Corbett - single gene disorders

Question 1

Compound heterozygous

Answer 1

both alleles are mutant but different mutations.So the mutations can be at different locations of the same gene.

Question 2

hemizygous

Answer 2

abnormal gene is located on the X chromosome. In male patients.

Question 3

allelic heterogeneity

Answer 3

different mutations occurring in the same gene. Sometimes the mutations will cause the same phenotype and sometimes it will cause different phenotypes. So in CF there are many mutations - some that cause the same clinical phenotype and some that cause others.

Question 4

phenotypic heterogeneity

Answer 4

different mutations in the same gene that produce very different phenotypes. Generally there is an increased severity depending on which mutation a patient has. So in CF, you can either have reduced receptors or no receptors.

Question 5

locus heterogeneity

Answer 5

mutations at different loci of the gene that cause the same phenotype. An example of this is Long QT syndrome, which causes the repolarization of the channels around the heart to be slower. Can be caused by Na channels, K channels, or structural proteins called ankyrin.

Question 6

Reduced penetrance

Answer 6

the probability that a patient who has the genotype will have the phenotype at all. For example, if a certain disease has a 70% penetrance, then only 70% of patients who have the genotype will have the phenotype.

Question 7

Variable expressivity

Answer 7

The severity of the disease varies between individuals. All individuals are still affected, but their clinical presentation varies.

Question 8

Factors that can confound pedigree analysis

Answer 8

1) Early lethality of disease
2) small family size
3) variable age of onset, decreased penetrance, or variable expressivity
4) non-mendelian inheritance

Question 9

Mitochondrial genome

Answer 9

DOES NOT FOLLOW MENDELIAN GENETICS

Question 10

What factors can affect the likelihood of inheriting an AR disease?

Answer 10

Carrier frequency
consanguinity (2nd cousins or closer)
inbreeding (individuals from a small population who choose mates from the same population)
Genetic isolates (example is tay-sachs in Ashkenazi Jews)

Question 11

Key features of AR

Answer 11

Male=Female
Parents are unaffected
On average, the recurrence rate of a child with an affected parent is 1/4
phenotype is found in siblings - usually not parents or kids
If it is a rare trait you should suspect consanguineous mating

Question 12

Features of an AD pedigree

Answer 12

1) every affected individual has an affected parent
2) males and females are equally affected
3) with an affected parent, children have a 50% chance of disease
4) normal siblings all have normal children

Question 13

Incomplete dominance

Answer 13

a person that has two copies of the AD mutation will have a more sever phenotype than the person with one mutation.

• familial hypercholesteremia
• achondroplasia (mutation in long bone growth - short stature)

Question 14

X linked recessive

Answer 14

ex - hemophilia

• NO MALE TO MALE TRANSMISSION - if a male has it, it can only give the Y chromosome to the male so he can’t give his mutated X to his sons.
• The daughters of an affected male will all at least be carriers.
• heterozygous females are usually unaffected depending on X-inactivation

Question 15

X linked dominant

Answer 15

• trait is never passed from father to son (no male to male transmission)
• In an affected father all daughters are affected

Question 16

XLR - sex-influenced phenotype

Answer 16

x-linked dominant with male sparing occurs in x-linked epilepsy

Question 17

exception to mendelian inheritance rules: sex limited traits

Answer 17

creates exception to mendelian rules

• the trait can be carried by both sexes but only one sex can have the phenotype because of anatomical or physiological differences.
• AD or AR
• AD ex is male limited precocious puberty in which the LHR gene is always on in boys which causes then to hit puberty at an early age.
• AR example is hemochromatosis, which is caused by a mutant HFE gene and causes excess iron stores. More common in men because women can shed excess iron through menstruation and pregnancy.

Question 18

exception to mendelian inheritance rules: mosaicism

Answer 18

• presence in an individual of at least 2 cell lines that differ genetically that are derived from a single zygote.
• germline mosaicism - when a healthy parent, who tests negative too be a carrier, has children with highly penetrant AD or XLR diseases.

Question 19

exception to mendelian inheritance rules: new mutations

Answer 19

Child will have the same alleles as parent with the exception of one new mutation, which occur very rarely. Even more rare in AR. If mutation is dominant and child can not live to pass on the new mutation it is termed genetic lethal.

Question 20

exception to mendelian inheritance rules: mis-attributed paternity

Answer 20

father is not the woman named by the mother.

Question 21

exception to mendelian inheritance rules: genomic imprinting

Answer 21

When there is only one active allele from one of the parents for a specific gene.
parent of origin - the specific gene imprinting is apparent in somatic cells but reversed in the germ line so that the offspring will be normal.

Question 22

trinucleotide repeats

Answer 22

repeating sequences of 3 base pairs in the genome.

• can be anywhere in the genome including noncoding regions.
• replication errors cause more repeats.
• molecular characteristics and consequences of expansion differ
• the tendency of repeats depends on transmitting parent
• individuals below the threshold of repeats are said to carry “pre-mutations”
• display genetic anticipation

Question 23

pre-mutation

Answer 23

When you are below the threshold of trinucleotide repeats to actually have the disease. You can be normal, have mild symptoms. In the example in class, it is between 55-200 repeats in the 5’ UTR.

Question 24

genetic anticipation

Answer 24

As you progress from generation to generation with trinucleotide repeats, the disease presents earlier and with much more severe symptoms.

Question 25

Single gene disorders

Answer 25

determined primarily by an allele at a single chromosomal locus.