DLA 12 Flashcards

1
Q

What is the difference between an allele and a locus

A

Locus - location of a gene

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

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2
Q

What is Recurrence risk?

A

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

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3
Q

What is a Consultand?

A

The person who approaches a physician or geneticist

for a consultation.

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4
Q

Who/what is a Proband?

A

The affected individual in the family who gains the

attention of the physician due to a genetic condition

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5
Q

What is a pedigree?

A

diagrammatic representation of the family history

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6
Q

Autosomal dominant disorders

A

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

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7
Q

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?

A

familial hypercholesterolemia (FHC) due to LDLR deficiency

very rare

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8
Q

Autosomal recessive disorders?

A

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

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9
Q

Homozygosity by descent?

A

increases the risk that an autosomal recessive disorder will be uncovered

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10
Q

What is suggestive of of autosomal dominant inheritance?

A

The pedigree shows vertical inheritance

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11
Q

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?

A

67 % (2/3)

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12
Q

Several different genetic (molecular) mechanisms

exist that can explain AD inheritance?

A
  1. Haploinsufficiency
  2. Gain of function
  3. Dominant negative
  4. Loss of heterozygosity
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13
Q

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

A

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

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14
Q

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

A

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

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

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15
Q

Is FHC a dominant or recessive disorder?

A

Dominant

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16
Q

What else can cause FHC?

A

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!

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17
Q

What is an example of locus heterogeneity?

A

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

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18
Q

Haploinsufficiency of an enzyme?

A

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

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19
Q

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

A

Acute intermittent porphyria

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

20
Q

What are the symptoms of AIP or acute intermittent porphria?

A

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

21
Q

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

A
  1. Mutation leads to the gene doing more than what it normally does
  2. the mutation leads the gene having a new function
22
Q

Explain why Achondroplasia occurs?

A

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

23
Q

What is the specific mutation that leads to Achondroplasia?

A

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

very little allelic heterogeneity

24
Q

Huntington’s disease?

A

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

25
Q

Marfan syndrome?

A

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

26
Q

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

A

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)

27
Q

Osteogenisis imperfecta (brittle bone disease)

A

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

28
Q

Dominant negative

A

A special case of gain of function

29
Q

Dominant negative Vs haploinsufficiency

A

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

30
Q

Neurofibromatosis

A

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

31
Q

What is the function of the NF1 gene?

A

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

32
Q

Neurofibromas?

A

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

33
Q

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?

A

cancer!

34
Q

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?

A

Haploinsufficiency

35
Q

Galactosemia

A

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

36
Q

Phenylketonuria: PKU

A
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

37
Q

What is PKU the inability to do?

A

inability to convert phenylalanine to tyrosine

38
Q

Homocystinuria

A

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

Autosomal recessive

Inborn error of metabolism

39
Q

Sickle cell disease (SCD) mutation

A

Caused by a mutation in the gene for beta-globin

Causes a Glu6Val change in the encoded protein

Causes hemoglobin to polymerize

40
Q

SCD is considered recessive or dominant?

A

autosomal recessive

41
Q

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

A

electrophoresis!

42
Q

What is Pseudo-dominant?

A

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

easily mistaken as dominant from a simple pedigree

43
Q

What factors increase the risk of autosomal recessive traits?

A
  1. Consanguinity
  2. Heterozygote advantage
  3. Genetic isolation
  4. Assortative mating
44
Q

Example of co-dominance?

A

blood group types

AB

45
Q

What is incomplete dominance?

A

Phenotype is intermediate between the parents

combination of two traits

red + white = pink