Genetics

Question 1

What do Class 4 & 5 gene variants mean?

Answer 1

Class 4: likely pathogenic variant
Class 5: pathogenic variant
Implications on testing: relatives eligible for gene testing

Question 2

What does Class 3 gene variant mean?

Answer 2

Class 3: variant of uncertain signifcance
Not associated with pathogenic variant/benign variant
Implications on testing: relatives not eligible for gene testing

Question 3

What cancers is BRCA1 associated with?

Answer 3

Breast Ca - 72%
Ovarian Ca - 44%
Prostate Ca - 8.6%
Pancreatic Ca - uncertain, may be increased

Question 4

What cancers is BRCA2 associated with?

Answer 4

Breast Ca - 69%
Ovarian Ca - 17%
Prostate Ca - 15%
Pancreatic Ca - <5%

Question 5

What cancers is PALB2 associated with?

Answer 5

Breast Ca - 33-55%
Ovarian Ca - 5%
Prostate Ca - NO INCREASE
Pancreatic Ca - 3%

Question 6

What cancers is TP53 associated with?

Answer 6

Breast Ca - 85%
Ovarian Ca - 5%

Question 7

What cancers is Lynch Syndrome associated with?

Answer 7

Colorectal Ca 30-40%
Endometrial Ca - 33%
Ovarian 9%

Question 8

What cancers is FAP associated with?

Answer 8

Colorectal Ca - >95%

Question 9

What pattern of inheritance are most hereditary cancers associated with?

Answer 9

Autosomal dominant

E.g.
BRCA1/2, p53, PALB2, PTEN, CDH1
Lynch Syndrome - MMR
FAP - APC
Peutz Jegher Syndrome - STK11

Question 10

Rate of spontaneous mutations in FAP, TP53, BRCA1/2?

Answer 10

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%

Question 11

What features are suggestive of familial cancer syndrome?

Answer 11

≥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

Question 12

ER negative breast cancers more likely associated with BRCA1/2 & PALB2; true or false?

Answer 12

TRUE

Question 13

CDH1 is associated with increased risk of ILC & DCIS; true or false?

Answer 13

FALSE
Only increased risk of ILC (invasive lobular carcinoma)
No increased risk of DCIS

Question 14

What are 6 histological features that can predict dMMR (i.e. Lynch Syndrome)?

Answer 14

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

Question 15

Somatic BRAF V600E mutation associated with MLH1 methylation is less likely to be associated with Lynch CRC - true or false?

Answer 15

TRUE, seen in only <1% of Lynch - more likely to be somatic mutation

Question 16

DNA repair deficient tumours have increased sensitivity to platinum salts - true or false?

Answer 16

True (e.g. BRCA1/2)

Question 17

dMMR CRC have reduced sensitivity to 5-FU chemotherapy - true or false?

Answer 17

True

Question 18

What is underlying mechanism behind Huntington Disease?

Answer 18

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

Question 19

What is risk factor for anticipation in Huntington Disease?

Answer 19

Paternal transmission (instability of CAG repeat during spermatogenesis)

Question 20

Spinocerebellar ataxia - mode of inheritance?

Answer 20

Autosomal dominant

> 40 types
- Repeat expansion SCAs
- Non-repeat expansion SCAs

Question 21

Features of spinocerebellar ataxia

Answer 21

Age of onset: 30-40

Progressive ataxia
Unsteady gait usually first symptoms
Coordination difficulties
Oculomotor abnormalities

Question 22

Myotonic dystrophy - mode of inheritance?

Answer 22

Autosomal dominant
High penetrance (nearly 100% by 50)

Question 23

What is the underlying mechanism behind myotonic dystrophy?

Answer 23

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

Question 24

What is risk factor for anticipation in myotonic dystrophy?

Answer 24

Maternal transmission (c.f. paternal with HD)

Question 25

What is the underlying mechanism in dystrophinopathies?

Answer 25

Pathogenic variants in DMD gene - encodes dystrophin

X-linked disorder

E.g. Duchenne (DMD), Becker (BMD)

Question 26

What is underlying mechanism in Marfan syndrome?

Answer 26

Defect with fibrillin-1 gene, FBN1 pathogenic variants

Question 27

Marfan syndrome - mode of inheritance?

Answer 27

Autosomal dominant

Question 28

Clinical features of Noonan syndrome

Answer 28

RASopathy

Short stature
Congenital heart disease (pulmonary valve stenosis most common)
Variable developmental delay
Coagulation defects
Lymphatic dysplasia
Cryptorchidism
Neoplasms

Question 29

Noonan syndrome - mode of inheritance?

Answer 29

Autosomal dominant

Question 30

What is underlying mechanism in Noonan syndrome?

Answer 30

RASopathy

Most common: PTPN11

Question 31

Tuberous sclerosis - mode of inheritance?

Answer 31

Autosomal dominant

Question 32

What is underlying mechanism in tuberous sclerosis?

Answer 32

Pathogenic variants in TSC1 (hamartin) or TSC2 (tuberin) genes

Question 33

Freiderich’s ataxia - mode of inheritance?

Answer 33

Autosomal recessive

Question 34

Small interfering RNAs - effect?

Answer 34

dsRNA molecules, causes mRNA to be broken down after transcription rather than translated

Question 35

Micro RNAs - effect?

Answer 35

dsRNA that are involved in RNA interference and inhibition of gene expression, causing targeted degradation/translation, regulate gene expression at post transcriptional level

Question 36

Haemophilia - mode of inheritance?

Answer 36

X-linked
Males&raquo_space;> females

Question 37

Familial cardiomyopathies - mode of inheritance (majority)?

Answer 37

Autosomal dominant
Variable/age-related penetrance

Question 38

What is MHY7 gene involved in?

Answer 38

Dilated cardiomyopathy + hypertrophic cardiomyopathy

Question 39

Majority of mutations involved in long QT syndrome are what kind?

Answer 39

> 70% missense mutations

Question 40

Main cardiac subunit affected in HCM

Answer 40

Sarcomere

Most prevalent genes: MYBPC3, MYH7

Question 41

Septum thickness for diagnosis of HCM

Answer 41

≥15mm
≥13mm in relative

Question 42

What genes involved in dilated cardiomyopathy?

Answer 42

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

Question 43

Long QT syndrome
- What kind of mutation involved in cardiac potassium channels?
- What kind of mutation involved in cardiac sodium channels?

Answer 43

• 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))

Question 44

Long QT syndrome:
- Which subtype most affected by physical activity/emotional stress?
- Which subtype most affected during rest/sleep?

Answer 44

> Physical activity/emotional stress/diving in water head first: LQT1 > LQT2 > LQT3
Rest and sleep: LQT3 > LQT2 > LQT1

Question 45

What is most common gene involved in catecholaminergic polymorphic VT (CPVT)?

Answer 45

(1) RYR2 gene
- Gain of function mutation
- Involved in calcium channel
- AD inheritance

(2) CASQ2 gene - rare
- AR inheritance

Question 46

Inheritance of Brugada syndrome and what kind of mutation involved?

Answer 46

AD inheritance

SCN5A loss of function mutation
(remember same gene involved in LQTS but it is gain of function mutation in SCN5A)