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LEC39: Mendelian Inheritance Flashcards

1
Q

what may changes in DNA sequence cause?

A

may be benign

can affect any aspect of txn/tln process

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2
Q

what is SNV?

A

single nucleotide variant

type of genetic variation

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3
Q

what is SNP?

A

single nucleotide polymorphism

benign change

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4
Q

what is a mutation?

A

pathogenic change

must be proven as pathogenic; any change is not necessarily a mutation

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5
Q

what is a VUS?

A

variant of unknown significance

change without clinical data to support whether it is benign or pathogenic

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6
Q

what is the rate of nucleotide variation in humans?

where do they usually occur?

A

50-80 de novo variants per generation

usually in intronic sequences, but sometimes not and in that case, could cause change cross-generationally

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7
Q

what information determines pathogenicity of a variant?

A

1) clinical data/phenotype
2) family info
3) type of variant
4) functional studies
5) databases/prediction models

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8
Q

does a DNA test necessarily make a diagnosis?

A

no. a variant may look pathogenic on molecular level, but patient may not have any phenotype, so isn’t pathogenic for the patient

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9
Q

change in txn factor binding site result?

A

causes loss of transactivation or inappropriate expression of a gene

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10
Q

result of mutation in conserved intron splice donor/acceptor site?

A

misspliced transcript

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11
Q

result of changes deep in intronic sequence?

A

can be benign

or

can cause splicing effects - retained intron, skipped exon, alternative splice site usage

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12
Q

what does mutation of ESE (exonic splice enhancer) cause?

A

missplicing

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13
Q

what does changes in sequence in coding region of transcript cause?

A

changes in amino acid identity:

missense mutations

nonsense mutations - premature STOP codon

insertion/deletion - alternations of reading frame

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14
Q

what does insertion/delition that is a multiple of 3 cause?

A

in-frame changes that result in gain or loss of short runs of amino acids

otherwise intact protein

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15
Q

what is B-globin thalassemia caused by?

A

decreased amount of transcript

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16
Q

what is gamma-globin persistence of fetal hemoglobin caused by?

A

increased amount of transcript

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17
Q

what variant effects result from a misspliced transcript?

A

1) retained intron
2) skipped exon
3) alternative splice junction
4) unstable transcript

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18
Q

what can cause variants due to transcription changes?

A

promoter/enhancer mutation

keeps RNA Pol Complex from binding to promoter/enhancer region

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19
Q

what does a promoter/enhancer mutation cause?

A

keeps RNA Pol Complex from binding to promoter/enhancer region

causes variants due to transcription changes

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20
Q

what is a microsatellite? what causes it? what does it cause?

A

di- and trinucleotide repeats of short tandem sequences

5-6 ntd in length

causes a kink in DNA

disruption of transcription, translation, protein function

**major cause of disease in humans **

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21
Q

what are the characteristics of a somatic variant?

A

1) mutation occurred after fertilization
2) not in all cells of the body
3) can be tissue or organ-specific
4) not passed down to offspring

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22
Q

what are the characteristics of a germline variant?

A

1) mutation occurred before fertilization
2) generally in every cell of body AND in oocytes or spermatocytes
3) passed on to next generation

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23
Q

for a somatic variant, when would more versus less cells be impacted?

A

if variants occurs closer to fertilizaiton = more cells impacted

later in development = less cells impacted

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24
Q

what is this?

A

family tree of recessive inheritance

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25
how does recessive inheritance happen?
in enzymes/proteins that perform a function that doesn't require 2 working copies of gene for normal cellular function
26
how could you test loss of function of recessively inherited protein?
test protein function look at enzyme activity via an enzyme assay; if what you're studying is cleaved by an enzyme, light is emitted; those who are affected have low enzyme activity, less light, for example
27
when does loss of function usually occur? from what?
mutations in recessively inherited genes from gene deletion, missense mutations affecting imp a.as, nonsense mutations, promoter/enhancer mutations
28
for disease to manifest in a recessively inherited gene, what must occur?
1 mutation in each chromosomal copy
29
what is homozygous recessive?
for recessive genes, when have 2 copies of the same recessive gene mutation need this in order to see effect of a recessive gene
30
what is consanguineous homozygous mutation?
when parents of an affected individual are related, = consanguineous same mutation thus presents
31
what is compound heterozygosit? when does it occur?
if parents are unrelated, get 2 different muations of disease gene in an individual affected by recessive gene muations
32
what is chance of recurrence of recessively-inherited disorders to parents who are mutation carriers?
1 in 4
33
what is dominant inheritance?
disorders that occur in succeeding generations
34
what does dominant inheritance cause?
gain of function - increased acivity, a new activity, or loss of normal regulation or loss of function
35
what does recessive inheritance usually cause?
loss of function
36
what is haploinsufficiency?
loss of function caused when a single functional copy of a gene (single allel) is insufficient for proper cell or tissue function or development ex. of autosomal dominant disorder loss of function
37
what is dominant negative effect?
loss of function in autosomal dominant disorder when encoded mutant protein disrupts a multiprotein complex despite the presence of a wild type protein in the cell **aka presence of mutant allele is pathogenic ** get overall loss of function
38
what does x-linked inheritance cause? who is more effected?
gain of function or loss of function females less affected by x-linked mutations, males more affected no male-male transmission
39
what is constituitive activity of an RTK an example of?
gain of function mutation effect
40
what is banding gradient in proteins being incorrect an example of?
loss of function by halopinsufficiency when activity of normal allele is insufficienct
41
what happens if have mutation in a collagen molecule?
disrupts complex helical conformation of collagen can impact entire ECM structure, lose ability to form higher order structure dominant negative issue
42
what is allelic heterogeneity?
different mutations in 1 gene causes different phenotypes or effects
43
what is genotype-phenotype correlation?
the association of a specific genetic variant (genotype) w/ a characteristic pattern of physical characteristics (phenotype)
44
when might genotype-phenotype correlation vary within a single gene?
in a gene that predisposes to milder or more severe diseases
45
what causes gain of function in FGFR3?
constituitve activity of the RTK, FGFR3 causes baseline to be "on"
46
where is FGFR3 expressed?
developing bone and growth plate
47
what do different FGFR3 mutations cause? what is this example of?
mildest: hypochondroplasia middle: achondroplasia (dwarfism) severe: thanatophoric dysplasia (incompatible w/ life) example of **allelic heterogeneity or allelic series: **different variants of a gene that's autosomal dominant inherited causing different phenotypes
48
what phenotype does a missense mutation cause?
mild disease
49
what phenotype does truncation or frameshift mutation cause?
severe disease
50
what is genetic or locus heterogeneity?
when mutations in different genes cause a similar phenotype
51
what is bardet-biedl syndrome an example of?
autosomal recessive disorder that shows genetic or locus heteroeneity for a clinical phenotype many genes, involved w/ the primary cilia, cause this "ciliopathies"
52
what are primary cilia?
sensory cilia that cell puts out during embryogenesis and mitosis to create signaling/receptor antenna required for cell to receive signal and stimuli (hormones, chemokines, growth factors); important in Wnt & SHH pathways has microtubule structure but also transports proteins is implicated in Bardet-Biedl syndrome
53
incomplete penetrance?
presence of a muation doesn't always cause disease
54
what is genetic inheritane of breast/ovarian cancer an example of?
incomplete penetrance risk for mutated gene presence is not 100%
55
what does penetrance depend on?
sex, age several other multigenic factors and modifiers can be "completely penetrant" in a male vs. female
56
what causes Huntington disease?
the expansion of CAG repeats in the Huntingtin gene ORF normal: 10-37 repeats; once reach a critical threshold copy number (38-86 repeats), reach disease state expasion of number of reepats is associated w/ increased disease severity expansion predominantly in males
57
clinical features of huntington disease?
progressive movement disorder, dementia, seizures, atrophy of caudate nucleus
58
what determines Huntington disease penetrance?
incomplete penetrance that's based on age higher expansion or repeats in a gene at an earlier age, earlier onset disease will be severity increases over generations
59
what is complete penetrance
mutation = disease
60
what is incomplete penetrance
"skipping generations"
61
what is age-related penetrance?
symptom onset w/ age
62
what is anticipation?
when symptoms of genetic disorder become apparent at an earlier age as it's passed on to next generation also usually see increase of severity of symptoms occurs in Huntington's disease
63
variable expressivity?
mutation in a gene doesn't always have the same phenotypic effect, even in the same family
64
what is neurofibromatosis 1?
autosomal dominant mutation of NF1 gene 100% penetrant example of variable expressivity - manifestations of skin neurofibromas, cafe au lait spots, lesions, freckles varies if lose NF1 function, increases RAS signaling; causes neurofibromas, etc
65
what is pleiotropy?
when a gene defect affects many distinct tissues
66
what is segmental neurofibromatosis (just on forehead) example of?
somatic mosaicism for NF1 mutation mutation of NF1 only occurs in localized area rather than all over body
67
what is somatic mosaicism?
spontaneous mutation acquired after fertilization, during development, that causes **segmental disease ** depending on when mutation occurred, determines how affected person is/which organ system is affected
68
what is proteus syndrome?
very early on somatic change causing somatic mosaicism not inherited caused by somatic AKT1 mutation
69
what might cause this incidence of neurofibromas?
germline mosaicism if mutation occurred in gonadogenesis could see mosaic imprint in children even though no disease manifestation in parents
70
germline mutation?
mutation inherited from a parent, present in all cells of the body
71
when can mutations arise?
any time during organism's life cycle
72
somatic mutations?
mutations that aren't inherited, if in non-reproductive tissues
73
what is smallest scale of mutation?
single cell but event may have signficantly health implications still, i.e. umorigenesis
74
muation event early in embryogenesis causes?
reproductive consequenes for the individual might include germ cell mutations
75
late mutation event causes?
segmental disease only portion of the body might manifest disease features

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