DLA 12

Question 1

What is the difference between an allele and a locus

Answer 1

Locus - location of a gene

allele - one of the alternative forms of a gene that occur at a locus

Question 2

What is Recurrence risk?

Answer 2

Probability that the offspring of a couple will express the genetic disorder.

Question 3

What is a Consultand?

Answer 3

The person who approaches a physician or geneticist

for a consultation.

Question 4

Who/what is a Proband?

Answer 4

The affected individual in the family who gains the

attention of the physician due to a genetic condition

Question 5

What is a pedigree?

Answer 5

diagrammatic representation of the family history

Question 6

Autosomal dominant disorders

Answer 6

manifest in the heterozygote

Affected children receive the disease-causing allele from an affected parent

Skipped generations NOT common (Vertical inheritance)

Males and females are typically affected with equal frequency

Question 7

It is very rare to find a homozygote that contains a mutation for a autosomal dominant disorder, but it is still possible. what is the disease?

Answer 7

familial hypercholesterolemia (FHC) due to LDLR deficiency

very rare

Question 8

Autosomal recessive disorders?

Answer 8

A person will show the trait (disorder) only when two disease alleles of the same gene are present

AR disorders typically occur when a disease allele is inherited from both parents

Question 9

Homozygosity by descent?

Answer 9

increases the risk that an autosomal recessive disorder will be uncovered

Question 10

What is suggestive of of autosomal dominant inheritance?

Answer 10

The pedigree shows vertical inheritance

Question 11

The second child of a couple has cystic fibrosis, an autosomal recessive disorder that is extremely highly penetrant, and easily detected in infancy. What is the likelihood that the first child of this couple is a carrier?

Answer 11

67 % (2/3)

Question 12

Several different genetic (molecular) mechanisms

exist that can explain AD inheritance?

Answer 12

1. Haploinsufficiency
2. Gain of function
3. Dominant negative
4. Loss of heterozygosity

Question 13

What is the purpose of the LDL receptor? what disease happen when that receptor is nonfunctional?

Answer 13

The LDL receptor (LDLR) is found on the hepatocyte

LDL receptor binds to LDL particles to clear them from the blood

Familial hypercholesterolemia is the result when this receptor does not work

Question 14

What are the clinical symptoms of familial hypercholesterolemia (FHC)?

Answer 14

have 2x the level of circulating LDL, and high circulating cholesterol

Xanthomas may form. Yellowish deposition of cholesterol near elbows, ankles, wrists, palpebral areas

Question 15

Is FHC a dominant or recessive disorder?

Answer 15

Dominant

Question 16

What else can cause FHC?

Answer 16

Hypercholesterolemia can be caused by variants in other genes in a Mendelian fashion.

So a person could have FHC and have two functional copies of the LDLR gene. Mutation is elsewhere!

Question 17

What is an example of locus heterogeneity?

Answer 17

The development of FHC even though their are two functional copies of the LDLR gene. The mutation is else where.

Question 18

Haploinsufficiency of an enzyme?

Answer 18

very rare!!

So in most cases, a person who is heterozygous for a loss of function mutation in just about ANY enzyme would not have phenotype (no disease). only one functional copy of that gene is needed

Question 19

What disease is an exception to the rule that only one functional copy of an enzymatic gene is needed?

Answer 19

Acute intermittent porphyria

Due to the demand of heme, both alleles must be functional

Question 20

What are the symptoms of AIP or acute intermittent porphria?

Answer 20

Intermittent symptoms of anxiety, nausea, pain, constipation, diarrhea

Question 21

What are the two examples of a mutation leading to a gain in function?

Answer 21

1. Mutation leads to the gene doing more than what it normally does
2. the mutation leads the gene having a new function

Question 22

Explain why Achondroplasia occurs?

Answer 22

A specific DNA base pair change causes the encoded protein to function in an unregulated manner.

FGFR3 gene encodes a receptor protein tyrosine kinase

Normally FGFR3 protein signals to bone growth plates during development to begin ossification

If FGFR3 signals in an unregulated manner, premature ossification of bone growth plates occurs, and person
developes disproportionate short stature

Question 23

What is the specific mutation that leads to Achondroplasia?

Answer 23

Leads to the Glycine 380 Arginine amino acid substitution (Gly380Arg)

very little allelic heterogeneity

Question 24

Huntington’s disease?

Answer 24

Huntington disease is caused by an expansion of an unstable triplet of bases in an exon of the huntingtin gene (HTT)

Leads to an expanded tract of glutamine amino acids in the encoded protein

Causes new function(s) of the gene (unknown), that leads to death of neurons

Question 25

Marfan syndrome?

Answer 25

mutation of the FBN1 gene which encodes a connective tissue protein called fibrillin-1

Question 26

What are two types of FBN1 mutations that cause marfan syndrome?

Answer 26

Mutations that lead to less fibrillin-1 protein – so this would be a FBN1 loss of function gene, and the AD inheritance would be explained by haploinsufficiency

A mutation that allow the fibrillin protein to be made in
normal amounts, but what is made will interact inappropriately with the normally formed fibrillin-1 (from the other allele) and also other connective tissue proteins (dominant negative)

Question 27

Osteogenisis imperfecta (brittle bone disease)

Answer 27

Caused by mutation of COL1A1 or COL1A2

caused by collagen defects

OI can be explained by either haploinsufficiency or dominant negative models of autosomal dominance

Question 28

Dominant negative

Answer 28

A special case of gain of function

Question 29

Dominant negative Vs haploinsufficiency

Answer 29

When considering Marfan syndrome, and OI, (in most cases) the disorder is likely to be more severe when caused by the dominant negative variant

Question 30

Neurofibromatosis

Answer 30

Caused by inheritance of one pathogenic NF1 allele from a gamete.

Question 31

What is the function of the NF1 gene?

Answer 31

The NF1 protein suppresses cellular proliferation

So loss of NF1 leads to formation of benign tumors
(neurofibromas), and also increased risk for other cancer types

Question 32

Neurofibromas?

Answer 32

usually noncancerous (benign) tumors that are often located on or just under the skin

Question 33

A 5-year-old girl is diagnosed with neurofibromatosis and she and her family are treated accordingly. Which of the following is this child most likely at increased risk for as she ages?

Answer 33

cancer!

Question 34

A 5-year-old girl is brought to the physician for follow-up examination because of facial dysmorphology and hypertelorism. Genetic testing shows that she has a pathogenic variant in the ALX4 gene which encodes a transcriptional regulator. The mutation which is not found in either parent, causes the gene to not be expressed. Which of the following best explains the inheritance of this disorder?

Answer 34

Haploinsufficiency

Question 35

Galactosemia

Answer 35

Caused by homozygous loss of function in one of 3 different enzymes responsible for metabolism of galactose

Treatment for galactosemia is, of course, restriction of milk sugar from the die

Question 36

Phenylketonuria: PKU

Answer 36

Inheritance of 2 loss of function alleles of the enzyme
phenylalanine hydroxylase (PAH gene)

Buildup of Phe is toxic, causes irreversible brain damage

treatment: don’t eat phenylalanine

Question 37

What is PKU the inability to do?

Answer 37

inability to convert phenylalanine to tyrosine

Question 38

Homocystinuria

Answer 38

The high levels of circulating homocysteine interact with connective tissue and also cause neurological manifestations

Autosomal recessive

Inborn error of metabolism

Question 39

Sickle cell disease (SCD) mutation

Answer 39

Caused by a mutation in the gene for beta-globin

Causes a Glu6Val change in the encoded protein

Causes hemoglobin to polymerize

Question 40

SCD is considered recessive or dominant?

Answer 40

autosomal recessive

Question 41

What lab technique can differentiate between sickle-cell trait, sickle-cell anemia, and normal?

Answer 41

electrophoresis!

Question 42

What is Pseudo-dominant?

Answer 42

Apparent autosomal dominant inheritance when a
heterozygote & homozygote for an autosomal recessive disorder have affected children

easily mistaken as dominant from a simple pedigree

Question 43

What factors increase the risk of autosomal recessive traits?

Answer 43

1. Consanguinity
2. Heterozygote advantage
3. Genetic isolation
4. Assortative mating

Question 44

Example of co-dominance?

Answer 44

blood group types

AB

Question 45

What is incomplete dominance?

Answer 45

Phenotype is intermediate between the parents

combination of two traits

red + white = pink