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genetics of human disease > summary of genetic diseases > Flashcards

summary of genetic diseases Flashcards

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Biology 101 flashcards
1
Q

what is a single gene disorder

A

when a certain gene is known to cause a disease

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2
Q

where are single gene disorders catalogued

A

OMIM

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3
Q

what causes chromosomal diseases

A

changes in either the number or structure of chromosomes

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4
Q

what percentage of conceptions terminate due to chromosomal abnormalities

A

8%

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5
Q

what percentage of live births suffer anueuplodies, translocation etc

A

0.1%

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6
Q

what are mitochondrial disorders

A

genetic disorder that occurs when the mitochondria of the cell fail to produce enough energy for cell or organ function

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7
Q

any problems with mtDNA can lead to what

A

multisystem disorders

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8
Q

mtDNA is …. inherited

A

maternally

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9
Q

if the mother is heteroplasmic then the children can be

A

affected at different severities due to the varying level of mutation passed down

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10
Q

why do we need to identify variants for SGD (4 reasons)

A
  • stop invasive testing
  • allows introduction of appropriate treatment/stops any inappropriate treatment
  • psychological benefits to affected and family
  • scientific knowledge (telling us the role of different genes)
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11
Q

what was the very first gene that was mapped

A

huntingtin gene

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12
Q

what was the very first gene that was identified to be responsible for a disease

A

DMD gene

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13
Q

there has been a decrease in genes identified for SGD is recent years T/F

A

T

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14
Q

what is the difference between WGS and WES

A

whole genome sequencing (WGS) attempts to sequence the entirety of the genome whereas whole exome sequencing (WES) instead focuses on sequencing protein coding sequence

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15
Q

what are the advantages of WES over WGS

A

variants for SGDs so far are all in coding sequence

  • cheaper
  • fewer variants to analyse
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16
Q

what are the disadvantages to WES

A

may miss some causative alleles (WGS is becoming more feasible)

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17
Q

each individual will show over 20,000 variants after WES, how can we identify the causative variant

A
  • predict effect on protein function
  • use population databases (disease allele will be rare)
  • pedigree info
  • same allele in unrelated individuals with same disorder
  • recapitulation in model system/organism
  • databases of pathogenic variants
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18
Q

what are likely to cause loss of function

A

frame shift, protein terminating variants, splice sites and exon deletion

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19
Q

what is the exception of frame shift and PTV leading to LOF

A

if they are near the end of the protein sequence they dont affect protein structure - function maintained

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20
Q

what computer programs predict whether an amino acid substitution affects protein function

A

SIFT (sorts intolerant from tolerant)

Polyphen2 - polymorphism phenotypic version 2

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21
Q

what is ExAC

A

consortium which has generated the largest catalogue so far of variation in human protein-coding regions. it puts the information in a publicly accessible database

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22
Q

what does ExAC allow you to do

A

identify which alleles are very rare and which potentially harmful alleles occur frequently in apparently healthy individuals

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23
Q

what is key about the ExAC databas

A

size

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24
Q

some alleles arent very frequent in the population but can still occur in healthy individuals T/F

A

T

25
Q

what may happen if the ExAC database is small

A

may muss alleles that although the are rare are not pathogenic

26
Q

what has succeeded ExAC

A

GnomAD

27
Q

frequencies can be different for different subpopulations. so an allele ay be rare worldwide but less rare in a subpopulation. if these individuals are healthy then it is not pathogenic T/F

A

T

28
Q

we all carry 100s of potentially harmful mutations T/F

A

T

29
Q

what is a compound heterozygote

A

The presence of two different mutant alleles at a particular gene locus (might not be exactly same bp change but will affect same gene)

30
Q

how can you tell that a mutation is de novo dominant

A

new allele is not present in either parent

31
Q

offspring of consanguineous relationships are on average more at risk of recessive disorders T/F

A

T

32
Q

some diseases are very rare. to match affected individuals who are geographically isolated what is needed

A

controlled vocabulary to describe disease - human phenotype ontogeny

33
Q

what is the major problem for datasharing about peoples diseasse phenotype/genetic data

A

ethics - fundamental right to privacy of genetic info

34
Q

to ensure compatability between different countried with different medcal organisations and labs need standardisation. how is this achieved

A

American college of medical genetics and genomics guidelines. agree on set of guidelines to categorise variants

35
Q

what is the simplest example of consanguinieous relationship

A

cousin marriage

36
Q

what is dangerous about consanguineous parent

A

can have an allele that is rare becoming homozygous in the offspring

37
Q

for each child there is a …… chance they will become homozygous for an allele that is heterozygous in their grandparent

A

1/64

38
Q

the more distant the retationship among affecteds the fewer homozygous regions to analyse. how many rare variants do children of cousins have compared to children of third cousins

A

children of cousins have about 15-20 rare variants

children of third cousins have only 5-10 rare variants

39
Q

what was the case study example given of a consanguineous autosomal recessive disorder

A

15yo saudi arabian girl with p.pro387leu mutation in SLC18A2 encoding the VMAT2 dopamine transporter

40
Q

what was an example of a consanguineous autosomal recessive disorder given by the paper

A

3 siblings in pakistani family had postaxial polydactlyl type A with single homozygous ZNF141 variant

41
Q

proline in the VMAT2 protein is highy conserved through evolution and in paralogous protein VMAT1 in c.elegans. what does this suggest

A

its substitution is likely to be deleterious

42
Q

what is VMAT2

A

translocator of dopamine and serotonin into synaptic vesicles

43
Q

how was the p.pro387leu mutation treated

A

direct dopamine agonist (pramipexole)

44
Q

what does the SLC18A2/VMAT2 study show

A

homozygosity mapping
choosing candidate genes by hypothetical function
mutation affecting functional part of protein
-mutation in highly conserved residue
-recapitulation in in vitro mode (c.elegans)
diagnosis and treatment in a rare and novel disorder

45
Q

how can you tell that a variant is autosomal dominant

A

heterozygous variant in affected family members not present in unaffected members

46
Q

why is the identification of autosomal dominant harder

A

need mapping info

47
Q

most dominant individuals are unlikely to have chioldren. why

A

most have severe health problems and dont want to pass on. they know they are affected

48
Q

what is meant by de novo dominant

A

spontaneous mutations that occur when sperm/egg is being made that lead to dominant disorders

49
Q

why are de novo dominant mutations easy to identify

A

each individual carries very few variants not found in either their parents

50
Q

what can be sufficient for the identification of de novo mutations in the disease causing gene

A

analysis of 2 unrelated parent-child trios with a sporadic presentation of the same presumed autosomal dominant disorder

51
Q

what are 2 examples of diseases caused by de novo mutations

A

floating harbour syndrome

weavers syndrome

52
Q

what mutation causes floating harbour syndrome

A

mutations in SCRAP - SNf2 related chromatin remodelling ATPase; a cofactor for CREB binding proteins

53
Q

what are the characteristics of floating harbour syndrome

A

dysmorphic features
short stature
intellectual disability
language defects

54
Q

what is weaver syndrome

A

weaver syndrome is a condition that involves tall stature with or without a large head size (macrocephaly), a variable degree of intellectual disability

55
Q

what was found as the causal gene of weaver syndrome

A

EZH2

56
Q

how many unrelated parent child trios were needed to identify EZH2 as the causal gene for weaver syndrome

A

2

57
Q

what mode of inheritance did diamond blackfan anemia be found to show

A

X linked

58
Q

what did WES of diamond blackfan anaemia affected male siblings show

A

A single GATA1 variant on the X chromosome

59
Q

disease causing mutations should be..

A

rare

genetics of human disease (10 decks)

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