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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

(85 cards)

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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
Statins and FH
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
26
AR pedigree
Horizontal pattern 50:50 male and female Parents of affected child can be asymptomatic carriers Possibility of consanguinity, especailly if allele is rare
27
PKU detection
Elevated Phe in serum leads to phenylpyruvic acid (keto acid) in the urine
28
PKU inheritance and what type of odd presentation?
Autosomal recessive...extensive allelic heterogeneity
29
Mechanism of PKU
Mutation of PAH...expressed in liver but brain is primary affecrtive origin
30
Mutations of PKU
Extensive allelic heterogeneity although most are point mutations
31
Mutations that can present as PKU
PAH | DHPR (dihydropteridine reductase)
32
PAH reaction
L-phenylalanine to L-tyrosine...needs BH4 in order react
33
DHPR reactions
As Phe converted to Tyr, converts | BH4 to qBH2
34
DHPR mutations also alter which hydroxylases
Tyr hydroxylase - makes dopamine via L-dopa Try hydroxylase - makes serotonin via 5-OH trp PAH - breaks down Phe to Tyr ALL NEED BH4
35
Enzyme replacement for PKU
PEG-PAL
36
LNAAs PKU
Large neutral amino acids...passage of Phe blocked to the brain
37
Kuvan
Improves Phe tolerance by increasing BH4 levels, the cofactor for the PAH enzyme...essentially stimulates the PAH enzyme
38
With genetic analysis can predict what with PKU
WHo will respond to Kuvan tx
39
Lyonization
X-inactivation is not always random in females
40
X-linked recessive inheritance
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
G6PD symptoms
Hemolytic crisis after infection, fava beans, treatment with drugs...hemolytic anemia
42
G6PD def mutation
in G6PD
43
G6PD disease that can be caused
Kidney and hemolytic anemia
44
Inheritance of G6PD
X-linked
45
Higher resistance to malarial infection corresponds with and why
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
G6PD can generate
NADPH and glutathione ...sole source of these antioxidants in RBCs...RBCs are highly sensitive to oxidative stress
47
Lower fitness, means
Higher proportioin of new mutations
48
Reduced penetrance or expressivity
Heterozygote does not express phenotype or have subclinical evidence of phenotype...could be due to polymorphisms of other genes or enviornment
49
Phenocopy
Environmentally caused trait mimic genetically inherited
50
Hereditary breast-ovarian cancer syndrome
In this cause, breast cancer is common in age over 50 so not unusual to see sporadic case in a hereditary family
51
New mutation contribution to auto rec and auto dom
Small to auto rec | Large to auto dom
52
Duchenne muscular dystrophy inheritance
X-linked recessive (35% de novo mutations)
53
Anchondroplasia inheritance
Autosomoal dominant (80% of mutation de novo)
54
Allelic heterogenity and disease
Same phenotype due to different mutations of same gene CF
55
Locus heterogeneity and disease
Same phenotype due to mutations in different genes | Tay-Sachs and Sandhoff disease
56
Phenotypic heterogeneity and disease
Different phenotypes due to different mutations in the same gene A1AT
57
Incomplete penetrance
Some individuals who carry mutation do not express the disease
58
Variable expressivity
Severity of disease varies | Allagile syndrome `
59
CFTR mutant
Does not move cloride ions outside of cell so mucus binds on the outside of the cell
60
CF inhertiance
Auto recessive with allelic heterogeneity
61
Positional cloning
Gene ID based solely on knowing chromosomal location
62
Tay-Sachs presentation
Neurological defects 3-6 months after birth
63
Tay-sachs type of disease
lysosomal storage disease
64
Mechanism of tay-sachs
Cannot degrade GM2 ganglioside (sphingolipid)...mutation in hexosaminidase A gene (HEXA)...accumulation of gangliosides in nerve cells leads to death
65
Tay-Sachs is similar to
Sandhoff (HEXB)
66
Tay-Sachs/Sandhoff is less common than
Activator defieicny
67
Caucasion disease
CF
68
AA disease
Sickle cell
69
Amish disease
Maple syrup urine
70
Ashkenazi Jeiwsh dz
Tay-Sachs, Gaucher
71
Mediterranean disease
B-thalaseemia
72
Founder effect
Loss of genetic variation when new pop established from small number
73
A1AT defieincy presentation
COPD, cirrhosis of the liver
74
A1AT def inheritance
Auto rec (S allele = mild), Z allele = severe
75
A1AT def other name and mech
PI (protease inhibitor deficiency)...controls activity of elastase typically...Increased damage in smokers (ecogenetics)
76
Z protein sensitive to
Oxidative damage
77
Z allele can result in
Lung and liver damage
78
Z/Z
Lungs lack A1AT so are damaged by neutrophil elastase...A1AT trapped in liver causing damage
79
Null/Null
No liver damage because not made | Still have lung damage
80
What causes liver disease with Z allele
Z protein has Gain of function properties...accumulates in the ER and can alter protein degradation, autophagy, and intracellular signaling pathways
81
Why is liver disease severity variable
Genetic variation - polymorphisms in genes | Environemtn - alcoholism, NAFLD, and inflammation
82
Alagille syndrome inheritance
Auto dom
83
Alagille syndrome affects
Liver (paucity of bile ducts), heart, kidney, skeletal, unique facial features
84
Alaggille syndrome mutations
Notch signalliing pathway via Jagged 1
85
3 options of FH
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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