Gen Complications Mastick Flashcards
Dominant and recessive disorders refers to the (blank) of a disease.
clinical manifestation
What is this:
different mutations in the same gene (alleles)
allelic heterogenity
Allelic heterogeneity can cause what?
- different modes of inheritance (dominant vs. recessive)
- different severity of disease.
Allelic heterogenity can affect diagnosis, prognosis, and/or progression of disease,
as well as (blank) in the family.
recurrence risk
What does cystic Fibrosis exhibit?
Allelic heterogeneity
Name that disease:
• One of the most common single gene disorders, autosomal recessive,
1/2000- 1/4000 in Northern European Caucasian population.
• Pleiotropic disorder.
Caused by mutation in CFTR transmembrane receptor
Cystic Fibrosis
Name that disease:
affects the epithelia in several organs resulting in a complex, multisystem disease that includes the exocrine pancreas, intestine, respiratory tract, male genital tract, hepatobiliary system, and exocrine sweat glands.
cystic fibrosis
the great majority of individuals with CF are pancreatic (blank)
insufficient
In CF, the overall median survival is (blank) years. A gender difference is present in CF with greater median survival in who?
31.6
males than in females
Disease expression varies by severity of CFTR mutations, (blank), and environmental factors.
genetic modifiers
How many mutations have been identified on the CFTR gene?
hundreds
Different mutations have different effects on (blank)
protein expression/activity.
The more severe the effect on CFTR function, the more severe the (blank).
the disease
what is the most common allele of CF?
delta 508
Familial isolated growth hormone deficiency (IGHD) has both (blank) and (blank) forms of this disease.
dominant and recessive
IGHD mutation is in a single gene (GH1), therefore it is showing (blank).
allelic heterogenity
GH1 shows haplo(blank)
sufficiency
The recessive form of IGHD mutations leads to reduced expression of (blank)
GH
The dominant form of IGHD mutations leads to altered (blank).
GH protein product
A dominant negative allele in IGHD results in what?
greater than 50% reducion in GH1 with one mutant allele.
What type of mutations have an altered gene product that acts antagonistically to the wild-type allele.
dominant negative alleles
What kind of heterogenity does osteogenesis imperfecta exhibit?
allelic heterogenity
Name that disease;
Clinically heterogeneous disease characterized by brittle bones.
- All forms caused by defects in type I collagen.
-All forms autosomal dominant, but differ in severity.
Osteogenesis imperfecta
Type I osteogenesis imperfecta (OI) is more common or less common than type II? Is it more severe or less severe?
more common 1/15,000 individuals
less sever
Why type of mutation does both Type II and Type I OI have ?
How come they differ in severity?
a single mutation in the COL1A1 gene on chromosome 17
Differences in severity are due to differences in the mutations at the molecular level.
Explain the differences at the molecular level b/w type I and type II of OI?
type I has reduced alpha 1 collagen which results in left over unpairs alpha 2 which is degraded.
Type II has mutant alpha 1 and any alpha 2 that pairs with it will be destroyed.
Name that disease:
Brittle bone disease caused by defects in COL1A1 leading to loss of expression (or rapid degradation) of the defective a1(I) collagen molecules. Normal collagen formed, but only 50% of normal level (excess a2(I) chains are degraded).
Type 1 OI
Name that disease:
Perinatal lethal bone disease caused by defects in
COL1A1 genes leading to mutant forms of a1(I)
collagen being expressed. Forms abnormal collagen complexes with the normal proteins; results in less than half of the normal protein level. Protein Suicide.
Type II OI
Type 2 OI can be caused by allelic heterogenity and (blank) heterogenity.
locus
What is this:
mutations in different genes cause the same disease (phenotypically). Can occur in multi-protein complexes or when proteins/enzymes
affect the same step in a biochemical pathway.
locus heterogeneity
achondroplasia has autosomal (blank) inheritance. 7/8 cases are sporatic!!
dominant
Diastrophic dwarfism is autosomal (blank)
recessive
What is considered all or none phenomenon; refers to the frequency of expression of a dominant disorder in an obligate heterozygote. Defined quantitatively as the proportion of obligate heterozygotes that express the disease (determined empirically from population data).
Penetrance
What is the penetrance of Familial Rb?
90%
Name that disease:
a form of eye tumor, expresses by age 5 in nearly all cases.
Rare disorder, approximately 1/20,000.
About 60% of the cases are sporatic, 40% are familial.
familial Rb
What is the penetrance of Familial Rb?
90%
Name that disease:
a form of eye tumor, expresses by age 5 in nearly all cases.
Rare disorder, approximately 1/20,000.
About 60% of the cases are sporatic, 40% are familial.
familial Rb
Rb is a (blank) process. A mutation in Rb (a tumor suppressor) is insufficient to cause a tumor. The second hit in Rb (a somatic cell mutation) is random, and in some individuals it never occurs.
“two-hit”
The susceptibility to retinoblastoma is an autosomal (blank) trait but the expression of retinoblastoma is a recessive one.
dominant
What is this:
penetrance is complete (100%), but the
severity is highly variable. Individuals with mild forms of the disease may not be diagnosed. Mildly affected parent can have a severely affected child.
variable expressivity
T or F
Penetrance is all or none; variable expression refers to extent.
True
Name that disease:
Common autosomal dominant disorder- affects 1/3000 individuals. Most (2/3) have only mild cutaneous involvement. Symptoms include café-au-lait spots, Lisch nodules, and a few neurofibromas (non-malignant).However, a mildly affected parent can have a severely affected child.
In its severe form an individual can have hundreds of neurofibromas, optic gliomas, learning disabilities, hypertension, scoliosis, and in about 10% of the cases, malignancies.
Neurofribromatosis type I (NFI)
NF1 and Marfan syndrome exhibits what type of inheritance?
variable expressivity
Name that disease:
Autosomal dominant disorder- affects 1/10,000 - 1/20,000
Defect in connective tissue; affects skeletal muscle, eye, and heart.
All affected individuals in one family have the identical mutation in the fibrillin gene, and all family members tested who carry the mutation express manifestations of disease in at least one organ system.
However, individuals in one family can have very different manifestation of the disease. May involve one, two or all three of the major organ systems, and the severity of the manifestation in each system varies widely.
Marfan Syndrome
Name that disease:
an autosomal dominant condition with variable expressivity, in which some individuals who inherit a mutation in the gene for this condition have lip pits only, some have hypodontia and/or missing teeth only, and some have only cleft lip with or without cleft palate. In addition, the penetrance is 80%, meaning that 20% of individuals with a Van der Woude gene mutation have no clinical manifestations, as appears to be the case with Donna.
Van der Woude Syndrome
What is the diverse affects of a single gene on several organ systems and functions.
pleiotropy
What is it called when a parent is mosaic for a mutation. Mutation is
found in the germline cells, but in few of the somatic cells. Occurs during embryogenesis. NF1, OI
germline mosaicism
What are three ways you can have a dominant disorder with no previous family history?
new mutation (gametogenesis), germline mosaicism, delayed age of onset (person died from unrelated cause before knowing they had disease and passed it on to child)
When you have an error in one of your sperm or eggs that randomly happened and so your child is effected means that you have a denovo mutation in gametogenesis called what? is there a recurrence risk with this?
a new mutation
nope
When you have mosaicism in your cells due to some issues in embryogenesis when you were a kid and it only affects some of your sex cells so you dont know and then you have a kid and he/she ends up all messed up you have what kind of mutation? Is there a recurrence risk with this?
A germ line mosacism.
yes
Is an individual who is affected by a new mutation likely to have offspring affected?
yup 50% chance they will pass it on if it is a dominant trait
If a dominant or x-linked mutation has a very deleterious affect on reproductive fitness or survival then a significant proportion of the affected individuals (or all) will be due to (blank)
new mutations
What is this:
If a population is at equilibrium with respect to incidence of disease, then the number of new mutations equal the number of mutations lost each generations.
Haldane Hypothesis
Rats of loss of alleles in a population vary widely for different genes. Name three ways.
loss due to lethality (die)
genetic lethality (cant reproduce)
general attrition rate
Name that disease:
rate of loss is high, because it is lethal AND 1/3 of alleles are carried in affected individuals and lost each generation. (X-linked recessive)
DMD
Name that disease:
rate of loss is high (7/8 lost each generation!) due to reduced reproductive fitness AND all alleles carried in affected individuals (Dominant)
Achondroplasia
name that disease:
: rate of loss is low even though all alleles in affected individuals are lost each generation. Only 2-3% are in affected individuals
Tay Sachs
name that disease:
rate of loss is low, because is largely treatable AND only 2% of alleles are carried in affected individuals. (Autosomal recessive)
cystic fibrosis
Name that disease:
every allele lost every generation, all mutations are new mutations. Lethal AND all alleles carried in affected individuals (Autosomal Dominant)
OI type II
what is the typically rate of spontaneous new mutations per gametogenesis?
10^-6 to 10^-4 genes per gametogenesis (depends on size and structure of gene)
The (blank) of a disease is determined in part by the
rates of spontaneous new mutations and loss of mutant alleles. Measured empirically, in populations that have reached steady state.
population frequency
Can you have a new mutation in an autosomal recessive mutation?
NO!!! only x-linked or dominant cuz its only 1 mutation!!!!
What are some new mutation diseases?
DMD and other X-linked; OI and other dominant;
HD, Fragile X, MD and other repeat expansions; not in auto. recessive!
What might indicate a new mutation?
only 1 affected individual in a family; a common ancestor that came out of nowhere and all subsequent family members are affected
What are some new mutation diseases?
DMD and other X-linked; OI and other dominant;
HD, Fragile X, MD and other repeat expansions; not in auto. recessive!
What might indicate a new mutation?
only 1 affected individual in a family; a common ancestor that came out of nowhere and all subsequent family members are affected
What is this:
A new somatic mutation occurs during embryogenesis in the germline
progenitor cells of one of the parents. A significant proportion of his/her
germline cells, but very few of his/her somatic cells carry the mutation. (occurs during development)
germline mosaicism
Can you do germ line mosaicism testing in females?
no, other x chromosome interferes
In DMD there is a 1-5% recurrence risk in “de novo” cases because of possibility of (blank).
This also accounts for accounting
for 10-20% of de Novo cases in both DMD and hemophilia
germline mosaicism.
Would you test the mother in DMD germ line mosaicism detection?
No because the other x would interfere
Name that disease:
The transmitting parent may have died of an unrelated cause before development of the disease, so appears sporatic. Autosomal dominant, 100% penetrant disorder characterized by progressive loss of motor control and dementia between ages 30 and 50. Affects 1/20,000 individuals of European descent.
Recurrence risk to offspring of affected individual is 50%.
Huntington Disease
