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Diagnosis of Genetic Diseases > Lecture 8 > Flashcards

Lecture 8 Flashcards

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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
where is BRCA2 localized?
chromosome 13
26
what percentage of early onset breast cancer is associated with BRCA1 and BRCA2?
40-85%
27
what percentage of contralateral breast cancer is associated with BRCA1 and BRCA2 mutations?
40-60%
28
what percentage of ovarian cancer is related to BRCA1 and BRCA2 mutations?
40%
29
in males, what have BRCA1 and BRCA2 mutations been linked to?
elevated risk of breast cancer and potentially na elevated risk for prostate and pancreatic cancer as well
30
how many exons does BRCA1 contain?
24
31
how many exons does BRCA2 contain?
23
32
what are BRCA1 and BRCA2?
tumor suppressor genes
33
what are the main mutations described with BRCA1 and BRCA2?
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
what is allelic heterogeneity?
different mutation on genes that are associated with the same phenotype
35
what is a BRCA1 mutation characterized by?
a lower penetrance in men and there is phenotypic variability
36
when males are affected by breast cancer, which gene do we assume is involved?
BRCA2
37
what percentage of total breast cancer does familiar breast cancer make up?
only 5-10%
38
what pathways are high penetrance genes associated with?
genes important for the mismatch repair pathway
39
what is Lynch syndrome?
a hereditary nonpolyposis colon cancer of HNPCC
40
what do we need to keep in mind when considering the symptoms involved and diagnosing breast cancer?
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
what pathways are moderate penetrance genes associated with?
Fanconi anemia
42
what pathways are low penetrance genes associated with?
Bloom syndrome (ex)
43
what is locus heterogeneity?
different genes associated with different disorders
44
what is allelic heterogeneity?
the number of mutations associated with a particular phenotype
45
what are the specific criteria for genetic testing for HBOC for the identification of the causative mutation according to the ACMG?
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
when does the ACMG suggest genetic testing be performed?
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
what ethnic group is 10x greater to have a deleterious mutation in the BRCA1 and 2?
Ashkenazi Jews
48
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?
BRACAPRO
49
what parameters are considered in BRACAPRO?
environmental factors, lifestyle, and family history
50
what is the result obtained by BRACAPRO used as?
NOT diagnostic - an indication for the laboratory and the "risk" that the patient carries the mutation
51
what score obtained by BRACAPRO is considered "high risk"?
scores of >30%
52
in what situation is defining the sequencing of nucleotides not the appropriate approach?
if we are interested in the detection of indels
53
what is the first level of genetic testing for HBOC?
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
what happens if the first level of sequencing comes up negative?
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
in the case that the first level of sequencing comes up negative, what second approach do we use?
MLPA (multiplex ligand probe amplification)
56
what is multiplex ligand probe amplification?
a quantitative technique for the detection deletions or duplications on these two genes
57
what happens if the second level of sequencing comes up negative as well?
we look for single nucleotide mutations on the other genes contained in the panel of genes associated to the breast and ovarian cancer
58
STUDY CLINICAL EXAMPLES
pg 8-9 of sbobine
59
what is Hirschsprung disease (HSCR)?
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
what class of disease does HSCR fall into?
classical oligogenic human disease (opposite condition to classical mendelian disorders)
61
who is most often affected by the megacolon in HSCR?
newborns → disease could be lethal but there are surgical procedures to fix this
62
what gene is associated with HSCR?
RET gene is associated with the disorder and its aetiogenesis
63
what do the RET genes encode for?
tyrosine kinase receptors
64
what does a loss of function mutation in the RET gene cause?
predisposition to Hirschprung disease
65
what does a gain of function mutation in the RET gene cause?
associated to multiple endocrine neoplasia
66
what does it mean that about 50% of patients with isolated HSCR have a RET mutation as well as some unaffected relatives?
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
what other gene is associated with HSCR?
another susceptibility gene that encodes for the EDNRB (endothelin receptor B) → may suggest autosomal recessive inheritance
68
if there is two different kinds of inheritance possible, what can this lead to?
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
what is a syndromic condition?
means that we have a syndrome in which we have different phenotypes and then also the megacolon
70
how many different loci have been described and associated with HSCR?
5 - but none of these loci are sufficient to have the phenotype
71
is it useful to perform genetic testing for HSCR?
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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