Summary Genetics and Public Health | VU Amsterdam

Lecture 1: Meet and greet Mendel




Pedigree:




In order of birth. See explanation of symbols on pp.

Autosomal dominant inheritance
 Characteristics
o 50% of children affected.
o In several generations.
o No sex inheritance.
 Examples
o Huntington’s disease
o BRCA1&2 (breast cancer, 60-70% inheritance)
o Lynch syndrome
o Achondroplasia

Autosomal recessive inheritance
 Characteristics
o If both parents are carrier, 25% of children are affected (25% in each pregnancy).
o Usually just in 1 generation.
o Sometimes parents are consanguineous (= from same ancestor). Children in those
families are usually affected a bit more.
 Examples
o Cystic fibrosis
o Hemoglobinopathies (sickle cell anemia)
o Phenylketonuria (PKU)

Case – Peter & Danielle
 DMD is x-linked.
 Sons are affected. Women are carriers (can pass it on). No inheritance men-men.
 In general, no increased risk on x-linked disorder if there is a healthy male in between.
 Chance Danielle passes DMD on to child > small.
o Mom of Danielle could be affected, but that is population risk. Can reassure Danielle
and Peter that they don’t have a higher risk for giving DMD to their children.
o Don’t send them to the clinic, otherwise could send everyone.

If parents not have a disease (and aren’t carrier) but children do (de novo) > new mutation.

,Case – Jasper & Lisa
 Isabelle has to be carrier (because Henk is healthy). Probably comes from her mother. Lisa’s
mother has 50% risk of getting the mutation. Lisa has 25% of having the mutation (50%
chance of getting it from her mother (0.5x0.5).
o The chance of Lisa passing it on to her child is 12.5%. When it is a boy, the child has
6.25% of being affected.
 Referral is necessary. Chance is much higher than for a normal couple.

Look at question carefully (if boy or if a child is affected, makes a difference)!!!!!

X-linked inheritance
 Characteristics
o Males affected, females pass it on (usually not affected)
o No inheritance man-man
o Fathers can have daughters who are carriers.
 Examples
o Duchenne
o Hemophilia (impaired blood clothing)
o Color blindness

,Lecture 2: Genes and diseases
Genes
 = a functional unit that is regulated by transcription and encodes a product (protein/RNA).
 2% of genome codes for proteins
o Large parts are non-coding (unexplained).

Human genetic variation
 Different classes
o Single nucleotide variant, deletion/insertion, etc.
 What makes us different.
 Increases the chance that some individuals will survive
o Leads to phenotypic variation.
 Survival of the fittest.
 Between 2 humans, we differ 1% in our DNA (polymorphisms, most of them SNPs).

Mutations
 Defined as changes in the DNA
 Different causes
o DNA replication
o Chemical damage
o Ionizing radiation
 In different cells (origin)
o Somatic cells
 Occur during live, can’t be inherited.
o Germ/sex cells
 Can be inherited. Can cause family syndrome
 Types of mutations
o Chromosome mutation
 Loss (monosomy) or gain (trisomy) of whole chromosome = aneuploidy
 Structural changes > translocations, deletions, etc.
o Gene mutations
 Alterations at gene level > point mutation, insertion, deletion, etc.

Importance of knowing something is hereditary > early screening and detection possible.

CF
 Caused by mutations in CFTR-gene. Autosomal recessive.
o Lot of people are carrier.

Hereditary
 Means derived from the parents.
 Genetic disorders is usually (but not always) inherited.

Congenital
 Means apparent at birth.
 Not al congenital disorders are genetically determined (e.g. fetal alcohol syndrome).
 Not all hereditary diseases are congenital (e.g. BRCA causing breast cancer).

, Lecture 3: Genetic testing
Categories of genetic diseases
 Chromosomal disorders
o 2 types
 Numerically > e.g. Down syndrome
 Structural > large deletion, duplication, etc.
o Many not compatible with live.
o Most affect autosome (non-sex chromosomes)
o Generally
 Loss of chromosomal material = more dangerous than gain.
 Abnormalities of sex chromosomes is better tolerated than autosomal.
 Usually origin de novo (both parents and siblings are normal).
 Monogenic disorder
o Examples > CF, sickle cell anemia, etc.
o 1 gene with genetic variant (the word variant used instead of mutation in the clinic,
because it can also describe a “normal variant” that doesn’t make you sick).
 Can have multiple mutations (e.g. CF has around 1000 mutations, but is still
monogenic).
o 2 types (recessive or dominant)
 Autosomal
 X chromosomal (on sex chromosomes)
o 4 categories
 Enzyme defects (errors of metabolism) > e.g. Tay-Sachs disease (waste builds up that
destroys nerve cells).
 Defects in membrane receptors/transport system > e.g. familial hypercholesterolemia
 Alterations in structure, function, or quantity of non-enzyme proteins > e.g. Marfan
syndrome (disorder of connective tissue).
 Genetic variants leading to unusual drugs reactions > e.g. cytochrome P450 enzymes.
 Mitochondrial disorders
o More rare
o Inherited through mitochondrial DNA
 Multifactorial and complex disorders (e.g. asthma, depression, etc)
o Polygenic = >1 gene
o Complex interaction between genes and environmental factors
o Predisposition for mental disorders (e.g. depression)

Genetic test
 In the early days, diagnostic genetic testing relied on detection of phenotypes
o Taste test > baby with salty-tasting skin indicated CF.
o Color of urine > black urine disease indicates alkaptonuria.
o Green ring around iris > copper build up indicating Wilson’s disease.
 Broad definition genetic test
o Any medical test that yields genetic data.
 Analyses of genotype, metabolites, phenotype.
 Why do a genetic test
o Confirm or rule out if you have a disease (e.g. hereditary breast cancer).
o Test whether you have high risk of developing/passing on genetic disorders.
 Different ways to take a DNA sample
o Saliva, blood draw, heel prick, amniocentesis, buccal smear (take cells from inside cheek).