Genetics 2.20-27

Question 1

What is genetic privacy?

Answer 1

The right of others e.g. employers not to know about your DNA

Question 2

Is aneuploidy hereditary?

Answer 2

No; one-off occurrence (ie de novo)

Question 3

Lifetime risk of breast cancer and ovarian cancer with BRCA-1?

Answer 3

80% and 40-60%

Question 4

Other genes assoc. with breast cancer?

Answer 4

TP53, CHEK2, polygenic

Question 5

Risks with BRCA-2?

Answer 5

Higher male risk of breast and prostate cancer, high female risk of triple-neg, pancreatic etc.

Question 6

Indications for genetic testing in breast cancer?

Answer 6

One close relative with breast cancer before 40 or bilateral, male relative with breast cancer, 2+ close relatives with breast cancer/ovarian cancer/ Ashkenazi.

Question 7

If have personal breast cancer history, what % chance of BRCA do you need for referral?

Answer 7

> 10% (use risk calculator e.g. IBIS) (of combined BRCA-1/2). Or if no personal history but risk >10% and affected relative unavailable for testing

Question 8

De novo VUS?

Answer 8

More likely to be pathogenic

Question 9

Rare conditions causing increased breast cancer risk?

Answer 9

Peutz-Jegher, Cowden, familial diffuse gastric cancer

Question 10

Low (near population), moderate and high breast cancer risk?

Answer 10

Low <17%; mod 17-29%; high >30% (includes all BRCA1/2, TP53 etc.)

Question 11

Surveillance for women with personal AND family history? (who remain at high risk)

Answer 11

50-69 = annual mammogram (must not have TP53)
30-49 = annual MRI
TP53 = MRI from 20!

Question 12

Annual mammogram surveillance for women with only family history?

Answer 12

40-49 for moderate risk; 40-59 for high risk

with <30% chance of BRCA/TP53, 40-69 if high risk (ie known BRCA1/2), 40-59 if >30% chance of BRCA.

Question 13

Annual MRI surveillance for women with only family history?

Answer 13

20-49 with known TP53 or >30% chance for TP53; 30-49 with known BRCA-1/2 or >30% chance of BRCA1/2.

Question 14

Oncogenes example in gut?

Answer 14

Normal = active only in embryo (onco) and inactive (proto) as adult; Hirschprung’s = inactivating mutation in embryo; MEN2 = activating mutation as adult. [RET]

Question 15

Mutator pathway and genes associated?

Answer 15

Germline defect in MMR system (mismatch repair); here = MLH1 (mismatch repair gene) mutation leads to MSI (microsatellite instability) and genomic instability (intragenic repeats) Allows other SPECIFIC mutations to be acquired (with mutator target)

Question 16

What is microsatellite instability?

Answer 16

Condition of genetic hypermutability due to impaired MMR; presence of MSI is phenotypical evidence of MMR defect. E.g. inability to copy repeated sequences; get frameshift etc.

Question 17

Suppressor pathway and genes associated?

Answer 17

FAP; Starts with APC; cascade of mutations in other cell cycle control genes without mutator targets. Non-specific.

Question 18

FAP??

Answer 18

Suppressor pathway. 1000s of adenomas; 95% penetrant by 35.

Question 19

FAP variations?

Answer 19

Gardner’s syndrome (FAP plus osteomas), Turcot syndrome (FAP + brain tumours)

Question 20

Diagnosing Lynch syndrome?

Answer 20

Amsterdam +ve (3,2,1); do histology; if high MSI (ie unstable) and BRAF v600E negative, Lynch is likely. If not, sporadic likely.

Question 21

How to find which MMR gene in Lynch?

Answer 21

Do amsterdam, MSI, BRAF then immunohistochemistry (MLH1, MSH2, MSH6, PMS2)

Question 22

Surveillance of Lynch?

Answer 22

2 yearly colonoscopy

Question 23

Lynch prophylaxis?

Answer 23

Long term low dose aspirin; surgical rarely indicated (ie colectomy)

Question 24

Rare bowel cancer predisposition syndromes?

Answer 24

Peutz-Jeghers, Cowden’s.

Question 25

How can ‘dominant’ disease present in probant with no FHx?

Answer 25

Could be de novo, mild expressivity/incomplete penetrance, mosaicism/non-paternity/imprinting, or not genetic!

Question 26

What are triple repeat disorders?

Answer 26

No. of copies of repeated trinucleotide; above certain threshold gives disease; often get anticipation between generations. Can be AD (Huntington’s, myotonic dystrophy) or AR (Fragile X, Friedrich’s ataxia).

Question 27

What is genetic heterogeneity and example?

Answer 27

Means that many genes can be implicated in same phenotype; need to do gene PANEL to test all of them. E.g. LQTS (1/5 have no identifiable mutation, but cause is still genetic).

Question 28

What do NF1 and TS (tuberous sclerosis) have in common?

Answer 28

High penetrance, significant variation in expression, and high rate of de novo mutations!!!

Question 29

Features of trisomy 13? (Patau)

Answer 29

Cleft lip/palate, VSD, polycystic kidneys, intellectual disability, dextrocardia, microcephaly, polydactyly.

Question 30

Balanced c’some changes?

Answer 30

No loss/gain of genetic material; just rearranged e.g. translocation, inversion. Problem arises during replication as get excess/deficiency.

Question 31

Unbalanced c’some changes?

Answer 31

Additional/missing information; can be deletions, rings, insertions or isochromosomes.

Question 32

When does balanced cause problems?

Answer 32

If breakage occurs in a gene, or the fusion produces a chimeric gene product that is damaging to the cell e.g. brc-abl. Brc-abl is somatic; others may occur in gametogenesis therefore are germline.

Question 33

What is an isochromosome?

Answer 33

Unbalanced structural abnormality; arms are mirror images of each other. Means, for a homologous pair, get partial trisomy and partial monosomy (simultanous duplication and deletion). Can manifest as Turner syndrome (15% cases) or neoplasia if TS genes are lost

Question 34

Balanced translocations and miscarriage?

Answer 34

Balanced reciprocal translocations can pair both normal/both translocated in segregation and be fine OR one of each; get loss/excess and prone to abortion/spontaneous miscarriage. Can be traumatic for families carrying translocations.

Question 35

QFPCR?

Answer 35

Rapid screen for aneuploidy (21, 13, 18, X/Y); if abnormal, do karyotype (G banding) to confirm!

Question 36

Balanced Robertsonian translocation?

Answer 36

Where two acrocentric c’somes lose short arms and fuse; may get 45 or 46 c’somes depending if short arms are kept. Individual usually unaffected but progeny may inherit trisomy (21) if get normal 21 and der(14,21).

Question 37

What is CMA/CGH?

Answer 37

Chromsomal microarray; looks at whole genome for copy number variants (CNVs); uses FISH techniques; intensity of test colour used to show deletions/duplications (red:green ratio). Much more resolution than karyotype. Good for Prader-Willi/Angelmann, del22q11.

Question 38

CGH/CMA for balanced translocations?

Answer 38

Does not work as only detects copy number variants.

Question 39

Advantage of FISH vs G banding?

Answer 39

FISH can detect submicroscopic deletions.

Question 40

How does c’somal microdeletion occur?

Answer 40

Misaligment and subsequent cross over at matching repetitive sequences leads to loss of BP in the middle.

Question 41

What is PGD/PIGD?

Answer 41

Preimplantation genetic diagnosis (test embryos, remove affected, insert others IVF-style)

Question 42

Skewed X inactivation?

Answer 42

If female embryo has one mutated X c’some, lyonisation can randomly give mostly unaffected (true carrier), or mild/mod/severe phenotype depending on inactivation. Skewed towards mutation can occur if this confers selection advantage to cell.

Question 43

Skewed X inactivation significance?

Answer 43

Fixed for X-linked diseases; means male phenotype always worse but for some diseases e.g. Rett syndrome, >80% of X skewed towards mutation so girls have severe phenotype. Essentially “dominance”.

Question 44

Three options with X linked disease, ‘unaffected’ mother and affected son?

Answer 44

1. De novo mutation
2. Non-manifesting heterozygote ie true carrier (more skewed towards normal)
3. Mother is manifesting heterozygote (skewed towards mutant) but not clinically detected b/c F phenotype more mild.

Question 45

What is (maternal) imprinting?

Answer 45

During oogenesis, paternally derived allele is methylated (maternal already methylated) to give eggs with two methylated (inactive) alleles. Sperm has two active alleles. = epigenetic modification that affects germline! Means may only manifest disease if inherit from particular parent; still carry it if from other.

Question 46

Somatic imprinting!?

Answer 46

Occurs in CRC; random hypermethylation of MLH1 promoter inactivates MLH1 and get mutator phenotype (high MSI) mimicking Lynch but with BRAF v600E present ie sporadic.