Inherited Disease

Question 1

Pathological variants of which genes are associated with breast cancer

Answer 1

BRCA1
BRCA2
TP 53 (rare)
All tumour suppressor genes

Question 2

oncogene

Answer 2

Mutated derivative of proto-oncogene

‘Gain of function mutation’-dominant manner at cell level

Question 3

A female with a BRCA 1 or BRCA 2 mutation is a higher risk of which cancers?

Answer 3

Breast & Ovarian

Question 4

Which BRCA mutation gives the highest risk of Breast Cancer for females?

Answer 4

BRCA1

Question 5

Males with which BRCA mutation are at increased risk of prostate cancer?

Answer 5

BRCA2

Question 6

BRCA 1 2 mutations are associated with increased risk of which cancers?

Answer 6

Breast, Ovarian, Pancreatic, Prostate

Question 7

Clinical indication of Breast cancer; you should be referred for further assessment if you have: (6 criteria)

Answer 7

• 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”

Question 8

Transcription

Answer 8

DNA copied to mRNA by RNA polymerase

Question 9

Translation

Answer 9

process in which ribosomes in the cytoplasm or ER synthesize proteins

Question 10

Codon

Answer 10

triplet nucleotides, 64 of these encode 20 amino acids (3 exceptions)

Question 11

Polymorphism

Answer 11

Change in triplet code results in same amino acid production
UAU to UAC = Tyr
(conservative)

Question 12

Mutation

Answer 12

Change in triplet code results in different amino acid production
UAU to UAG = STOP
(truncating)

UAU to UUC = Phe
(non-conservative substitution)

Question 13

Expressivity

Answer 13

Degree to which a phenotype is expressed in individuals with the same geneotype

Question 14

MEN2

Answer 14

Autosomal dominant 
Medullary Thyroid carcinoma
Phaeochromocytoma
RET gene mutation
MEN2A represents 90%

Question 15

MEN2

Answer 15

Autosomal dominant

Question 16

MEN2 mutation

Answer 16

example of mutation in oncogene (gain of function)

Medullary Thyroid carcinoma, Phaeochromocytoma (benign)

Question 17

Familial cancers involving tumour suppressor genes

Answer 17

Retinoblastoma- RB1
Li-Fraumeni syndrome (brain tumours, sarcomas, leukemia)-TP53
Familial adenomatous polyposis-APC

Breast and/or ovarian cancer-BRCA1/2

Question 18

Colon Cancer Mutator pathway

Answer 18

Lynch Syndrome- MSH2, MLH1
<100 adenomas
High colorectal cancer risk
High endometrial cancer risk

Question 19

Colon Cancer Suppressor pathway

Answer 19

FAP- APC gene
Classical-1000s of colonic adenomas
95% penetrant by 35
Malignancy risk ~100%

Question 20

Gardeners Syndrome

Answer 20

FAP plus
Osteomas
Soft tissue tumours:
 Sebaceous cysts
 Fibromas
 Desmoid tumours

Question 21

Germline Mutation

Answer 21

Affects all cells and can be passed on-responsible for hereditary cancers

Question 22

Somatic mutation

Answer 22

acquired genetic changes- only affects cells where mutation occurs and their direct offspring Responsible for sporadic cancer development

Question 23

Amsterdam Criteria

Answer 23

identifies families in which Lynch syndrome is likely

3 colorectal tumours
2 generations
1 diagnosed <50

Question 24

Lynch syndrome management

Answer 24

Surveillance
Chemoprophylaxis-Aspirin
Surgical prophylaxis
Family cascade management

Question 25

CHARGE Syndrome

Answer 25

Coloboma of the eye
Heart defects
Atresia of choanae
Retardation of Growth and Development
Genital and Urinary Tract abnormalities
Ear abnormalities and hearing loss

Question 26

Fetal Valporate Syndrome facial features

Answer 26

Tall forehead 
medial eyebrow deficiency
flat nasal bridge
broad nasal root
Shallow philtrum
Long upper lip
thin vermillion border

Question 27

Aneuploidy

Answer 27

An abnormal number of chromsomes

Question 28

Viable autosomal trisomies (3)

Answer 28

21(Down Syndrome)
13 (Patau syndrome)
18 (Edward syndrome)

Question 29

Only viable monosomy

Answer 29

45,X Turners syndrome

Question 30

Balanced Rearrangement

Answer 30

No loss or gain of genetic material
Reciprocal translocation, Inversion, Insertion
Requires karyotype to detect

Question 31

Unbalanced

Answer 31

Deletion
Duplication
Will be detected by microarray

Question 32

Presentation of Turners Syndrome

Answer 32

45, X – 98% conceptions end in miscarriage
75% loss of X or Y in paternal meiosis
Presents at all ages
Prenatal ↑NT or generalised oedema, hypoplastic aortic arch
Neonates neck webbing puffy hands and feet
Children short stature
Adolescents pubertal arrest, amenorrhoea

Question 33

Fluorescent In situ Hybridisation (FISH)

Answer 33

White cell culture as for G banded karyotype analysis
Metaphase spread
Uses DNA probes carrying a fluorescent label which hybridise specifically to a known chromosome region
Used to detects submicroscopic deletions
Used to detect chromosome rearrangements of relatively large DNA sequences
Requires prior knowledge of chromosome location of variant of interest
in this you glue down the chromosome and the probe is added which binds

Question 34

How is X gene expression controlled

Answer 34

XIST functional RNA expression ‘turns off’ that X chromosome and results in variation in phenotype of carriers with X linked conditions- Skewed X inactivation

Question 35

What if the XIST RNA region is methylated?

Answer 35

The XIST RNA is not expressed and that X is active

Question 36

Lyonisation

Answer 36

The activation or inactivation of X via the XIST RNA

Question 37

Paraganglioma

Answer 37

Imprinted inherited from paternal allele via dominant pattern SDHD

Question 38

Unmethylated alleles (germline)

Answer 38

Are active and expressed when inherited-imprinting

Question 39

Methylated alleles (germline)

Answer 39

Are hidden and not expressed even though person can be a carrier of a dominant condition because during oogenesis/spermatogenesis methylation and demethylation occur to match with maternally/paternally derived allele type-imprinting

Question 40

Somatic imprinting

Answer 40

Random hypermethylation of the genes
Eg Colon Cancer;of the promoter of MLH1 (inactivates it)results in mutator pathway tumour phenotype, looks like Lynch syndrome but tumours acquire the BRAF V600E driver
mutation

Question 41

Karyotype

Answer 41

Displays all of persons chromosomes and can identify the number, sex type, deletions, duplication, translocation, inversion and derivatives

Question 42

Array Comparative Genomic Hybridisation (aCGH)

Answer 42

Microarray-looking at copy number variants- doesn’t require prior knowledge of chromosomal location of variants

Glue down the probe and add in DNA(labelled with dye)
Uses competitive hybridisation between control (red) and test DNA (Green)- Yellow indicates equal amounts of both, red means there is deletion in the test, and green means there are duplication’s

Question 43

DNA sequencing

Answer 43

Single base changes to whole genome

Question 44

Downs Syndrome

Answer 44

Flat facial profile
epicanthal fold
CHD
duodenal atresia
Brushfield spots on iris
Single palmar crease
Sandal Gap
Cognitive impairment

Question 45

Penetrance

Answer 45

in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (the genotype) that also express an associated trait (the phenotype)