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MCG > LEC39: Mendelian Inheritance > Flashcards

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
Q

how does recessive inheritance happen?

A

in enzymes/proteins that perform a function that doesn’t require 2 working copies of gene for normal cellular function

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26
Q

how could you test loss of function of recessively inherited protein?

A

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

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27
Q

when does loss of function usually occur? from what?

A

mutations in recessively inherited genes

from gene deletion, missense mutations affecting imp a.as, nonsense mutations, promoter/enhancer mutations

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28
Q

for disease to manifest in a recessively inherited gene, what must occur?

A

1 mutation in each chromosomal copy

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29
Q

what is homozygous recessive?

A

for recessive genes, when have 2 copies of the same recessive gene mutation

need this in order to see effect of a recessive gene

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30
Q

what is consanguineous homozygous mutation?

A

when parents of an affected individual are related, = consanguineous

same mutation thus presents

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31
Q

what is compound heterozygosit? when does it occur?

A

if parents are unrelated, get 2 different muations of disease gene in an individual affected by recessive gene muations

32
Q

what is chance of recurrence of recessively-inherited disorders to parents who are mutation carriers?

A

1 in 4

33
Q

what is dominant inheritance?

A

disorders that occur in succeeding generations

34
Q

what does dominant inheritance cause?

A

gain of function - increased acivity, a new activity, or loss of normal regulation

or loss of function

35
Q

what does recessive inheritance usually cause?

A

loss of function

36
Q

what is haploinsufficiency?

A

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
Q

what is dominant negative effect?

A

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
Q

what does x-linked inheritance cause?

who is more effected?

A

gain of function or loss of function

females less affected by x-linked mutations, males more affected

no male-male transmission

39
Q

what is constituitive activity of an RTK an example of?

A

gain of function mutation effect

40
Q

what is banding gradient in proteins being incorrect an example of?

A

loss of function by halopinsufficiency

when activity of normal allele is insufficienct

41
Q

what happens if have mutation in a collagen molecule?

A

disrupts complex helical conformation of collagen

can impact entire ECM structure, lose ability to form higher order structure

dominant negative issue

42
Q

what is allelic heterogeneity?

A

different mutations in 1 gene causes different phenotypes or effects

43
Q

what is genotype-phenotype correlation?

A

the association of a specific genetic variant (genotype) w/ a characteristic pattern of physical characteristics (phenotype)

44
Q

when might genotype-phenotype correlation vary within a single gene?

A

in a gene that predisposes to milder or more severe diseases

45
Q

what causes gain of function in FGFR3?

A

constituitve activity of the RTK, FGFR3

causes baseline to be “on”

46
Q

where is FGFR3 expressed?

A

developing bone and growth plate

47
Q

what do different FGFR3 mutations cause? what is this example of?

A

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
Q

what phenotype does a missense mutation cause?

A

mild disease

49
Q

what phenotype does truncation or frameshift mutation cause?

A

severe disease

50
Q

what is genetic or locus heterogeneity?

A

when mutations in different genes cause a similar phenotype

51
Q

what is bardet-biedl syndrome an example of?

A

autosomal recessive disorder that shows genetic or locus heteroeneity for a clinical phenotype

many genes, involved w/ the primary cilia, cause this

“ciliopathies”

52
Q

what are primary cilia?

A

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
Q

incomplete penetrance?

A

presence of a muation doesn’t always cause disease

54
Q

what is genetic inheritane of breast/ovarian cancer an example of?

A

incomplete penetrance

risk for mutated gene presence is not 100%

55
Q

what does penetrance depend on?

A

sex, age

several other multigenic factors and modifiers

can be “completely penetrant” in a male vs. female

56
Q

what causes Huntington disease?

A

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
Q

clinical features of huntington disease?

A

progressive movement disorder, dementia, seizures, atrophy of caudate nucleus

58
Q

what determines Huntington disease penetrance?

A

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
Q

what is complete penetrance

A

mutation = disease

60
Q

what is incomplete penetrance

A

“skipping generations”

61
Q

what is age-related penetrance?

A

symptom onset w/ age

62
Q

what is anticipation?

A

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
Q

variable expressivity?

A

mutation in a gene doesn’t always have the same phenotypic effect, even in the same family

64
Q

what is neurofibromatosis 1?

A

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
Q

what is pleiotropy?

A

when a gene defect affects many distinct tissues

66
Q

what is segmental neurofibromatosis (just on forehead) example of?

A

somatic mosaicism for NF1 mutation

mutation of NF1 only occurs in localized area rather than all over body

67
Q

what is somatic mosaicism?

A

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
Q

what is proteus syndrome?

A

very early on somatic change causing somatic mosaicism

not inherited

caused by somatic AKT1 mutation

69
Q

what might cause this incidence of neurofibromas?

A

germline mosaicism

if mutation occurred in gonadogenesis could see mosaic imprint in children even though no disease manifestation in parents

70
Q

germline mutation?

A

mutation inherited from a parent, present in all cells of the body

71
Q

when can mutations arise?

A

any time during organism’s life cycle

72
Q

somatic mutations?

A

mutations that aren’t inherited, if in non-reproductive tissues

73
Q

what is smallest scale of mutation?

A

single cell

but event may have signficantly health implications still, i.e. umorigenesis

74
Q

muation event early in embryogenesis causes?

A

reproductive consequenes for the individual

might include germ cell mutations

75
Q

late mutation event causes?

A

segmental disease

only portion of the body might manifest disease features

MCG (77 decks)

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