LEC39: Mendelian Inheritance Flashcards Preview

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Flashcards in LEC39: Mendelian Inheritance Deck (75):

what may changes in DNA sequence cause?

may be benign 

can affect any aspect of txn/tln process


what is SNV?

single nucleotide variant 

type of genetic variation


what is SNP?

single nucleotide polymorphism 

benign change 


what is a mutation?

pathogenic change

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



what is a VUS?

variant of unknown significance

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



what is the rate of nucleotide variation in humans?

where do they usually occur?

50-80 de novo variants per generation 

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


what information determines pathogenicity of a variant?

1) clinical data/phenotype

2) family info

3) type of variant 

4) functional studies 

5) databases/prediction models 


does a DNA test necessarily make a diagnosis?

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


change in txn factor binding site result?

causes loss of transactivation or inappropriate expression of a gene


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

misspliced transcript


result of changes deep in intronic sequence?

can be benign 


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


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



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

changes in amino acid identity: 

missense mutations

nonsense mutations - premature STOP codon

insertion/deletion - alternations of reading frame 


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

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

otherwise intact protein 


what is B-globin thalassemia caused by?

decreased amount of transcript 


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

increased amount of transcript


what variant effects result from a misspliced transcript?

1) retained intron

2) skipped exon 

3) alternative splice junction 

4) unstable transcript


what can cause variants due to transcription changes?

promoter/enhancer mutation

keeps RNA Pol Complex from binding to promoter/enhancer region



what does a promoter/enhancer mutation cause?


keeps RNA Pol Complex from binding to promoter/enhancer region 

causes variants due to transcription changes



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

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 


what are the characteristics of a somatic variant?

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



what are the characteristics of a germline variant?

1) mutation occurred before fertilization 

2) generally in every cell of body AND in oocytes or spermatocytes

3) passed on to next generation


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

if variants occurs closer to fertilizaiton = more cells impacted 

later in development = less cells impacted


what is this?

Q image thumb

family tree of recessive inheritance


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


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


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


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

1 mutation in each chromosomal copy 


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 


what is consanguineous homozygous mutation?

when parents of an affected individual are related, = consanguineous

same mutation thus presents


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


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

1 in 4


what is dominant inheritance?

disorders that occur in succeeding generations 


what does dominant inheritance cause?

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

or loss of function 


what does recessive inheritance usually cause?

loss of function


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


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 


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


what is constituitive activity of an RTK an example of?

gain of function mutation effect


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

loss of function by halopinsufficiency 

when activity of normal allele is insufficienct


A image thumb

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 




what is allelic heterogeneity?

different mutations in 1 gene causes different phenotypes or effects


A image thumb

what is genotype-phenotype correlation?

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


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

in a gene that predisposes to milder or more severe diseases


what causes gain of function in FGFR3?

constituitve activity of the RTK, FGFR3

causes baseline to be "on" 


where is FGFR3 expressed?

developing bone and growth plate


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


what phenotype does a missense mutation cause?

mild disease


what phenotype does truncation or frameshift mutation cause?

severe disease


what is genetic or locus heterogeneity?

when mutations in different genes cause a similar phenotype

A image thumb

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 



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



incomplete penetrance?

presence of a muation doesn't always cause disease


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

incomplete penetrance 

risk for mutated gene presence is not 100%



what does penetrance depend on?

sex, age 

several other multigenic factors and modifiers

can be "completely penetrant" in a male vs. female


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


A image thumb

clinical features of huntington disease?

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


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


what is complete penetrance

mutation = disease 


what is incomplete penetrance

"skipping generations"


what is age-related penetrance?

symptom onset w/ age


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



variable expressivity?

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


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


what is pleiotropy?

when a gene defect affects many distinct tissues


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


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


what is proteus syndrome?

very early on somatic change causing somatic mosaicism

not inherited 

caused by somatic AKT1 mutation 



what might cause this incidence of neurofibromas?


Q image thumb

germline mosaicism 

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


germline mutation?

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


when can mutations arise?

any time during organism's life cycle


somatic mutations?

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


what is smallest scale of mutation?

single cell 

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


muation event early in embryogenesis causes?

reproductive consequenes for the individual 

might include germ cell mutations


late mutation event causes?

segmental disease 

only portion of the body might manifest disease features

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