Inheritable Diseases Flashcards
how to investigate a congenital dysfunction?
detailed history of family, pregnancy, examination
find out possible cause.
is it de novo, or syndromic, is it familial or sporadic?
when to use karyotyping vs chromosome microarray
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
what is the challenge with whole exome sequencing?
finding out which variants are significant in causing phenotype
what are the rules of inheritance in X linked diseases?
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
how can women be affected by X linked diseases?
thru random X inactivation
what are the steps in invesigating familial diseases
make the right clinical diagnosis draw the pedigree choose the right genetic test do molecular genetic diagnosis if necessary do cascade genetic test
how many % of x linked diseases happen de novo and how many are inherited?
1/3 are de novo
2/3 are from carrier mothers
(if from father, will know)
if a male child is affected, what are the chances that his grandmother was a carrier?
2/3 chance his mother was carrier
2/3 chance her mother was carrier, therefore 4/9 chance grandma was carrier
if a mother carries an X linked recessive gene has a daughter, what are the chances that the daughter will also be a carrier?
1/2, because the father will pass on healthy copy
what does imprinting mean?
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
what do oncogenes generally do?
promote cellular proliferation
when are oncogenes usually switched on and off?
usually on during embryogenesis and off by adulthood.
what happens if the RET oncogene is switched off in fetal stage?
Hirschsprungs disease
what is the APC gene associated with?
FAP
what is the RB1 gene associated with
retinoblastoma
what gene is associated with breast and/or ovarian cancer?
brca1 and brca2
what gene is li fraumeni syndrome associated with?
TP53
what are the two common pathways of colorectal carcinogenesis?
mutator pathway or suppresor pathways
what disease is associated with mutator pathway route of CRC and what disease is associated with the suppresor pathway of CRC?
mutator: Lynch syndrome
suppresor: FAP
describe classical FAP
thousands of adenomas in the colon
how does lynch syndrome compare with FAP?
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
describe MSI in LSd and how it causes disease
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
how to differentiate sporadic CRC from lynch Sd?
amsterdam 3 2 1 criteria
presence of BRAF mutation
and IHC proteins
what is the amsterdam 321 criteria?
3 colorectal tumours in the family
2 generations across
1 diagnosed <50 y/o
why is aspirin given to someone with lynch Sd?
shown to reduce polyp growth
what gene is li fraumeni syndrome associated with
p53
what is a tumour suppresor gene, how many mutations required for disease?
suppresses proliferation, 2 mutations required
what is an oncogene, how many mutations required for disease?
promotes cell proliferation, usually switched off in adulthood. 1 mutation required
what does P53 do?
induce apoptosis
list the 10 hallmarks of cancer
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
what cancer is the philadelphia translocation associated with?
chronic myeloid leukaemia
what is the difference between germ line mutations and somatic mutations
germ line mutations are present in embryogenesis and are inheritable
somatic mutations occur later in life and are implicated in sporadic cancers
what cancers is alcohol associated with
liver
gut
breast
ovary
how does alcohol cause cancer?
prolonged exposure to acetyldehyde causing oxidative stress
difference between metaplasia and dysplasia
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
what are some causes of carcinogenesis?
chemical, physical (radiation), biological (virus/bacteria/parasites), drugs/hormones, nutrition, lifestyle, genetic factors
most common cause of human cancer?
chemicals e.g. smoking
what cancers is smoking associated with? other than lung
oropharynx, osephagus, pancreas, bladder, renal, AML
ovarian and skin cancer are associated with smoking, T or F?
False
how does ionising radiation cause cancer?
causes damage to cellular structures and DNA by displacing electrions and creating ion pairs
what tissue are more prone to ionising radiation?
breast, bone marrow, thyroid
what kind of radiation is UV light?
non-ionising
most common cause of non-ionising radiation cancers?
sun exposure
chronic inflammation has no role in cancers, T or F
F - it plays a central role in biologically caused cancers
what are some viruses that are associated with cancer?
HHV 6 7 and 8 HSV CMV EBV HBV HCV HPV
what cancer are HIV patients more prone to getting?
HHV 8 - kaposi’s sarcoma
what cancer conditions is EBV associated with
hodgkins or burkitts lymphoma
example of bacteria associated with cancer
helicobacter pylori
what is the likelihood of autosomal dominant inheritance in offspring
1/2
eg of triple repeat disorders
huntington’s disease, myotonic dystrophys, fragile x
5 ways to diagnose an autosomal dominant disorder
1) clinically
2) specific gene test
3) gene panel test
4) predictive genetic testing
5) from family history/pedigree
when is a gene panel test used?
when a phenotype exhibits genetic heterogeniety, i.e. many different genes can cause the same phenotype
when is predictive genetic testing done?
in a healthy individual who is identified to have a high risk of having a genetic mutation
what does penetrance mean
in people with the genetic mutation how many % will develop the phenotype
what does anticipation mean?
when a genetic mutation is known to get worse with each passing generation, e.g triple repeat d/o like HD
what does variable expressivity entail
means the same gene mutation can manifest in different ways in different people
if someone has a genetic condition unseen in his family, what are 7 possible explanations for it?
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
what is a triple repeat disorder?
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
why is there a spectrum of expression in some triple repeat disorders?
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
why do some people not have huntinton’s disease but their offspring do
they could have too few repeats to exhibit the disease, but due to anticipation, their children end up with a pathogenic number of repeats
what occurs at genetic counselling?
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
what is an example of an inherited cardiac condition
long QT syndrome
what clinical criteria is used to diagnose Marfan’s syndrome?
Ghent criteria
what are the downfalls of genetic testing of multifactorial inherited diseases
unknown significance of positive or negative result
results interpreted on specific population sample (e.g. white)
what cancers are associated with BRCA1 genes?
breast, ovary, pancreas, prostate, colon cancer, stomach cancer, melanoma
what is the screening program for breast cancer in uk for the general population?
women 50-70 every 3 year mammogram
what family history would put a woman at increased risk of breast cancer?
- 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”
what is the manchester score?
score used to determine if someone should go for genetic testing for brca
in someone with breast cancer, what would qualify them immediately for BRCA testing?
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)
what would give you a higher manchester score in female Breast cancer an older or younger age of diagnosis?
younger
how would you qualify for genetic testing if you dont have breast cancer?
have relatives who have had breast cancer, and yourself have a manchester score of >17
which gene mutation has a higher risk of breast cancer for women, BRCA1 or BRCA 2?
BRCA1
which gene mutation has a higher risk of prostate cancer for men, BRCA1 or BRCA 2?
BRCA2
which gene mutation has a higher risk of ovarian cancer for women, BRCA1 or BRCA 2?
BRCA1
other than normal NHS breast cancer screening program, what other programs can inviduals with BRCA mutations be on?
annual mammography from 40-70
or annual MRI from 30-50
neonatal features of downs syndrome
brachycephaly epicanthic folds low set ears flat nasal bridge protruding tongue loose skin on nape of neck single palmar crease
associated conditions of down’s syndrome
congenital heart defects reduced immunity i.e. prone to infections lymphoproliferative disease hearing loss eye disease sleep apnea
median survival age of Patau’s syndrome
2.5 days
symptoms/signs of patau’s syndrome
craniofacial abnormalities e.g. cleft lip, palate, microcephaly,
NTDs, learning disabilities
median age of edwards syndrome patients
14 days
risk factors for trisomies?
rising maternal age
family history
kidney and thyroid cancers are associated with the BRCA gene, T or F?
F
example of a familial inherited cancer caused by an oncogene?
BCR-ABL (CML)
HER2/NEU
function of TP53 in health?
suppresses cell proliferation, checks for damage to DNA and induces apoptosis if found
how many copies of APC gene has to be mutated to cause disease?
2
function of APC gene in health?
cell-cell contact inhibition
frequency of cell division
ensuring chromosomal integrity
pathphysiology of lynch syndrome AKA HNPCC
mutation in dna mismatch repair gene causing microsatellite instablities
features of HNPCC
early onset colon cancer (before 50)
more common in right colon
associated cancers of HNPCC other than colorectal cancer
stomach, small intestine
bladder, skin, brain
HPB
endometrial ovarian
when to suspect lynch syndrome?
amsterdam criteria
3 family members with colorectal cancer
2 generations across
1 before age of 50
how does attenuated FAP differ from normal FAP
fewer adenomas
presents later in life
describe clinical course of FAP
adenoma usually in teenage years
colorectal cancer before 40 years old.
almost 100% penetrance
which gene is more associated with triple negative breast cancer?
BRCA1
which gene is associated with a higher chance of breast cancer in males
brca2
how does BRCA mutation lead to cancer?
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
which familial cancer syndrome is associated with adrenocortical tumours, sarcomas and osteosarcomas ?
p53 - li fraumeni syndrome
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?
li fraumeni - P53
what does genetic heterogeniety imply?
different genes, cause same phenotype
examples of conditions that show genetic heterogeneity
cystic fibrosis, alzheimers diease, autistic spectrum disorder, inherited breast cancer syndromes
what is the pattern of inheritance for long QT syndrome?
autosomal dominant
what gene is often mutated in marfan’s syndrome?
FBN1
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
NF1 - ?neurofibromatosis 1
what is the only viable monosomy in humans?
45X - Turner’s
how does Turner’s syndrome present?
female. delayed puberty, primary amenorrhea, short stature, dysmorphic features, infertility, ovarian failure
what kind of dysmorphic features can be present in turner’s syndrome?
epicanthic eye folds, low set ears, posterioly rotated micrognathia webbed neck short fingers broad chest, widely spaced nipples
what associated complications and conditions can be found with turner’s syndrome
congenital cardiac abnormalities diabetes infertility obesity bone problems (osteoporosis) renal malformations hearing loss hypertension
how/what to investigate turners syndrome?
chromosomal analysis LH and FSH TFTs HBa1C renal function tests bone tests
how does klinefelter’s syndrome present?
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
classifical features of klinefelters syndrome
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
how to investigate/diagnose klinefelters syndrome
amniocentesis or CVS antenatally
high FSH LH, low/normal testosterone
diagnose thru chromsomal analysis
what syndrome should be considered in a 26 year old male presenting with hypogonadism, infertility, low libido and decreased facial hair
klinefelters.
associated disease with klinefelters
endocrine - DM, hypothyroidism osteoporosis autoimmune diseases germ cell tumours male breast cancer
what drug used in pregnancy is associated with
neural tube defects, cardiac defeects, orofacial clefts, autism spectrum disorders, cognitive impairments, motor delay
sodium valproate
which drug has a higher associated with teratogenicity - valproate or carbamazepine
valproate
which anti epileptic drugs are least associated with teratogenicity
levetiricatem and lamotrigine
is phenytoin safe to use in pregnancy?
no
tetracyclines are safe to use in pregnancy - T or F
F
ACEi are safe to use in pregnancy - T or F
F
other than genetic causes, what can cause congenital malformations?
during pregnancy, maternal illness (infections, or autoimmune), medicine use, recreational drug (cocaine), alcohol, ionising radiation
what can chromosomal microarray do?
detect copy number variation in genome
what is the routine testing method in suspected chromosomal abnormalities
microarray testing
how does microarray testing work?
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
what other testing methods could be done if microarray testing cannot find an abnormality?
whole genome sequencing, FISH, g band karyptyping, SNP testing, PCR
what is the issue with doing whole genome sequencing?
cannot tell what is a significant variation, cannot detect balanced chromosomal rearrangement
which method of testing can find balanced chromosomal rearrangement?
karyotyping, FISH
what signs do trisomies 13 and 18 have that 21 don’t?
cleft palate, cleft lip, polydactyly, neural tube defects
which trisomy is associated with choroid plexus cyst?
trisomy 18
signs and symptoms of triple X syndrome
often undiagnosed
taller than average female epicanthal fold curve in 5th/4th finger microcephaly lower IQ psychiatric problems
