Genetics and public health
Inhoud
Meet and greet: Mendel........................................................................................................................2
Genes and diseases................................................................................................................................6
Public health and genetics......................................................................................................................9
Genetic testing.....................................................................................................................................11
Translation of genomics into healthcare..............................................................................................15
More than Mendel...............................................................................................................................18
Genetic screening.................................................................................................................................24
Clinical genetics....................................................................................................................................27
Prenatal screening................................................................................................................................30
Consanguinity.......................................................................................................................................36
Preconception care...............................................................................................................................40
From genetics to genomics and further................................................................................................42
Whole genome sequencing..................................................................................................................47
Ethical, Legal and Social aspects of WES/WGS.....................................................................................50
Epigenetics...........................................................................................................................................53
New developments in gene editing......................................................................................................58
(In)equality in genetics.........................................................................................................................61
Psychological and behavioural aspects of genetic testing....................................................................64
The shadow of eugenics.......................................................................................................................68
Pharmacogenomics..............................................................................................................................71
Clinical validity......................................................................................................................................76
New possibilities outside clinical genetics............................................................................................79
Potential use of polygenic risk scores...................................................................................................81
Clinical utility........................................................................................................................................84
Working lecture Screening criteria and parameters.............................................................................86
Working lecture: Population genetics...................................................................................................88
Working lecture: calculations between genes and environment.........................................................92
,Meet and greet: Mendel
Mendelian/monogenic/single-gene diseases = diseases caused by mutations in one gene, sometimes
run in families
Autosomal recessive single-gene diseases
Individual has two mutant alleles of disease-associated gene
Individual has to inherit a mutated copy of the gene form both the mother and father
Pedigree: often a pattern in which disease ‘’skips’’ one or more generations
Examples: Phenylketonuria (PKU), cystic fibrosis, sickle-cell anaemia, and oculocutaneous albinism.
Autosomal dominant single-gene diseases
Individual only has a single mutant allele of disease-associated gene
Individuals can inherit the mutant copy of the disease-associated gene from either an affected
mother or an affected father.
Examples: Huntington’s disease, myotonic dystrophy, familial hypercholesterolemia,
neurofibromatosis, and polycystic kidney disease.
X chromosome-linked recessive single gene diseases
Males are far more likely to be affected by X chromosome-linked recessive diseases than woman,
because they don’t have a second copy of an unaffected X chromosome to ‘’cancel out’’ the
mutation.
Female: have to inherit a mutated copy from both parents. One from the affected father and one
from the mother who is often a carrier (heterozygous), but sometimes affected.
Male: inherit one copy which is always from the mother
Examples: the blood-clotting disorder haemophilia A, Duchenne muscular dystrophy
X chromosome-linked dominant single-gene diseases
Rare; there are few dominantly inherited forms of human disease are X chromosome linked.
Females with an X chromosome-linked dominant disease can inherit the mutant gene from either an
affected mother or an affected father,
Males always inherit such diseases from an affected mother.
Y chromosome-linked single gene disease
Extremely rare
Always passed on from affected fathers to their sons.
It makes no difference whether the Y chromosome-linked mutation is dominant or recessive,
because only one copy of the mutated gene is ever present; thus, the disease-associated phenotype
always shows.
More often research in common diseases are more funded, but these disease often have a more
complex inheritance pattern associated with mutations in multiple genes (polygenic).
Also recently a number of diseases initially characterized as monogenic have been shown to be
caused or modified by an additional gene or genes. These diseases have been categorized as
oligogenic rather than polygenic, because they involve only a relatively small number of genes
,Pedigree:
Typical autosomal dominant inheritance pattern:
- Several generations
- On average 50% of children of affected parent are also affected
- Inheritance from man to woman, man to man, woman to man and woman to woman
- Examples: • Huntington disease • BRCA1 & 2 • Lynch syndrome • Achondroplasia
Typical autosomal recessive inheritance pattern
- On average, if both parents are carrier, a quarter of their children are affected
- (families in which none of the children are affected, but both parents are carrier, are not
observed)
- Sometimes parents are consanguineous (bloedverwant)
- Usually just 1 generation
- • Cystic fibrosis (CF) • Hemoglobinopathies (sickle cell anemia, thalassemia) •
Phenylketonuria (PKU)
, Typical X linked inheritance pattern:
- Males are affected, females pass on the disorder but are (usually) not affected
- No inheritance from man to man
- Fathers (if fertile!) can have daughters who are carriers
- • Duchenne Muscular Dystrophy • Hemophilia A and B (impaired blood clotting) • Color
blindness
Inhoud
Meet and greet: Mendel........................................................................................................................2
Genes and diseases................................................................................................................................6
Public health and genetics......................................................................................................................9
Genetic testing.....................................................................................................................................11
Translation of genomics into healthcare..............................................................................................15
More than Mendel...............................................................................................................................18
Genetic screening.................................................................................................................................24
Clinical genetics....................................................................................................................................27
Prenatal screening................................................................................................................................30
Consanguinity.......................................................................................................................................36
Preconception care...............................................................................................................................40
From genetics to genomics and further................................................................................................42
Whole genome sequencing..................................................................................................................47
Ethical, Legal and Social aspects of WES/WGS.....................................................................................50
Epigenetics...........................................................................................................................................53
New developments in gene editing......................................................................................................58
(In)equality in genetics.........................................................................................................................61
Psychological and behavioural aspects of genetic testing....................................................................64
The shadow of eugenics.......................................................................................................................68
Pharmacogenomics..............................................................................................................................71
Clinical validity......................................................................................................................................76
New possibilities outside clinical genetics............................................................................................79
Potential use of polygenic risk scores...................................................................................................81
Clinical utility........................................................................................................................................84
Working lecture Screening criteria and parameters.............................................................................86
Working lecture: Population genetics...................................................................................................88
Working lecture: calculations between genes and environment.........................................................92
,Meet and greet: Mendel
Mendelian/monogenic/single-gene diseases = diseases caused by mutations in one gene, sometimes
run in families
Autosomal recessive single-gene diseases
Individual has two mutant alleles of disease-associated gene
Individual has to inherit a mutated copy of the gene form both the mother and father
Pedigree: often a pattern in which disease ‘’skips’’ one or more generations
Examples: Phenylketonuria (PKU), cystic fibrosis, sickle-cell anaemia, and oculocutaneous albinism.
Autosomal dominant single-gene diseases
Individual only has a single mutant allele of disease-associated gene
Individuals can inherit the mutant copy of the disease-associated gene from either an affected
mother or an affected father.
Examples: Huntington’s disease, myotonic dystrophy, familial hypercholesterolemia,
neurofibromatosis, and polycystic kidney disease.
X chromosome-linked recessive single gene diseases
Males are far more likely to be affected by X chromosome-linked recessive diseases than woman,
because they don’t have a second copy of an unaffected X chromosome to ‘’cancel out’’ the
mutation.
Female: have to inherit a mutated copy from both parents. One from the affected father and one
from the mother who is often a carrier (heterozygous), but sometimes affected.
Male: inherit one copy which is always from the mother
Examples: the blood-clotting disorder haemophilia A, Duchenne muscular dystrophy
X chromosome-linked dominant single-gene diseases
Rare; there are few dominantly inherited forms of human disease are X chromosome linked.
Females with an X chromosome-linked dominant disease can inherit the mutant gene from either an
affected mother or an affected father,
Males always inherit such diseases from an affected mother.
Y chromosome-linked single gene disease
Extremely rare
Always passed on from affected fathers to their sons.
It makes no difference whether the Y chromosome-linked mutation is dominant or recessive,
because only one copy of the mutated gene is ever present; thus, the disease-associated phenotype
always shows.
More often research in common diseases are more funded, but these disease often have a more
complex inheritance pattern associated with mutations in multiple genes (polygenic).
Also recently a number of diseases initially characterized as monogenic have been shown to be
caused or modified by an additional gene or genes. These diseases have been categorized as
oligogenic rather than polygenic, because they involve only a relatively small number of genes
,Pedigree:
Typical autosomal dominant inheritance pattern:
- Several generations
- On average 50% of children of affected parent are also affected
- Inheritance from man to woman, man to man, woman to man and woman to woman
- Examples: • Huntington disease • BRCA1 & 2 • Lynch syndrome • Achondroplasia
Typical autosomal recessive inheritance pattern
- On average, if both parents are carrier, a quarter of their children are affected
- (families in which none of the children are affected, but both parents are carrier, are not
observed)
- Sometimes parents are consanguineous (bloedverwant)
- Usually just 1 generation
- • Cystic fibrosis (CF) • Hemoglobinopathies (sickle cell anemia, thalassemia) •
Phenylketonuria (PKU)
, Typical X linked inheritance pattern:
- Males are affected, females pass on the disorder but are (usually) not affected
- No inheritance from man to man
- Fathers (if fertile!) can have daughters who are carriers
- • Duchenne Muscular Dystrophy • Hemophilia A and B (impaired blood clotting) • Color
blindness
