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4 CSIM2 > Inheritable Diseases > Flashcards

Inheritable Diseases Flashcards

1
Q

how to investigate a congenital dysfunction?

A

detailed history of family, pregnancy, examination
find out possible cause.
is it de novo, or syndromic, is it familial or sporadic?

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2
Q

when to use karyotyping vs chromosome microarray

A

usually do CMA first then if abnormality found, do karyotyping. CMA is faster, but doesn’t tell you about balanced translocations. karyotyping takes 14 days

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3
Q

what is the challenge with whole exome sequencing?

A

finding out which variants are significant in causing phenotype

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4
Q

what are the rules of inheritance in X linked diseases?

A

affected males cannot pass it to their sons

carrier moms have 1/4 chance of passing it onto their children

all affected males will pass it onto their daughters

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5
Q

how can women be affected by X linked diseases?

A

thru random X inactivation

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6
Q

what are the steps in invesigating familial diseases

A 
make the right clinical diagnosis
draw the pedigree
choose the right genetic test
do molecular genetic diagnosis
if necessary do cascade genetic test
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7
Q

how many % of x linked diseases happen de novo and how many are inherited?

A

1/3 are de novo
2/3 are from carrier mothers

(if from father, will know)

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8
Q

if a male child is affected, what are the chances that his grandmother was a carrier?

A

2/3 chance his mother was carrier

2/3 chance her mother was carrier, therefore 4/9 chance grandma was carrier

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9
Q

if a mother carries an X linked recessive gene has a daughter, what are the chances that the daughter will also be a carrier?

A

1/2, because the father will pass on healthy copy

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10
Q

what does imprinting mean?

A

means that depending on maternal or paternal derived copy, the gene can be silenced or unsilenced, thus masking the true status of the gene. even if it was faulty

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11
Q

what do oncogenes generally do?

A

promote cellular proliferation

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12
Q

when are oncogenes usually switched on and off?

A

usually on during embryogenesis and off by adulthood.

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13
Q

what happens if the RET oncogene is switched off in fetal stage?

A

Hirschsprungs disease

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14
Q

what is the APC gene associated with?

A

FAP

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15
Q

what is the RB1 gene associated with

A

retinoblastoma

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16
Q

what gene is associated with breast and/or ovarian cancer?

A

brca1 and brca2

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17
Q

what gene is li fraumeni syndrome associated with?

A

TP53

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18
Q

what are the two common pathways of colorectal carcinogenesis?

A

mutator pathway or suppresor pathways

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19
Q

what disease is associated with mutator pathway route of CRC and what disease is associated with the suppresor pathway of CRC?

A

mutator: Lynch syndrome
suppresor: FAP

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20
Q

describe classical FAP

A

thousands of adenomas in the colon

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21
Q

how does lynch syndrome compare with FAP?

A

LSd onset is usually younger, fewer adenomas, malignancy can appear anywhere in the body, commonly colon and endometrium

FAP has more polyps usually in colonc

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22
Q

describe MSI in LSd and how it causes disease

A

micro satellite instabilities

due to mutations in gene responsible for replication/correcting errors in copying repetitive genes.

this leads to frameshift errors in translation and production of novel peptides, triggering immune response

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23
Q

how to differentiate sporadic CRC from lynch Sd?

A

amsterdam 3 2 1 criteria
presence of BRAF mutation
and IHC proteins

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24
Q

what is the amsterdam 321 criteria?

A

3 colorectal tumours in the family
2 generations across
1 diagnosed <50 y/o

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25
Q

why is aspirin given to someone with lynch Sd?

A

shown to reduce polyp growth

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26
Q

what gene is li fraumeni syndrome associated with

A

p53

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27
Q

what is a tumour suppresor gene, how many mutations required for disease?

A

suppresses proliferation, 2 mutations required

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28
Q

what is an oncogene, how many mutations required for disease?

A

promotes cell proliferation, usually switched off in adulthood. 1 mutation required

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29
Q

what does P53 do?

A

induce apoptosis

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30
Q

list the 10 hallmarks of cancer

A 
self sufficiency in growth signal
insensitivity to anti-growth signals
evading apoptosis
limitless replicative potential
sustained angiogenesis
tissue invasion/metastasis
deregulated metabolism
evading immune system
genome instability
inflammation
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31
Q

what cancer is the philadelphia translocation associated with?

A

chronic myeloid leukaemia

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32
Q

what is the difference between germ line mutations and somatic mutations

A

germ line mutations are present in embryogenesis and are inheritable

somatic mutations occur later in life and are implicated in sporadic cancers

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33
Q

what cancers is alcohol associated with

A

liver
gut
breast
ovary

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34
Q

how does alcohol cause cancer?

A

prolonged exposure to acetyldehyde causing oxidative stress

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35
Q

difference between metaplasia and dysplasia

A

metaplasia is the replacement of one type of cell by another fully specialised cell type

dysplasia is the derangement of cell growth including failure of cells to mature, usually considered pre-cancerous

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36
Q

what are some causes of carcinogenesis?

A

chemical, physical (radiation), biological (virus/bacteria/parasites), drugs/hormones, nutrition, lifestyle, genetic factors

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37
Q

most common cause of human cancer?

A

chemicals e.g. smoking

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38
Q

what cancers is smoking associated with? other than lung

A

oropharynx, osephagus, pancreas, bladder, renal, AML

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39
Q

ovarian and skin cancer are associated with smoking, T or F?

A

False

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40
Q

how does ionising radiation cause cancer?

A

causes damage to cellular structures and DNA by displacing electrions and creating ion pairs

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41
Q

what tissue are more prone to ionising radiation?

A

breast, bone marrow, thyroid

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42
Q

what kind of radiation is UV light?

A

non-ionising

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43
Q

most common cause of non-ionising radiation cancers?

A

sun exposure

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44
Q

chronic inflammation has no role in cancers, T or F

A

F - it plays a central role in biologically caused cancers

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45
Q

what are some viruses that are associated with cancer?

A 
HHV 6 7 and 8
HSV
CMV
EBV
HBV HCV
HPV
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46
Q

what cancer are HIV patients more prone to getting?

A

HHV 8 - kaposi’s sarcoma

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47
Q

what cancer conditions is EBV associated with

A

hodgkins or burkitts lymphoma

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48
Q

example of bacteria associated with cancer

A

helicobacter pylori

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49
Q

what is the likelihood of autosomal dominant inheritance in offspring

A

1/2

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50
Q

eg of triple repeat disorders

A

huntington’s disease, myotonic dystrophys, fragile x

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51
Q

5 ways to diagnose an autosomal dominant disorder

A

1) clinically
2) specific gene test
3) gene panel test
4) predictive genetic testing
5) from family history/pedigree

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52
Q

when is a gene panel test used?

A

when a phenotype exhibits genetic heterogeniety, i.e. many different genes can cause the same phenotype

53
Q

when is predictive genetic testing done?

A

in a healthy individual who is identified to have a high risk of having a genetic mutation

54
Q

what does penetrance mean

A

in people with the genetic mutation how many % will develop the phenotype

55
Q

what does anticipation mean?

A

when a genetic mutation is known to get worse with each passing generation, e.g triple repeat d/o like HD

56
Q

what does variable expressivity entail

A

means the same gene mutation can manifest in different ways in different people

57
Q

if someone has a genetic condition unseen in his family, what are 7 possible explanations for it?

A

1) de novo mutation
2) dominant condition with incomplete penetrance
3) variable expressivity
4) recessive condition
5) x-linked
6) non-genetic d/o
7) other causes e.g. imprinted d/o, mosaicism, non-paternity

58
Q

what is a triple repeat disorder?

A

some segments of genetic code consist of repeats of 3 specific bases corresponding to a specific AA.

disorders arise when there is an increase in number of repeats

59
Q

why is there a spectrum of expression in some triple repeat disorders?

A

e.g. HD, healthy people have <26 repeats, and people with >= 40 repeats have 100% penetrance of HD. thus those who have in between number of repeats have variability of expressing the disease

60
Q

why do some people not have huntinton’s disease but their offspring do

A

they could have too few repeats to exhibit the disease, but due to anticipation, their children end up with a pathogenic number of repeats

61
Q

what occurs at genetic counselling?

A

explain the disease, the inheritance, the risks
the meaning of the test results, different scenarios, implications and treatment options
timing of the test
who the results will be shared with
what it will mean for other family members

62
Q

what is an example of an inherited cardiac condition

A

long QT syndrome

63
Q

what clinical criteria is used to diagnose Marfan’s syndrome?

A

Ghent criteria

64
Q

what are the downfalls of genetic testing of multifactorial inherited diseases

A

unknown significance of positive or negative result

results interpreted on specific population sample (e.g. white)

65
Q

what cancers are associated with BRCA1 genes?

A

breast, ovary, pancreas, prostate, colon cancer, stomach cancer, melanoma

66
Q

what is the screening program for breast cancer in uk for the general population?

A

women 50-70 every 3 year mammogram

67
Q

what family history would put a woman at increased risk of breast cancer?

A
  • one close relative who has had breast cancer before the age of 40
  • two or more close relatives who have had breast cancer
  • close relatives who have had breast cancer and others who have had ovarian cancer
  • one close relative who has had breast cancer in both breasts (bilateral breast cancer)
  • a male relative who has had breast cancer
  • Ashkenazi Jewish ancestry”
68
Q

what is the manchester score?

A

score used to determine if someone should go for genetic testing for brca

69
Q

in someone with breast cancer, what would qualify them immediately for BRCA testing?

A

BC under 40 y/o
triple negative BC
bilateral BC both under 60 y/o
has ovarian cancer as well
has male BC
have relative with cancer AND manchester score >15
has a relative with BC diagnosed under 50 (patient also dx <50)

70
Q

what would give you a higher manchester score in female Breast cancer an older or younger age of diagnosis?

A

younger

71
Q

how would you qualify for genetic testing if you dont have breast cancer?

A

have relatives who have had breast cancer, and yourself have a manchester score of >17

72
Q

which gene mutation has a higher risk of breast cancer for women, BRCA1 or BRCA 2?

A

BRCA1

73
Q

which gene mutation has a higher risk of prostate cancer for men, BRCA1 or BRCA 2?

A

BRCA2

74
Q

which gene mutation has a higher risk of ovarian cancer for women, BRCA1 or BRCA 2?

A

BRCA1

75
Q

other than normal NHS breast cancer screening program, what other programs can inviduals with BRCA mutations be on?

A

annual mammography from 40-70

or annual MRI from 30-50

76
Q

neonatal features of downs syndrome

A 
brachycephaly
epicanthic folds
low set ears
flat nasal bridge
protruding tongue
loose skin on nape of neck
single palmar crease
77
Q

associated conditions of down’s syndrome

A 
congenital heart defects
reduced immunity i.e. prone to infections
lymphoproliferative disease
hearing loss
eye disease
sleep apnea
78
Q

median survival age of Patau’s syndrome

A

2.5 days

79
Q

symptoms/signs of patau’s syndrome

A

craniofacial abnormalities e.g. cleft lip, palate, microcephaly,

NTDs, learning disabilities

80
Q

median age of edwards syndrome patients

A

14 days

81
Q

risk factors for trisomies?

A

rising maternal age

family history

82
Q

kidney and thyroid cancers are associated with the BRCA gene, T or F?

A

F

83
Q

example of a familial inherited cancer caused by an oncogene?

A

BCR-ABL (CML)

HER2/NEU

84
Q

function of TP53 in health?

A

suppresses cell proliferation, checks for damage to DNA and induces apoptosis if found

85
Q

how many copies of APC gene has to be mutated to cause disease?

A

2

86
Q

function of APC gene in health?

A

cell-cell contact inhibition
frequency of cell division
ensuring chromosomal integrity

87
Q

pathphysiology of lynch syndrome AKA HNPCC

A

mutation in dna mismatch repair gene causing microsatellite instablities

88
Q

features of HNPCC

A

early onset colon cancer (before 50)

more common in right colon

89
Q

associated cancers of HNPCC other than colorectal cancer

A

stomach, small intestine
bladder, skin, brain
HPB
endometrial ovarian

90
Q

when to suspect lynch syndrome?

A

amsterdam criteria

3 family members with colorectal cancer
2 generations across
1 before age of 50

91
Q

how does attenuated FAP differ from normal FAP

A

fewer adenomas

presents later in life

92
Q

describe clinical course of FAP

A

adenoma usually in teenage years
colorectal cancer before 40 years old.

almost 100% penetrance

93
Q

which gene is more associated with triple negative breast cancer?

A

BRCA1

94
Q

which gene is associated with a higher chance of breast cancer in males

A

brca2

95
Q

how does BRCA mutation lead to cancer?

A

BRCA1 and 2 are involved in double stranded DNA repair. if the gene is not working, then DNA damages are more likely causing more mutations in other genes which increases the risk of accumulation of mutated genes which can lead to cancer

96
Q

which familial cancer syndrome is associated with adrenocortical tumours, sarcomas and osteosarcomas ?

A

p53 - li fraumeni syndrome

97
Q

a 22 year old female with a family history of leukaemia and sarcomas develops breast cancer before puberty, what familial cancer syndrome is this associated with?

A

li fraumeni - P53

98
Q

what does genetic heterogeniety imply?

A

different genes, cause same phenotype

99
Q

examples of conditions that show genetic heterogeneity

A

cystic fibrosis, alzheimers diease, autistic spectrum disorder, inherited breast cancer syndromes

100
Q

what is the pattern of inheritance for long QT syndrome?

A

autosomal dominant

101
Q

what gene is often mutated in marfan’s syndrome?

A

FBN1

102
Q

what gene should be tested in a 5 year presenting with

multiple ‘cafe au lait’ spots
history of arthritis
brown streaks on iris
and suspicion of learning disablity

A

NF1 - ?neurofibromatosis 1

103
Q

what is the only viable monosomy in humans?

A

45X - Turner’s

104
Q

how does Turner’s syndrome present?

A

female. delayed puberty, primary amenorrhea, short stature, dysmorphic features, infertility, ovarian failure

105
Q

what kind of dysmorphic features can be present in turner’s syndrome?

A 
epicanthic eye folds, 
low set ears, posterioly rotated
micrognathia
webbed neck
short fingers
broad chest, widely spaced nipples
106
Q

what associated complications and conditions can be found with turner’s syndrome

A 
congenital cardiac abnormalities
diabetes
infertility
obesity
bone problems (osteoporosis)
renal malformations
hearing loss
hypertension
107
Q

how/what to investigate turners syndrome?

A 
chromosomal analysis
LH and FSH
TFTs
HBa1C
renal function tests
bone tests
108
Q

how does klinefelter’s syndrome present?

A

male phenotype

speech or learning difficulties
unusually rapid growth in mid childhood, truncal obesity

adults may present with hypgonadism or subfertility, failure of sexual maturation

may have development or learning disabilities

109
Q

classifical features of klinefelters syndrome

A

infertility, small firm testes, decreased facial and pubic hair, loss of libido, impotence

tall slender long legs narrow shoulders and wide hips

gynacomastia, undescended testes

tiredness, reduced muscle power

110
Q

how to investigate/diagnose klinefelters syndrome

A

amniocentesis or CVS antenatally

high FSH LH, low/normal testosterone

diagnose thru chromsomal analysis

111
Q

what syndrome should be considered in a 26 year old male presenting with hypogonadism, infertility, low libido and decreased facial hair

A

klinefelters.

112
Q

associated disease with klinefelters

A 
endocrine - DM, hypothyroidism
osteoporosis
autoimmune diseases
germ cell tumours
male breast cancer
113
Q

what drug used in pregnancy is associated with

neural tube defects, cardiac defeects, orofacial clefts, autism spectrum disorders, cognitive impairments, motor delay

A

sodium valproate

114
Q

which drug has a higher associated with teratogenicity - valproate or carbamazepine

A

valproate

115
Q

which anti epileptic drugs are least associated with teratogenicity

A

levetiricatem and lamotrigine

116
Q

is phenytoin safe to use in pregnancy?

A

no

117
Q

tetracyclines are safe to use in pregnancy - T or F

A

F

118
Q

ACEi are safe to use in pregnancy - T or F

A

F

119
Q

other than genetic causes, what can cause congenital malformations?

A

during pregnancy, maternal illness (infections, or autoimmune), medicine use, recreational drug (cocaine), alcohol, ionising radiation

120
Q

what can chromosomal microarray do?

A

detect copy number variation in genome

121
Q

what is the routine testing method in suspected chromosomal abnormalities

A

microarray testing

122
Q

how does microarray testing work?

A

by hybridising labelled segments of DNA to tested DNA, and measuring the relative strength of each segment.

if missing copy number - detected strength lower, if added copy number - strength higher

123
Q

what other testing methods could be done if microarray testing cannot find an abnormality?

A

whole genome sequencing, FISH, g band karyptyping, SNP testing, PCR

124
Q

what is the issue with doing whole genome sequencing?

A

cannot tell what is a significant variation, cannot detect balanced chromosomal rearrangement

125
Q

which method of testing can find balanced chromosomal rearrangement?

A

karyotyping, FISH

126
Q

what signs do trisomies 13 and 18 have that 21 don’t?

A

cleft palate, cleft lip, polydactyly, neural tube defects

127
Q

which trisomy is associated with choroid plexus cyst?

A

trisomy 18

128
Q

signs and symptoms of triple X syndrome

A

often undiagnosed

taller than average female
epicanthal fold
curve in 5th/4th finger
microcephaly
lower IQ
psychiatric problems

4 CSIM2 (11 decks)

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