffering from or passing on an
inherited disorder, in the case of autosomal dominant, autosomal recessive and X-linked recessive
transmission
Pedigree and inheritance
- Squares are men, circles are women
- Affected = marked
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, - Children in order of birth (first-borns at the left)
- Half black half white = carrier (only in recessive inheritance)
- Line through it = dead
- Double line = cousin marriages (family members)
Typical autosomal dominant inheritance
- About 50% chance of passing it on, when one of the parents is heterozygous
- When one of the parents is homozygous dominant (no healthy allele anymore), all the children will be
affected → rare phenomenon
- Everyone with the gene gets the disease, because it’s dominant
- Disease comes back in multiple generations, goes through the family pedigree
- Inheritance from man to woman, woman to man, man to man, woman to woman
Examples of autosomal dominant disorders
- Huntington disease (holes in the brain)
- 100% penetrance → you always get the disease
- BRCA1 & 2 (hereditary breast cancer)
- 60-80% penetrance → you don’t always get sick when you have the allele
- Lynch syndrome
- Achondroplasia
Typical autosomal recessive inheritance
- Both parents have to be carriers in order to get an affected child (25% chance)
- The parents don’t have to have the disease, they can be just carriers → healthy, so usually unaware of the
risk (child with a recessive disease usually comes very unexpected)
- Families in which none of the children are affected, but both parents are carrier, are not observed
- Sometimes parents are consanguineous → higher chance
- Usually just 1 generation
Examples of autosomal recessive disorders
- Cystic fibrosis (CF)
- Hemoglobinopathies (sickle cell anemia, thalassemia)
- Phenylketonuria (PKU)
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,Example cases of X-linked inherited disorders
Example 1: Peter and Daniëlle
Peter and Daniëlle have a relationship. A nephew of Daniëlle has Duchenne Muscular Dystrophy (DMD). Peter does
not want to have children if his children have a high risk to have DMD. However, Daniëlle would very much like to
have children. Cousin Edward is Daniëlle brother’s son. DMD is X-linked recessive.
- What is the chance that Daniëlle passes DMD on to her child? → 0% (mother of Edward isn’t related)
- Does the physician have to refer them to a clinical genetics center for genetic counselling? → no
- Characteristics of X-linked recessive inheritance pattern: sons are affected, women are not affected (they are
carrier, they can pass on the predisposition), no inheritance from man to man
Example 2: Jasper and Lisa
Jasper and Lisa have a relationship. The cousin of Lisa, Tim, has DMD. Jasper does not want to have children if they
have a high risk to have DMD. However, Lisa would very much like to have children. Tim is the son of Henk and
Isabelle. Isabelle is the sister of Lisa’s mother.
- The grandmother of Lisa has the X-linked allele, which she gave to her daughter Isabelle (she is carrier of the
X-linked disorder) and she gave it to her son Tim
- The grandmother of Lisa could have given the X-linked allele to the mother of Lisa (50% chance) and she
could have given it to Lisa (25% chance)
- Lisa can give it to her child if she has it (12,5%) (daughter would be a carrier)
- The risk of getting a boy that is affected is 6,25% (50% chance of getting a boy)
- Does the physician have to refer them to a clinical genetics center for genetic counselling? → yes
Examples of X-linked inherited disorders
- Duchenne Muscular Dystrophy
- Hemophilia A and B (impaired blood clotting)
- Color blindness
Genes & diseases
Learning goals
The student is able to:
- Explain what is meant by genetic variation
- Describe the following classification of genetic diseases using an example: chromosomal disorders,
monogenic disorders, Mendelian subsets of common diseases, multifactorial and complex disorders
Genetics: fast moving field
- Science of genes, heredity and variation
- Fast technological developments, increasingly multidisciplinary (geneticists, physicians, etc.)
- Can have high impact on individuals, families and populations (hypes and hopes)
Terms in genetics
Gene
A functional unit that is regulated by transcription and encodes a product (protein or RNA):
- About 20.000-25.000 genes in the human genome (less than first expected)
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, - Located on chromosomes (23 pairs)
- Only 2% of genome codes for proteins (exons) (‘cut-and-paste’)
- Exons are expressed (translate to proteins → determine hereditary traits), introns are cut out
- Large parts are non-coding (unexplained)
- Used to call this ‘junk DNA’?
- Recently discovered other functions: e.g. regulatory functions of distant gene; ‘switch gene’
Genetic variation
Phenotypic differences between humans and other apes:
- Number of genes doesn’t determine complexity of the species (pufferfish and flowers might have more
genes than we do), but one gene codes for multiple protein complexes → determines complexity
What makes us unique/different? → human genetic variation
- Distinguished in different classes:
- Genetic variation leads to phenotypic variation
- Genetic variation in a population increases the chance that some individuals will survive (survival benefit)
- On average, two individuals each differ 1 base in 1000 basepairs (handy in forensics and paternity testing)
- Change in DNA with frequency >1% = polymorphism
- In our genome: circa 15.000.000 genetic variants (polymorphisms, e.g. SNPs (single nucleotide
polymorphisms) → most have no phenotypic consequences, some contribute to phenotypic traits (height)
- Polymorphism vs. (pathogenic) mutations → normal sequence variations vs. rare and deleterious changes
Mutations
Defined as a change in the DNA (disturbs protein function):
- DNA replication
- Chemical damage
- Ionizing radiation
Origin: somatic cells or germ/sex cells
- Somatic mutations: occur in non-germline tissues,
can’t be inherited (for example in tumor)
- Germline (sex) mutations: present in egg or sperm, can be inherited, cause cancer family syndrome
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,Types of mutations:
- Chromosome mutation
- Loss (monosomy) or gain (trisomy) of whole chromosomes
= aneuploidy
- Structural changes within the chromosome – translocations
(rearrangement of chromosome), deletions, etc.
- Balanced translocation: normal functioning when
all the parts all still there, but if you have offspring
and pass on one chromosome, there’s a missing
part (chromosome material is not complete anymore)
- Gene mutation
- Alterations at gene level: point mutation (single base), insertion, deletions, etc.
Hereditary
What is the relevance of knowing something is hereditary?
- If known about the genetic risk (for children): early screening & early detection possible
- The importance of taking an adequate family history and an appropriate follow-up of that
Examples:
- Peter 15 months: diagnosed at clinical genetics centre with retinoblastoma (eye tumor), caused by mutation
in RB gene (autosomal dominant) → father also had enucleated eye (never realised/had been told of
possible genetic aetiology)
- Second child of healthy parents, from birth: colds, coughing, 4 times antibiotics, doesn’t grow well →
pediatrician: cystic fibrosis (CF) (incurable, lungs and nutritional malabsorption, daily physiotherapy, dietary
supplements, intensive treatment for chest infections, limited life expectancy) → caused by mutations in
CFTR-gene (autosomal recessive), 1 in 30 carrier (European), birth prevalence is 1:3600-4000
- So it’s hereditary and the risk in their next child is 1 in 4 (both parents have a recessive allele), also
risk for family members to be a carrier
Terminology
- Hereditary: inherited, derived from parents (genetic disorder is usually, but not always inherited, e.g.
acquired mutations)
- For example: cancer (oncogenetics), cardiovascular diseases (cardiogenetics), neurological disorders
(neurogenetics), storage diseases, errors of metabolism, skin disorders, blood disorders
- Congenital: apparent at birth, not all congenital disorders are genetically determined (e.g. fetal alcohol
syndrome, toxoplasmosis infection): 40-60% unknown cause, not all hereditary diseases are congenital
Classification of genetic diseases
Chromosomal disorders
- Numerical or structural changes (0,6% live-born)
- Most affect autosome (= chromosomes other than sex chromosomes)
- Generally: loss of chromosomal material = more dangerous than gain, abnormalities of sex chromosomes =
better tolerated than autosomal, usually origin de novo (both parents and siblings are normal)
Down syndrome (most common chromosomal disorder):
- Trisomy 21, 47 chromosomes instead of 46
- Birth prevalence 1:700
Klinefelter:
- XXY sex chromosomes
- 47 chromosomes
- 1:500-1000 males
- Extra X is either of paternal or maternal origin
- Clinical characteristics, e.g.: disproportional long arms, IQ mostly
normal, gynaecomasty, reduced body and facial hair, infertility
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, Monogenic disorders
- Individually rare, collectively with chromosomal common 1-2% birth disorders
- Most follow Mendelian pattern of inheritance
- Single gene
- There are exceptions
- Online Mendelian Inheritance in Man (OMIM)
- Since 1995 online via NIH
- Mendelian disorders: caused by mutations in single genes of large effect (1% liveborn)
- 2019: 5281 autosomal, 342 X-linked, 5 Y-linked, 33 mitochondrial
Mechanisms of single gene disorders:
- Enzyme defects (e.g. ‘inborn errors of metabolism’): storages diseases
- Material to be degraded builds up in certain cells in the body and causes problems
- Example: Tay-Sachs disease → deficiencies of enzyme hexosaminidase, GM2 ganglioside (waste)
builds up, destroys nerve cells, children: loss of sight, hearing, movement, etc., death age 4
- Defects in membrane receptors/transport systems
- Example: familial hypercholesterolemia → receptor disease, mutation in gene encoding LDL receptor
(involved in transport and metabolism of cholesterol), elevated cholesterol levels (atherosclerosis),
early onset heart disease
- Alterations in structure, function or quantity of non-enzyme proteins
- Example: Marfan syndrome → 1:5000, disorder of connective tissues of the body (defect in
extracellular glycoprotein fibrillin-1), affects skeleton, eyes and cardiovascular system (dilation of
aorta → aneurysm), about 80% of cases are familial (autosomal dominant)
- Genetic variants leading to unusual drugs reactions
- Example: cytochrome P450 enzymes → used by the liver to metabolize drugs, changes in CYP
enzyme levels affect drug metabolism
- Rapid metabolization: higher dose
Multifactorial and complex disorders
- Frequent: about 10% lifetime risk
- Most common disorders are multifactorial: asthma,
arthritis, dementia, depression, heart disease, cancer, cleft
lip, spina bifida, etc.
- Multi- or polygenic: >1 gene, each convey low risk
- Environmental factors (very important)
- Complex interactions between genes and environmental
factors
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