Genetics Flashcards
What do Class 4 & 5 gene variants mean?
Class 4: likely pathogenic variant
Class 5: pathogenic variant
Implications on testing: relatives eligible for gene testing
What does Class 3 gene variant mean?
Class 3: variant of uncertain signifcance
Not associated with pathogenic variant/benign variant
Implications on testing: relatives not eligible for gene testing
What cancers is BRCA1 associated with?
Breast Ca - 72%
Ovarian Ca - 44%
Prostate Ca - 8.6%
Pancreatic Ca - uncertain, may be increased
What cancers is BRCA2 associated with?
Breast Ca - 69%
Ovarian Ca - 17%
Prostate Ca - 15%
Pancreatic Ca - <5%
What cancers is PALB2 associated with?
Breast Ca - 33-55%
Ovarian Ca - 5%
Prostate Ca - NO INCREASE
Pancreatic Ca - 3%
What cancers is TP53 associated with?
Breast Ca - 85%
Ovarian Ca - 5%
What cancers is Lynch Syndrome associated with?
Colorectal Ca 30-40%
Endometrial Ca - 33%
Ovarian 9%
What cancers is FAP associated with?
Colorectal Ca - >95%
What pattern of inheritance are most hereditary cancers associated with?
Autosomal dominant
E.g.
BRCA1/2, p53, PALB2, PTEN, CDH1
Lynch Syndrome - MMR
FAP - APC
Peutz Jegher Syndrome - STK11
Rate of spontaneous mutations in FAP, TP53, BRCA1/2?
FAP - 15-20% denovo
TP53 - 15% denovo
BRCA1/2 - very rare
With de novo mutations: siblings are not at increased risk, offspring risk remains at 50%
What features are suggestive of familial cancer syndrome?
≥2 relatives with same type of cancer on same side
Multiple generations affected
Earlier onset than typically seen
Individuals with multiple primary cancers
Occurrence of cancers in one family known to be linked
ER negative breast cancers more likely associated with BRCA1/2 & PALB2; true or false?
TRUE
CDH1 is associated with increased risk of ILC & DCIS; true or false?
FALSE
Only increased risk of ILC (invasive lobular carcinoma)
No increased risk of DCIS
What are 6 histological features that can predict dMMR (i.e. Lynch Syndrome)?
Sensitivity 98%, Specificity 48%
1) Mucinous histology
2) Absence of intraglandular neutrophil-rich necrosis
3) Poor differentiation
4) Lymphocytic infiltrate
5) Expanding growth pattern
6) Right sided
MAPLE-R
Somatic BRAF V600E mutation associated with MLH1 methylation is less likely to be associated with Lynch CRC - true or false?
TRUE, seen in only <1% of Lynch - more likely to be somatic mutation
DNA repair deficient tumours have increased sensitivity to platinum salts - true or false?
True (e.g. BRCA1/2)
dMMR CRC have reduced sensitivity to 5-FU chemotherapy - true or false?
True
What is underlying mechanism behind Huntington Disease?
CAG trinucleotide repeats
- Encode glutamine in exon 1
> Normal ≤26 repeats
Intermediate: 27-35 repeats, no HD but unstable
HD causing:
36-39 repeats (reduced penetrance)
≥40 repeats (full penetrance)
≥60 repeats (juvenile)
- Toxic gain of function mutation
What is risk factor for anticipation in Huntington Disease?
Paternal transmission (instability of CAG repeat during spermatogenesis)
Spinocerebellar ataxia - mode of inheritance?
Autosomal dominant
> 40 types
- Repeat expansion SCAs
- Non-repeat expansion SCAs
Features of spinocerebellar ataxia
Age of onset: 30-40
Progressive ataxia
Unsteady gait usually first symptoms
Coordination difficulties
Oculomotor abnormalities
Myotonic dystrophy - mode of inheritance?
Autosomal dominant
High penetrance (nearly 100% by 50)
What is the underlying mechanism behind myotonic dystrophy?
Expansion of CTG trinucleotide repeats in DMPK gene
- Repeats 38-49: no symptoms, but unstable
- Repeats 50-150: mild disease
- Repeats 50-1000: classical
- Repeats >800: childhood onset
- Repeats >1000: congenital
What is risk factor for anticipation in myotonic dystrophy?
Maternal transmission (c.f. paternal with HD)
What is the underlying mechanism in dystrophinopathies?
Pathogenic variants in DMD gene - encodes dystrophin
X-linked disorder
E.g. Duchenne (DMD), Becker (BMD)
What is underlying mechanism in Marfan syndrome?
Defect with fibrillin-1 gene, FBN1 pathogenic variants
Marfan syndrome - mode of inheritance?
Autosomal dominant
Clinical features of Noonan syndrome
RASopathy
Short stature
Congenital heart disease (pulmonary valve stenosis most common)
Variable developmental delay
Coagulation defects
Lymphatic dysplasia
Cryptorchidism
Neoplasms
Noonan syndrome - mode of inheritance?
Autosomal dominant
What is underlying mechanism in Noonan syndrome?
RASopathy
Most common: PTPN11
Tuberous sclerosis - mode of inheritance?
Autosomal dominant
What is underlying mechanism in tuberous sclerosis?
Pathogenic variants in TSC1 (hamartin) or TSC2 (tuberin) genes
Freiderich’s ataxia - mode of inheritance?
Autosomal recessive
Small interfering RNAs - effect?
dsRNA molecules, causes mRNA to be broken down after transcription rather than translated
Micro RNAs - effect?
dsRNA that are involved in RNA interference and inhibition of gene expression, causing targeted degradation/translation, regulate gene expression at post transcriptional level
Haemophilia - mode of inheritance?
X-linked
Males»_space;> females
Familial cardiomyopathies - mode of inheritance (majority)?
Autosomal dominant
Variable/age-related penetrance
What is MHY7 gene involved in?
Dilated cardiomyopathy + hypertrophic cardiomyopathy
Majority of mutations involved in long QT syndrome are what kind?
> 70% missense mutations
Main cardiac subunit affected in HCM
Sarcomere
Most prevalent genes: MYBPC3, MYH7
Septum thickness for diagnosis of HCM
≥15mm
≥13mm in relative
What genes involved in dilated cardiomyopathy?
50% idiopathic
Titin gene mutations (TTN)
- Up to 20%
- Heart specific isoforms N2B, N2BA
LMNA gene
- Up to 5%
- Also see cardiac conduction abnormalities with this group
- High penetrnace
Long QT syndrome
- What kind of mutation involved in cardiac potassium channels?
- What kind of mutation involved in cardiac sodium channels?
- Mutations in >10 LQTS related genes
> Loss of function mutations in genes involved in cardiac potassium channels (e.g. LQT1 (KCNQ1) and LQT2 (KCHN2)
> Gain of function mutations in genes involved in cardiac sodium channels (e.g. LQT3 (SCN5A))
Long QT syndrome:
- Which subtype most affected by physical activity/emotional stress?
- Which subtype most affected during rest/sleep?
> Physical activity/emotional stress/diving in water head first: LQT1 > LQT2 > LQT3
Rest and sleep: LQT3 > LQT2 > LQT1
What is most common gene involved in catecholaminergic polymorphic VT (CPVT)?
(1) RYR2 gene
- Gain of function mutation
- Involved in calcium channel
- AD inheritance
(2) CASQ2 gene - rare
- AR inheritance
Inheritance of Brugada syndrome and what kind of mutation involved?
AD inheritance
SCN5A loss of function mutation
(remember same gene involved in LQTS but it is gain of function mutation in SCN5A)
