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Foundations test 2 > Principles of pedigree Analysis and Genetic Mechanisms (Penetrance and heterogeneity) > Flashcards

Principles of pedigree Analysis and Genetic Mechanisms (Penetrance and heterogeneity) Flashcards

1
Q

Dominant traits (hetero vs homo)

A

Homo will be more severe

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2
Q

Gene dosage effect

A

Semi-dominance or incomplete dominance of a dominant allele means heterozygote will be less severe than homozygote

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3
Q

Haploinsufficiency

A

Contribution from normal allele is insufficient to prevent disease due to loss of function at other allele

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4
Q

Gain of function

A

Product of disease causing allele acquires a new or enhanced product…mutant allele must make a product

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5
Q

Null mutation

A

Makes no protein

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6
Q

Hypermorphic mutation

A

Protein with reduced activity

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7
Q

Compound heterozygote

A

Having two different mutant recessive alleles at a given locus

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8
Q

Hemizygote

A

Posses one copy of a gene (x-linked in males)

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9
Q

Homozygote

A

Two identical copies at same locus on homologous chromosomes

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10
Q

Probability

A

Ratio of selected outcomes to total number of possible outcomes

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11
Q

Risk

A

Probability that something will happen

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12
Q

Genetics risk

A

Prob that specific phenotype or genotype will occur in a specific membrer of a family

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13
Q

Recurrence risk

A

Prob that something will happen again

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14
Q

Recurrence risk in genetics

A

Prob that geno or phenotype will occur in a family member given that it has already occurred in that family

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15
Q

Siblings are drawn

A

L to R, oldest to youngest

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16
Q

AD pedigree charactersitics

A 
Male to male transmission 
Vertical pattern
Males can have unaffected daughters
50:50 male to female
Unaffected family members do not inherit disease causing gene
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17
Q

FH and inheritance

A

Familial hypercholesterolemia

Auto dominant

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18
Q

FH causes

A

Hypercholesterolemia, xanthomas (cholesterol depostis in joints), CAD

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19
Q

Mutation of FH

A

LDLR

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20
Q

Heterozygote FH timeline

A

Hyperchol at birth, tendon xanthomas appear at 2nd decade, CAD at 4th decade

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21
Q

Homozygote FH timeline

A

Hyper chol at birth, tendon xanthomas at birth (all by age 4), first sign of CAD at 2nd decade…death at age 30

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22
Q

FH inheritance

A

Autosomal dominant with clear dosage effect (co-dominant)

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23
Q

Ways cells can make cholesteroal

A

de novo via HMG CoA reductase
OR
Acquire it from outside using LDLR

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24
Q

If cells don’t synthesize enough cholesterol via de novo,

A

Increase transcription of LDLR gene to increase levels to get more cholesterol

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25
Q

Statins and FH

A

Blocks HMG CoA redcutase so increased expression of LDLR and therefore more wild type LDLR…especially helpful for heterozygotes because they have a copy of wild-type

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26
Q

AR pedigree

A

Horizontal pattern
50:50 male and female
Parents of affected child can be asymptomatic carriers
Possibility of consanguinity, especailly if allele is rare

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27
Q

PKU detection

A

Elevated Phe in serum leads to phenylpyruvic acid (keto acid) in the urine

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28
Q

PKU inheritance and what type of odd presentation?

A

Autosomal recessive…extensive allelic heterogeneity

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29
Q

Mechanism of PKU

A

Mutation of PAH…expressed in liver but brain is primary affecrtive origin

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30
Q

Mutations of PKU

A

Extensive allelic heterogeneity although most are point mutations

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31
Q

Mutations that can present as PKU

A

PAH

DHPR (dihydropteridine reductase)

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32
Q

PAH reaction

A

L-phenylalanine to L-tyrosine…needs BH4 in order react

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33
Q

DHPR reactions

A

As Phe converted to Tyr, converts

BH4 to qBH2

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34
Q

DHPR mutations also alter which hydroxylases

A

Tyr hydroxylase - makes dopamine via L-dopa
Try hydroxylase - makes serotonin via 5-OH trp
PAH - breaks down Phe to Tyr
ALL NEED BH4

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35
Q

Enzyme replacement for PKU

A

PEG-PAL

36
Q

LNAAs PKU

A

Large neutral amino acids…passage of Phe blocked to the brain

37
Q

Kuvan

A

Improves Phe tolerance by increasing BH4 levels, the cofactor for the PAH enzyme…essentially stimulates the PAH enzyme

38
Q

With genetic analysis can predict what with PKU

A

WHo will respond to Kuvan tx

39
Q

Lyonization

A

X-inactivation is not always random in females

40
Q

X-linked recessive inheritance

A

Incidence higher in males
Transmitted from affected to male to all daughters
Cannot pass from father to son
Heterozygous females are usually unaffected, but may express depending on X-inactivation

41
Q

G6PD symptoms

A

Hemolytic crisis after infection, fava beans, treatment with drugs…hemolytic anemia

42
Q

G6PD def mutation

A

in G6PD

43
Q

G6PD disease that can be caused

A

Kidney and hemolytic anemia

44
Q

Inheritance of G6PD

A

X-linked

45
Q

Higher resistance to malarial infection corresponds with and why

A

Heterozygosity (females) and hemizygosity (males) of G6PD…this is why it keeps getting passed on…creates harsh environment so that plasmodium parasites could not grow

46
Q

G6PD can generate

A

NADPH and glutathione …sole source of these antioxidants in RBCs…RBCs are highly sensitive to oxidative stress

47
Q

Lower fitness, means

A

Higher proportioin of new mutations

48
Q

Reduced penetrance or expressivity

A

Heterozygote does not express phenotype or have subclinical evidence of phenotype…could be due to polymorphisms of other genes or enviornment

49
Q

Phenocopy

A

Environmentally caused trait mimic genetically inherited

50
Q

Hereditary breast-ovarian cancer syndrome

A

In this cause, breast cancer is common in age over 50 so not unusual to see sporadic case in a hereditary family

51
Q

New mutation contribution to auto rec and auto dom

A

Small to auto rec

Large to auto dom

52
Q

Duchenne muscular dystrophy inheritance

A

X-linked recessive (35% de novo mutations)

53
Q

Anchondroplasia inheritance

A

Autosomoal dominant (80% of mutation de novo)

54
Q

Allelic heterogenity and disease

A

Same phenotype due to different mutations of same gene CF

55
Q

Locus heterogeneity and disease

A

Same phenotype due to mutations in different genes

Tay-Sachs and Sandhoff disease

56
Q

Phenotypic heterogeneity and disease

A

Different phenotypes due to different mutations in the same gene
A1AT

57
Q

Incomplete penetrance

A

Some individuals who carry mutation do not express the disease

58
Q

Variable expressivity

A

Severity of disease varies

Allagile syndrome `

59
Q

CFTR mutant

A

Does not move cloride ions outside of cell so mucus binds on the outside of the cell

60
Q

CF inhertiance

A

Auto recessive with allelic heterogeneity

61
Q

Positional cloning

A

Gene ID based solely on knowing chromosomal location

62
Q

Tay-Sachs presentation

A

Neurological defects 3-6 months after birth

63
Q

Tay-sachs type of disease

A

lysosomal storage disease

64
Q

Mechanism of tay-sachs

A

Cannot degrade GM2 ganglioside (sphingolipid)…mutation in hexosaminidase A gene (HEXA)…accumulation of gangliosides in nerve cells leads to death

65
Q

Tay-Sachs is similar to

A

Sandhoff (HEXB)

66
Q

Tay-Sachs/Sandhoff is less common than

A

Activator defieicny

67
Q

Caucasion disease

A

CF

68
Q

AA disease

A

Sickle cell

69
Q

Amish disease

A

Maple syrup urine

70
Q

Ashkenazi Jeiwsh dz

A

Tay-Sachs, Gaucher

71
Q

Mediterranean disease

A

B-thalaseemia

72
Q

Founder effect

A

Loss of genetic variation when new pop established from small number

73
Q

A1AT defieincy presentation

A

COPD, cirrhosis of the liver

74
Q

A1AT def inheritance

A

Auto rec (S allele = mild), Z allele = severe

75
Q

A1AT def other name and mech

A

PI (protease inhibitor deficiency)…controls activity of elastase typically…Increased damage in smokers (ecogenetics)

76
Q

Z protein sensitive to

A

Oxidative damage

77
Q

Z allele can result in

A

Lung and liver damage

78
Q

Z/Z

A

Lungs lack A1AT so are damaged by neutrophil elastase…A1AT trapped in liver causing damage

79
Q

Null/Null

A

No liver damage because not made

Still have lung damage

80
Q

What causes liver disease with Z allele

A

Z protein has Gain of function properties…accumulates in the ER and can alter protein degradation, autophagy, and intracellular signaling pathways

81
Q

Why is liver disease severity variable

A

Genetic variation - polymorphisms in genes

Environemtn - alcoholism, NAFLD, and inflammation

82
Q

Alagille syndrome inheritance

A

Auto dom

83
Q

Alagille syndrome affects

A

Liver (paucity of bile ducts), heart, kidney, skeletal, unique facial features

84
Q

Alaggille syndrome mutations

A

Notch signalliing pathway via Jagged 1

85
Q

3 options of FH

A

No drugs
Bile acid depletion - LDLR expressed more because fewer bile acids come back into the cell as cholesterol
Bile acid depletion PLUS Reductase inhibitor - Inhibit de novo synthesis AND bile acids depleted so even less cholestoeral in cell..increase LDLR

Foundations test 2 (13 decks)

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