Samenvatting
Samenvatting Genetics and Public Health
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MEET AND GREET:MENDEL
Punnett square
The Punnett square is a square diagram that is used to predict the genotypes of a particular cross or
breeding experiment. The Punnett square is a visual representation of Mendelian inheritance.
Male Female Affected male Affected female Deceased male
Consanguineous Heterozygous Heterozygous Female carrier of
Mating
mating male female X-linked trait
The children in the Punnett square are in order of birth, so the first-borns are at the left. There are
several types of Punnett squares, which each have different characteristics:
Autosomal dominant inheritance pattern
o Several generations
o On average 50% of children of affected parents are also affected
o Inheritance from man to woman, woman to woman, man to woman, woman to man
o Examples are Huntington disease, BRCA1 & 2, Lynch syndrome, Achondroplasia
Autosomal recessive inheritance pattern
o On average, if both parents are carrier, a quarter of their children are affected
o Sometimes parents are consanguineous
o Usually just 1 generation
o Examples are Cystic fibrosis, Hemoglobinopathies (sickle cell anemia, thalassemia) and
Phenylketonuria (PKU)
X-linked recessive inheritance pattern
o Sons are affected
o Women are not affected, they are carrier and can pass on the predisposition
o No inheritance from man to man
o In general: no increased risk on X-linked disorder if there is a healthy male in between
o Fathers (if fertile) can have daughters who are carriers
o Examples are Duchenne Muscular Dystrophy, Hemophilia A and B and color blindness
GENES & DISEASES
Genetics is a fast moving field. Due to fast technological developments, it is also increasingly
multidisciplinary. Also, genetics can have a high impact on individuals, families and populations.
A gene is a functional unit that is regulated by transcription and encodes a product (protein or RNA). In
our human genome, there are 20 to 25 thousand genes. The genes are located on our chromosomes, of
,which we have 23 pairs. Only 2% of the genome codes for proteins (exons). So, the exons determine the
hereditary traits. Large part of the other 98% is still unexplained, which is called junk DNA. This has a
more regulatory function by switching genes on and off.
Genetic variation
What makes a human unique is human genetic variation. This can be distinguished in different classes,
which are single nucleotide variant, insertion-deletion variant, block substitution, inversion variant and
copy number variant. Genetic variation leads to phenotypic variation. It also increases the chance that
some individuals in a population will survive. On average, 2 individuals each differ 1 base in 1000 base
pairs. This is very useful in forensic or paternity testing. Change in DNA that are observed with a
frequency of more than 1% are polymorphisms. In our genome, there are about 15,000,000 genetic
variations, of which most are SNPs. Most polymorphisms have no phenotypic consequences. However,
some are pathogenic mutations that can cause disease.
Mutations are defined as a change in the DNA, which disturbs the protein function. This can be caused
by, for example, DNA replication, chemical damage, ionizing radiation, etc. Mutations can occur in both
somatic and germ/sex cells. Somatic mutations occur in non-germline tissues and can’t be inherited.
Germline mutations are present in egg or sperm cells. They can be
inherited and cause cancer family syndromes.
There are 2 types of mutations, which are chromosome mutations and
gene mutations. The loss (monosomy) or gain (trisomy) of whole
chromosomes is called aneuploidy. Structural changes within the
chromosome, such as translocations, deletions, etc. are also chromosome
mutations. Gene mutations are alterations at the gene levels, such as
point mutations (single base), insertions, deletions, etc.
Genetic diseases
Cystic fibrosis is caused by mutations in the CFTR-gene. It is an autosomal recessive disease and 1 in 30
people of European descent are carrier. The birth prevalence is 1 in 3600/4000. When already having a
child with CF, the risk of the next child is 1 in 4.
Hereditary means inherited, derived from parents. Genetic disorders are usually, but not always
inherited, e.g. acquired mutations. Congenital means apparent at birth. However, not all congenital
disorders are genetically determined, e.g. fetal alcohol syndrome, toxoplasmosis infection, etc. 40-60% of
congenital disorders have an unknown cause. Also, not all hereditary diseases are congenital (BRCA).
Hereditary disorders can be grouped into categories, such as cancer (oncogenetics), cardiovascular
diseases (cardiogenetics), neurological disorders (neurogenetics), storage diseases, errors of metabolism,
skin disorders, blood disorders, etc. Genetic disorders can be divided into chromosomal disorders,
monogenic disorders, mitochondrial disorders, multifactorial and complex disorders. Chromosomal and
monogenic disorders are individually quite rare, but collectively they are seen in 1-2% of births.
Chromosomal disorders can be numerical or structural changes, which are 0.6% of liveborn. Most of the
chromosomal disorders affect the autosomes. Generally, a loss of chromosomal material is more
dangerous than a gain. Abnormalities of the sex chromosomes is better tolerated than autosomal.
Usually, the origin of chromosomal disorders is de novo, which means both parents and siblings are
normal. An example of a sex chromosomal disorder is Klinefelter syndrome, in which a male has 2 copies
of the X-chromosome.
Monogenic disorders are caused by a single gene mutation and mostly follow the Mendelian pattern of
inheritance. Mendelian disorders are caused by mutations in single genes of large effect, which affect 1%
of liveborn. These monogenic disorders can be divided into 2 categories:
Enzyme defects (e.g. ‘inborn errors of metabolism’)
o Material to be degraded builds up in certain cells in the body and causes problems
o Storage diseases, such as Tay-Sachs disease
Defects in membrane receptors/transport systems
o Example: Familial Hypercholesterolemia
Alterations in structure, function or quantity of non-enzyme proteins
o Example: Marfan syndrome, which is a disorder of connective tissue
, Genetic variants leading to unusual drug reactions
o Example: Cytochrome P450 enzymes
Mitochondrial disorders inherit via the mitochondrial DNA.
The multifactorial and complex disorders are very frequent, with a 10%
life time risk. Most people have some genetic liability, but to develop
these diseases, environmental factors are very important. Examples are
asthma, arthritis, dementia, depression, heart disease, cancer, cleft lip,
spina bifida, etc. These diseases are multi- or polygenic, which means
there are more than 1 gene involved, which each convey a low risk.
Genetic testing
Before DNA testing, diagnostic genetic testing relied on the detection of phenotypes (physical
examination) and/or metabolites, such as taste test (baby with salty-tasting skin CF), color of urine
(black urine alkaptonuria), green ring around iris (copper build up Wilson’s disease). In some cases,
these tests are still used today. Nowadays, a genetic test is any medical test that yields genetic data.
these are analyses of genotype (DNA, RNA, gene,
chromosome), metabolites (proteins, enzymes) or phenotype
(appearance, characteristics). Genetic tests are used to rule out
a suspected genetic disorder, to determine a person’s chance
of developing a genetic disorder or to determine a person’s
chance of passing on a genetic disorder. Genetic diseases can
be diagnosed with karyotyping, blood test, biomarkers, genome
sequencing, etc.
There are different types of tests, which are tests for gene
variants (mutations) with high penetrance (there is a high chance that the phenotype will show up, 100%
for Huntington’s) or tests for gene variants that are associated with genetic susceptibility.
Symptomatic testing is used to confirm or rule out a known or suspected genetic disorder in a person
with disease symptoms. Next to symptomatic testing, there is also predictive genetic testing, which is
offered to individuals who do not have symptoms at the time of testing, but e.g. have a family history of a
genetic disorder. It tells a person if he carries a mutation that will cause or put him at higher disease risk
later in life. A presymptomatic test is done in case a disease runs in the family and someone wants to
know whether he/she has the mutation, without symptoms present. There are also predisposition tests,
in which case having the mutation means an increased risk, but not a certainty (not fully penetrant).
Presymptomatic tests are only used for dominant disorders. Carrier testing only used for recessive
diseases. When X-linked, only mother needs to be tested.
Prenatal diagnostic testing is done to identify a genetic condition in a fetus. It is done in high-risk families
or when abnormalities are seen on ultrasound. Amniocentesis around 14-16 weeks, but chorionic villi
testing can be done earlier.
A genetic test can test for a single gene, gene panels, the whole exome or even the whole genome. The
test results of a monogenic disorder can be positive (pathogenic mutation present), negative or variants
of unknown significance (VUS). In VUS, there is not known what the mutation does. But person is tested
again in few years when there is probably more knowledge.
There are also tests for gene variants that are associated with genetic susceptibility. These are used to
test genetic variants predisposing to multifactorial and common complex diseases, such as type 2
diabetes, heart disease, etc. This is often done outside the clinic in private companies or via direct-to-
consumer (DTC) testing. In pharmaco-genetic testing, there can be tested for drug response. A mutation
can indicate use of more medication or a different medication. These people can have pharmacogenetic
passport.
, MORE THAN MENDEL
Not all heritable diseases inherit in a classical Mendelian inheritance pattern. This often results in
complications in interpretation and disease gene identification (research) or, when known, can guide
genetic testing (diagnostics). Other inheritance patterns are phenocopy, incomplete penetrance, late
onset inherited disorders, imprinting, mosaicism, X-chromosome inactivation, mitochondrial inheritance,
genetic heterogeneity, dynamic mutations, anticipation and the founder effect.
In phenocopy, there is an individual with the disease phenotype but without a mutation in the disease
gene (getting breast cancer, without being mutation carrier). It is also possible that someone carries the
mutation but doesn’t get sick (reduced penetrance).
Late-onset genetic disorders are hereditary diseases which do not present themselves until a certain age
has been reached. The penetrance of the disease increases with age. For example, Parkinson’s, dementia,
breast cancer. These were both still mendelian inheritance patterns. But there are other inheritance
patterns.
Genomic imprinting & mosaicism
Hereditary paragangliomas are rare tumors of the autonomic nervous system (sporadic and hereditary
forms). Usually benign and low mortality. However, they cause significant morbidity related to their mass
effect. Genetic predisposition can occur within familial tumor syndromes:
Multiple endocrine neoplasia type 2 (MEN 2)
Von Hippel-Lindau (VHL)
Neurofibromatosis type 1 (NF-1)
Or paraganglioma only
Succinate dehydrogenase (SDHA-D), SDHD located on the long arm of chromosome 11 (11q23)
There are also carriers who don’t get paragangliomas. Disease can only be given when father transmits
the mutation, but it doesn’t matter if father is sick or not. This has to do with imprinting. This is maternal
imprinting, because moms copy is not active and dads copy carries mutation. In genomic imprinting, one
of the alleles is methylated. This makes it condensed and genes are not expressed. In imprinted regions, it
depends from whom the chromosome is received (mom or dad) whether it is expressed. This results in
monoallelic expression. There is maternal and paternal imprinting of DNA. There are certain regions of
the chromosomes that have this, not all.
All sperm cells have paternal imprinting and all egg cells have maternal imprinting. There is only
imprinting from mom and dad, the imprinting from grandparents is removed and new imprinting is made.
If the mutation is on the part that is imprinted by dad, the moms is shut off and the disease will be
present. Prader Willi syndrome (paternal) and Angelman syndrome (maternal) are the same mutation,
but depends on whether it is copy of mother or
father. About 70% of patient has de novo
microdeletion.
There is also uniparental disomy (UPD), which
results in 2 copies of a chromosome that both come
from 1 parent. In 30% of Prader Willi, they have both
copies form mom and none from dad, so the genes
that are only expressed on dads alleles are missed
and person gets sick. There are multiple ways in
which UPD can occur.
Mosaicism means different genetic make-up in different cells of the body (occurs in everyone). Mutations
don’t occur in all cells at the same time. Proteus syndrome is example of this. There is tissue and bone
overgrowth (division without control). This is caused by an activating mutation in kinase. When this
occurs, it stimulates growth of cells. If it occurs during embryogenesis, this cell will divide and spread the
mutation to different body parts. Mosaicism down syndrome is a rare form of down syndrome. These
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