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).
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).
