Summary Genetics And Public Health (AB_1025) – Vrij Univesiteit Amsterdam
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Lecture 1 Mendel................................................................................................................................2
Lecture 2 Genes and diseases.............................................................................................................2
Lecture 3 Public health and genetics..................................................................................................4
Lecture 4 Genetic Testing...................................................................................................................6
Lecture 5 Translation of genomics into healthcare.............................................................................7
Lecture 6 More than Mendel..............................................................................................................9
Lecture 7 Genetic Screening.............................................................................................................11
Lecture 8 Clinical Genetics................................................................................................................13
Lecture 9 Prenatal screening............................................................................................................15
Lecture 10 Consanguinity.................................................................................................................18
Lecture 11 Preconception care.........................................................................................................19
Lecture 12 From genetics to genomics and further..........................................................................20
Lecture 13 Whole Genome Sequencing............................................................................................21
Lecture 14 Ethical, legal, and social aspects of WES/WGS................................................................23
Lecture 15 Epigenetics......................................................................................................................26
Lecture 16 New developments in gene editing................................................................................28
Lecture 17 (In)equality and genetics.................................................................................................30
Lecture 18 Psychological and Behavioural Implications of genetic testing.......................................32
Lecture 19 The shadows of eugenics................................................................................................34
Lecture 20 Pharmacogenomics.........................................................................................................36
Lecture 21 Clinical validity................................................................................................................37
Lecture 22 New possibilities outside of clinical genetics..................................................................39
Lecture 23 Potential use of Polygenic Risk Scores............................................................................42
Lecture 24 Clinical Utility..................................................................................................................43
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, Lectures Genetics and Public Health
Lecture 1 Mendel
Pedigree: children in order of birth, firstborns at the left.
AUTOSOMAL DOMINANT : Several generations, on average 50% of children of affected
parents are also affected, not gender related.
- Huntington’s disease: neurodegenerative disorder, BRCA1&2, Lynch Syndrome,
Achondroplasia
AUTOSOMAL RECESSIVE : parents are usually not affected, but if both are carriers 1/4 of
their children is affected, sometimes parents are consanguineous, usually just one
generation, first child in the family that is affected, not gender-related, we are all carriers
for 3-4 diseases.
- Cystic fibrosis, hemoglobinopathies (sickle cell anaemia), phenylketonuria (PKU).
X-LINKED : sons/males are affected, women are (usually) not affected: they are carrier, they can pass
on the predisposition, no inheritance from man to man, fathers (if fertile!) can have daughters who
are carriers.
Duchenne Muscular Dystrophy, X-linked recessive; sons are affected, women are not affected.
- DMD, haemophilia A and B, colour blindness
Lecture 2 Genes and diseases
Genetics is a science of genes, heredity and variation. Genetics is increasingly multidisciplinary, and
can have a high impact on individuals, families and populations (hypes &hopes).
A gene is a functional unit that is regulated by transcription and encodes a product (protein or RNA).
20-25.000 genes in human genome, located on chromosomes (23 pairs). Only 2% of genome codes
for proteins (‘cut-and-paste’). The exons codes for proteins and determine our hereditary traits.
Large parts of the genome are non-coding, this is still unexplained, maybe junk DNA. But also,
regulatory functions of distant genes, switch genes.
Phenotypic differences between humans and other apes, but the number of genes is similar.
Pufferfish, have 35.00 genes, and a flower 25.000 genes. The number of genes is not what makes us
who we are, and determines not the complexity of species. 1 gene codes for more proteins, which
determines the complexity of the species
Human genetic variation makes us unique. Class 1: single nucleotide variant: only 1 nucleotide is
different. Class 2: insertion deletion, multiple nucleotides involved. These different classes make us
different. Genetic variation leads to phenotypic variation. Genetic variation in a population increases
the chance that some individuals will survive. Darwin’s Finches, if the environment changes, some
animals will have survival benefit, because of the genetic variation they have more chance to
reproduce.
2 individuals each differ 1 base in 1000 base pairs (forensic, paternity testing). Change in DNA with
frequency > 1% = polymorphism. In our genome we have a lot of SNPs, ca. 15.000.000 genetic
variants. Polymorphisms have no phenotypic consequents but contribute to common phenotypic
traits. Polymorphisms are common in population, vs. mutations that can cause diseases.
Mutations: a change in the DNA (disturbs protein function). Mutation occurs due to endogenous
things: DNA replication. Exogenous: Chemical damage or ionizing radiation. DNA changes can lead to
a disease. Origin of mutations: somatic cells or germline of sex cells.
Somatic mutations: occur in non-germline tissues, these mutations cannot be inherited (mutation in
tumour only, for example in the breast).
Germline mutations: present in egg or sperm, can be inherited. These mutations cause cancer family
syndrome.
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, Types of mutations
CHROMOSOME MUTATION : (1) loss (monosomy) or gain (trisomy) of whole chromosomes =
aneuploidy (instead of euploid). (2) Structural changes within the chromosome: deletion, or
translocation. Balanced translocation: all parts of the chromosome are still in the chromosome,
but changed between the chromosomes.
GENE MUTATION: alterations at gene level: point mutation (single base), insertion, deletion, etc.
Relevance of knowing something is hereditary. Case 1: Peter at 10 months, at age 15 months
diagnosed with retinoblastoma, mutation in RB gene (AD). Father also had eye removed when he
was a child, never realised that this mutation was genetic. 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.
Case 2: 2nd child, problems from birth. Diagnosis cystic fibrosis: incurable disorder: lungs and
nutritional malabsorption. Daily physiotherapy, dietary supplements, intensive treatment for chest
infections. Limited life expectancy. CF is caused by mutations in CFTR gene, there are a lot of
mutations in this gene that lead to CF. Most common F508, autosomal recessive. 1 in 30 carrier
(European descent). Birth prevalence: 1: 3600. Yes, it is hereditary, risk for the next child is 1 in 4.
Also risk for family members for being carriers.
Hereditary: inherited, derived from parents (genetic disorder is usually, but not always inherited, e.g.
acquired mutations). Cancer (oncogenetics), cardiovascular diseases (cardiogenetics), neurological
disorders (neurogenetics), etc.
Congenital: apparent at birth, not all congenital disorders are genetically determined (e.g. foetal
alcohol syndrome, toxoplasmosis infection): 40-60% unknown cause. Not all hereditary diseases are
congenital (BRCA, comes apparent when someone is much older).
Genetic diseases: chromosomal disorders and monogenic disorders: individually rare, collectively
common 1-2% birth prevalence.
CHROMOSOMAL DISORDERS ; numerical (gain or loss) or structural changes, 0.6% live-born children.
Most affect autosome (=chromosomes other than sex chromosomes).
Generally: (1) loss of chromosomal material = more dangerous than gain. (2) Abnormalities of sex
chromosomes = better tolerated than autosomal. (3) Usually origin de novo (both parents and
siblings are normal). The most common chromosomal abnormality is Down Syndrome, birth
prevalence 1:700. Klinefelter, 47 XXY, 1:500-1000 males. The extra X is either paternal or maternal
origin. Clinical characteristics: disproportional long arms/legs, IQ mostly normal, gynaecomasty,
reduced body and facial hair and infertility.
MONOGENIC DISORDERS : one gene is affected, most follow Mendelian pattern of inheritance.
1. Enzyme defects (e.g. “inborn errors of metabolism”, stofwisselingsziekte). Tay-Sachs Disease:
deficiencies of enzyme hexosaminidase. Material to be degraded builds up in certain cells in the body
and causes problems. GM2 ganglioside (waste) builds up in the brain, destroys nerve cells. children:
loss of sight hearing, movement etc, death age 4.
2. Defects in membrane receptors/transport systems. Familial Hypercholesterolemia (FH), receptor
disease. Mutation in gene encoding LDL receptor, elevated cholesterol levels (atherosclerosis), early
onset heart disease.
3. Alterations in structure, function, or quantity of non-enzyme proteins. Marfan syndrome, longer
joints, disorder of connective tissues of the body (defect in extracellular glycoprotein fibrillin-1).
Affects skeleton, eyes, and cardiovascular system (dilation of aorta=> aneurysm). ~80% of cases are
familial (autosomal dominant).
4. Genetic variants leading to unusual drug reactions. Cytochrome P450 enzymes, changes in CYP
enzyme levels affect drug metabolism.
MULTIFACTORIAL AND COMPLEX DISORDERS : frequent, 10% lifetime risk. Probably most people have
some genetic liability, environmental factors are very important. Most common disorders are
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, multifactorial: asthma, arthritis, dementia, depression, heart disease, cancer,
cleft lip, spina bifida, etc. Multi- or polygenic: >1 gene, each convey low risk &
environmental factors. The genes add up to a polygenic risk model, together
increasing the risk of developing the disease. Complex interactions! Mendelian subsets of common
disease: subset of CVD or cancers that have Mendelian subset. For breast cancer, single gene
mutation in BRCA1 and 2 is very important.
Lecture 3 Public health and genetics
Genomics and genetics translating to public health, to use in public health. How can we use the
knowledge of genetic and genomics in health care? Public Health Genomics: The responsible and
effective translation of genome-based knowledge and technologies into public policy and health
services for the benefit of population health. Genomic Healthcare, including: (1) diagnosis &
personalized medicine, (2) prevention (screening), (3) research.
Neonatal screening in NL identifies 25 treatable conditions, most of which are genetic. It is in the
interest of the infant to participate. Statement: responsible translation implies trying to achieve an
uptake of 100%. In “responsible translation” ethical arguments are taken into account. In this case: it
is certainly in the child’s best interest to participate to NBS, but voluntary participation is also a
principle. Responsible translation; let room for people to choose, and to not participate.
2000 genome sequence published; it will revolutionize the diagnosis, prevention and treatment of
most, if not all, human diseases. Sequencing was very expensive, but the price is dropping very fast.
Costs are not related to sequencing itself, but for interpretation of the data.
Big changes in costs? partly because of sequencing techniques, but also conversing techniques. Big
data e.g. could lead to predictive, preventive, personalized, participatory health care. Clinical
procedures and information technology could lead to P4 health care.
Mammography for breast cancer starts at 50 years of age. But genomics can also be used: Polygenic
risk scores for only 24 SNPs lead to risk from 21% to 51% at 70 years of age (study group is high risk
group). Precision breast cancer screening: groups made on basis of mutations, leads to higher or
lower risk and also earlier or later development of breast cancer. So, the screening could start at 45,
50 or 65, depending on the mutation. Now risk scores of 300 or thousands of SNPs available for <
100€. Now thinking about integration of genomics into breast cancer screening.
Clinical geneticist cannot explain the consequences to patients, because lot of that knowledge has
not been translated into the clinic.
Translation is needed. Moving knowledge off the shelves and into practise requires translation.
Genetics in healthcare: primary care and clinical genetics, individual patients. Public health: public
health genomics.
GENETICS IN MEDICINE – PRIMARY CARE e.g. GP, midwives, child health centres get the most (simple)
questions: what are the risks, two aunts got breast cancer, am I at risk?
However, genetic knowledge relevant for primary care is not adequate, there are fast developments,
often not core business. They do not know everything that is relevant for their clients.
CLINICAL GENETICS: medical specialty. Higher risk, diagnosis, prognosis and recurrence risk? Not only
for cancer, but also for other (hereditary) disorder. What is the cause behind the disease, what does
it mean for prognosis or other people will have the same conditions? Involves few people, complex
decisions; have more children or not, prenatal diagnosis and selective abortion, have both breasts
removed? The goal is: helping people make a choice that suits their moral considerations and/or
what they consider important in life: “Informed decision making”. Clinical genetics: individualism &
autonomy health care insurance payment. Goal is to empower counselees, outcome: informed
choice, personal control. 4
Genetic testing (DNA test) guidelines: counselling is needed, because of psychological consequences
of testing. Also family issues, someone that is carrier, has also impact on the whole family. Issues of
genetic discrimination, e.g. insurance that doesn’t want to pay or no partner. Traditionally, tests have
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