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diagnosis of genetic diseases > Lecture 8 > Flashcards

Lecture 8 Flashcards

1
Q

what is a mendelian disorder?

A

monogenic disorder associated with a single locus involved in the phenotype

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2
Q

what is the analysis of a mendelian disorder focused on?

A

focused on a specific locus and alteration that we detect are often causative mutations

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3
Q

what is penetrance?

A

if a mutated individual presents clinical symptoms - in some cases we can have incomplete penetrance (cardiomyopathies)

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4
Q

what is expressivity?

A

the different degrees of severity of the clinical phenotype - different degree of disorders in different familiar members carrying the same causative mutations

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5
Q

what three inheritance patterns are linked to mendelian disorders?

A

autosomal dominant, autosomal recessive, and X-linked inheritance

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6
Q

describe a single gene condition:

A

the presence of a single causative gene - same as the classical mendelian inheritance explained before, but we also have the reduction of both penetrance and heterogeneity of the genotype

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7
Q

what is a polygenic disorder?

A

the presence of different mutations in different genes associated with the same phenotype

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8
Q

what is the difference in oncological disorders such as breast and ovarian cancer?

A

we have a picture of a multifactorial and complex disorder in which there is a role of the environmental factors and genetic predisposition

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9
Q

what are most human genetic human disorders characterized by?

A

a heterogenous or complex etiology

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10
Q

what is the abbreviation for phenotype?

A

Ph

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11
Q

what are some examples of environmental factors?

A

lifestyle, cultural factors, smoke, geographical area

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12
Q

what is sex?

A

biological difference

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13
Q

what is gender?

A

a mixture of biological differences and cultural habits, hormones, and environmental factors

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14
Q

in general, what is a rare form of breast cancer?

A

characterized by an early onset and mendelian inheritance

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15
Q

in general, what is the common form of breast cancer like?

A

characterized by late onset and associated genetic factors

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16
Q

what is the most common form of breast cancer?

A

sporadic form

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17
Q

what occurs when there is a predisposition to breast cancer?

A

there is a mutation in one of the two allele genes that are associated to breast and ovarian cancer - mutations are caused by environmental factors

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18
Q

what is the genetic form of breast cancer called?

A

familiar form

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19
Q

what occurs during the familiar form?

A

one mutation is genetically present and the second mutation occurs due to the exposure to environmental factors and therefore the development of a tumor - typically early onset

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20
Q

what is HBOC?

A

human breast and ovarian cancer

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21
Q

why is it important to only perform genetic testing in a case where there is an affected individual who we want to better evaluate and characterize?

A

if we detect a variation on a gene, we are not bale to calculate the risk for the individual to actually develop hboc

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22
Q

who has a higher risk to develop breast cancer, a carrier or a non-carrier?

A

carrier

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23
Q

what are the two most famous genes associated with hboc?

A

BRCA1 and BRCA2

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24
Q

where is BRCA1 localized?

A

on chromosome 17

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25
Q

where is BRCA2 localized?

A

chromosome 13

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26
Q

what percentage of early onset breast cancer is associated with BRCA1 and BRCA2?

A

40-85%

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27
Q

what percentage of contralateral breast cancer is associated with BRCA1 and BRCA2 mutations?

A

40-60%

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28
Q

what percentage of ovarian cancer is related to BRCA1 and BRCA2 mutations?

A

40%

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29
Q

in males, what have BRCA1 and BRCA2 mutations been linked to?

A

elevated risk of breast cancer and potentially na elevated risk for prostate and pancreatic cancer as well

30
Q

how many exons does BRCA1 contain?

A

24

31
Q

how many exons does BRCA2 contain?

A

23

32
Q

what are BRCA1 and BRCA2?

A

tumor suppressor genes

33
Q

what are the main mutations described with BRCA1 and BRCA2?

A

For sure single nucleotide mutation (missense, nonsense, splice site mutations…) and also partial
or complete deletion of the entire exon → this is important to be considered because it influences the different levels of approaches/analysis that we should performed for diagnostic genetic testing

34
Q

what is allelic heterogeneity?

A

different mutation on genes that are associated with the same phenotype

35
Q

what is a BRCA1 mutation characterized by?

A

a lower penetrance in men and there is phenotypic variability

36
Q

when males are affected by breast cancer, which gene do we assume is involved?

A

BRCA2

37
Q

what percentage of total breast cancer does familiar breast cancer make up?

A

only 5-10%

38
Q

what pathways are high penetrance genes associated with?

A

genes important for the mismatch repair pathway

39
Q

what is Lynch syndrome?

A

a hereditary nonpolyposis colon cancer of HNPCC

40
Q

what do we need to keep in mind when considering the symptoms involved and diagnosing breast cancer?

A

this might be a typical condition related also to the Lynch syndrome, and so in this case, HBOC is not the “primary” disease but it is associated to another disease → there is genetic overlapping

41
Q

what pathways are moderate penetrance genes associated with?

A

Fanconi anemia

42
Q

what pathways are low penetrance genes associated with?

A

Bloom syndrome (ex)

43
Q

what is locus heterogeneity?

A

different genes associated with different disorders

44
Q

what is allelic heterogeneity?

A

the number of mutations associated with a particular phenotype

45
Q

what are the specific criteria for genetic testing for HBOC for the identification of the causative mutation according to the ACMG?

A
  1. if we have two first degree relatives with BC less than or 50 yo (early onset)
  2. 3 first or second degree relatives affected by BC regardless of age
  3. 1 relative affected by BC and 1 affected by OC (heterogeneity of the phenotype)
  4. 1 case of bilateral BC regardless of age (bilateral BC is associated with mutations on both BRCA1 and BRCA2)
  5. 2 first or second degree relatives affected by OC regardless of age
  6. 1 case associated with BC and OC synchronous or metachronous (no family history needed)
  7. 1 case of male BC
  8. 1 case of female BC diagnosed at less than 30 years of age
46
Q

when does the ACMG suggest genetic testing be performed?

A

in all cases where there is a clear family involvement, with genetic basis, and in case in which we have heterogeneity in the affected organs

47
Q

what ethnic group is 10x greater to have a deleterious mutation in the BRCA1 and 2?

A

Ashkenazi Jews

48
Q

what is a genetic software the is used during genetic counseling in order to calculate the risk (probability) that an individual carries a causative genetic mutation on BRCA1 or 2?

A

BRACAPRO

49
Q

what parameters are considered in BRACAPRO?

A

environmental factors, lifestyle, and family history

50
Q

what is the result obtained by BRACAPRO used as?

A

NOT diagnostic - an indication for the laboratory and the “risk” that the patient carries the mutation

51
Q

what score obtained by BRACAPRO is considered “high risk”?

A

scores of >30%

52
Q

in what situation is defining the sequencing of nucleotides not the appropriate approach?

A

if we are interested in the detection of indels

53
Q

what is the first level of genetic testing for HBOC?

A

sequencing the panel of genes that are associated with the phenotype via NGS - generally focused on the 2 main genes in which we have a high percentage of positive cases (BRCA1 and 2)

54
Q

what happens if the first level of sequencing comes up negative?

A

we cant exclude that we don’t have alterations in those genes, so it is important to consider even if there are deletions on those genes

55
Q

in the case that the first level of sequencing comes up negative, what second approach do we use?

A

MLPA (multiplex ligand probe amplification)

56
Q

what is multiplex ligand probe amplification?

A

a quantitative technique for the detection deletions or duplications on these two genes

57
Q

what happens if the second level of sequencing comes up negative as well?

A

we look for single nucleotide mutations on the other genes contained in the panel of genes associated to the breast and ovarian cancer

58
Q

STUDY CLINICAL EXAMPLES

A

pg 8-9 of sbobine

59
Q

what is Hirschsprung disease (HSCR)?

A

a congenital absence of ganglia in some or all of the large intestine or colon - causes a lack of peristaltic action producing a grossly distended megacolon

60
Q

what class of disease does HSCR fall into?

A

classical oligogenic human disease (opposite condition to classical mendelian disorders)

61
Q

who is most often affected by the megacolon in HSCR?

A

newborns → disease could be lethal but there are surgical procedures to fix this

62
Q

what gene is associated with HSCR?

A

RET gene is associated with the disorder and its aetiogenesis

63
Q

what do the RET genes encode for?

A

tyrosine kinase receptors

64
Q

what does a loss of function mutation in the RET gene cause?

A

predisposition to Hirschprung disease

65
Q

what does a gain of function mutation in the RET gene cause?

A

associated to multiple endocrine neoplasia

66
Q

what does it mean that about 50% of patients with isolated HSCR have a RET mutation as well as some unaffected relatives?

A

we don’t have a causality, but a predisposition - we also have the weight of the other alleles and other loci that are associated to the predisposition together with the RET locus

67
Q

what other gene is associated with HSCR?

A

another susceptibility gene that encodes for the EDNRB (endothelin receptor B) → may suggest autosomal recessive inheritance

68
Q

if there is two different kinds of inheritance possible, what can this lead to?

A

in this case it could suggest the potential for an additive effect of mutation (NOT causative), so the sun of different alteration on those genes

69
Q

what is a syndromic condition?

A

means that we have a syndrome in which we have different phenotypes and then also the megacolon

70
Q

how many different loci have been described and associated with HSCR?

A

5 - but none of these loci are sufficient to have the phenotype

71
Q

is it useful to perform genetic testing for HSCR?

A

no → we don’t have any criteria in which the genetic testing may have a clinical utility - we may perform it for research purposes in order to identify a new molecular basis for the disorder, but not in the clinical setting

diagnosis of genetic diseases (18 decks)

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