Medical Genetics Chapter 4
Learning Objectives
1. What are Mendel’s 2 Principles?
Principle of Segregation: sexually reproducing organisms possess genes that occur in pairs, and
that only one member of this pair is transmitted to the offspring
Principle of Independent Assortment: The genes at different loci are transmitted independently,
that is that the transmission of a specific allele at one locus has no effect on which allele is
transmitted at the other locus.
2. What is genotype? Phenotype?
Genotype – an individual’s genetic constitution at a locus; genotypes do not uniquely
correspond to phenotypes
Phenotype – what is observed physically or clinically; phenotype is the result of the interaction
of genotype and environmental factors (including the genetic environment)
3. What is the most common mutation in cystic fibrosis? Describe the disease:
Mutation of CFTR that encodes the cystic fibrosis transmembrane conductance regulator. CFTR
encodes cAMP regulated Cl- channels that span the membranes of specialized epithelial cells
(lining the bowel and lung). Defective ion transport causes salt imbalances, depleting the airway
of water and producing thick, obstructive secretions in the lungs. The pancreas is also
obstructed by thick secretions, leading to fibrosis and pancreatic insufficiency.
The most common mutation in CFTR is the loss of a phenylalanine residue at residue 508. The
mutation is labeled ΔF508, and it accounts for nearly 70% of CF mutations.
4. What are treatment options for CF?
Administration of drugs: gentamicin – cause ribosomes to read through the premature stop
codons that cause about 7% of CFTR mutations.
Drugs – increase activity of Cl- channels in patients with Class III or IV mutation
Gene therapy – normal CFTR gene is placed in viral or other vectors that are then introduced to
the airway.
5. What is the proband?
The first person in whom a disease is diagnosed in a pedigree. Also called the index case, or
propositus.
6. Describe autosomal dominant, give an example?
Vertical transmission, a lack of skipped generations, roughly equal numbers of affected males
and females (father to son transmission may be observed)
Ex: postaxial polydactyly – an extra digit
7. What is the recurrence risk for an autosomal dominant disorder?
If one parent is a heterozygote and the other is normal, the recurrence risk for each child is ½.
Because of independence, this risk remains constant, no matter how many affected or
unaffected children are born.
8. What are the characteristics of autosomal recessive inheritance? Give an example:
Clustering of the disease phenotype among siblings, the disease is usually not seen among
parents or other ancestors. There are equal numbers of affected males and femals, and
consanguinity may be present.
Ex: Oculocutaneous albinism
9. What would qualify as ‘quasidominant inheritance’?
A carrier of a recessive disease causing allele mates with a person who is homozygous for the
allele. In this case, roughly half of their children will be affected, and half will be heterozygous
carriers. The recurrence risk is 50%
10. What is the recurrence risk of an autosomal recessive disease?
25%
11. Give 2 examples of diseases that are both dominant and recessive inheritance:
Diseases may be inherited inautosomal domanint fashion in some cases and in autosomal
recessive fashion in others depending on the nature of the mutation that alters the gene
product.
Examples: Familial Isolated Growth Hormone Deficiency (IGHD), β-thalassemia
12. What is de novo mutation?
A new mutation – the gene transmitted by one of the parents underwent a change in DNA
sequence, resulting in a mutation from a normal to a disease-causing allele. New mutations are
a common cause of the appearance of genetic disease in a person with no previous family
history of the disorder. The recurrence risk for the person’s siblings is very low, but the risk for
the person’s offspring may be substantially increased.
13. What is germline mosaicism?
A mutation that occurs that affects all or part of the germline but few or none of the somatic
cells of the embryo. Thus, the parent carries the mutation in his or her germline but does not
actually express the disease because the mutation is absent in other cells of the body. As a
result, the parent can transmit the mutation to numerous offspring.
Ex: Lethal perinatal form of osteogenesis imperfecta (OI type II), achondroplasia,
neurofibromatosis type 1, Duchenne muscular dystrophy, hemophilia A.
14. What is incomplete penetrance?
A person who has a disease- causing genotype might not exhibit the disease phenotype at all,
even though he or she can transmit the disease.
Ex: retinoblastoma
15. How does Retinoblastoma exhibit incomplete penetrance?
Retinoblastoma is the most common childhood eye tumor. In 60% of cases, it is caused by
somatic mutations that occur in early development, and are therefore not transmitted to the
individuals’ offspring. The other 40% are the result of new mutations. Both cases involve
mutations of RB1. However, having inherited a disease-causing RB1 mutation is not sufficient to
cause tumor formation because the presence of one normal RB1 allele is sufficient to prevent
the tumor. So, there must be a second somatic event that occurs to disable the normal RB1
allele. The second event, which can be considered a somatic mutation, has a relatively low
probability of occurring in any given cell.
16. What is the treatment for Retinoblastoma?
Cryotherapy or laser photocoagulation, radiation, chemotherapy, or enucleation of the eye
17. Describe Huntington Disease, Transmission, Treatment:
Huntington Disease – progressive loss of motor control, dementia, psychiatric disorders,
substantial loss of neurons in the brain detectable by imaging techniques
Transmission – Mutation is a CAG expanded repeat in exon 1; normal repeat ranges from 10-26,
person with 27-35 are unaffected but are more likely to transmit a larger number of repeats to
their offspring. The inheritance of 36 or more copies can produce the disease, although there is
incomplete penetrance with this number. There is greater repeat expansion when the father,
rather than the mother transmits the disease-causing mutation, and these patients have earlier
mortality
Treatment - benzodiazepines to control choreic movement, antipsychotic trugs, tricyclic
antidepressants
18. What is variable expression?
This is the degree of severity of the disease phenotype.
19. How does neurofibromatosis exhibit variable expression?
Some patients have only café-au lait spots and a few fibromas, while others have hundreds to
thousands of neurofibromas, plexiform neurofibromas, optic pathway gliomas, learning
disabilities, hypertension, scoliosis, and malignancies.
20. Describe neurofibromatosis type 1 and 2:
NF1 has highly variable expression, and the penetrance of disease causing mutation is almost
100%. The gene product of NF1, neurofibromin, acts as a tumor suppressor.
NF2 is much rarer than NF1 and is characterized by vestibular schwannomas and occasionally
café-au-lait spots. These are not true neurofibromas.
21. What is locus heterogeneity? 2 Examples?
Locus heterogeneity – a single disease phenotype is caused by mutation at different loci in
different families.
Ex: adult polycystic kidney disease (APKD), Osteogenesis imperfect I
22. What is pleiotropy?
Genes that have more than one discernible effect on the body
23. What is Marfan Syndrome? How does it exhibit pleiotropy?
Marfan Syndrome is an autosomal dominant disorder that affects the eye, skeleton, and
cardiovascular system. Most cases are caused by mutation in the gene that encodes fibrillin, a
component of connective tissue that is expressed in most of the tissues and organs affected by
Marfan Syndrome.
Marfan is caused by mutations in FBN1 gene, expressed in the aorta, periosteum, and the
suspensory ligament of the lens.
Treatment – regular opthalmological examinations, and the avoidance of heavy exercise and
contact sports. Beta blockers can be administered to decrease the strength and baruptmess of
heart contractions. This reduces stress on the aorta. Also, administration of TGF-b antagonists
prevents aortic dilation. Losartan is an Angiotensin II type 1 receptor antagonist used to treat
high blood pressure and may be useful here too.
24. Why is consanguinity bad?
Consanguinity increases the chance that a mating couple will both carry the same diseasecausing mutation. It is seen more often in pedigrees involving rare recessive diseases than in
those involving common recessive diseases.
25. How do you measure the coefficient of relationship?
-
Each individual can appear only once
Always begin with one individual, proceed up the pedigree to the common ancestor, then
down to the other individual
The coefficient of relationship for one route is given by (1/2)n-1, where n is the number of
individuals in the route
If there are multiple routes, add the probabilities of each route