Genetics OSFA

Question 1

Repeat size categories for Huntington Disease?

Repeat and gene?

Answer 1

Normal: 6-26 stable, no phenotype
Intermediate: 27-35, may be unstable, no phenotype
Incomplete penetrance: 36-39, unstable
Full mutation: 40+, unstable, affected

CAG in exon 1 of HTT gene - translated into polyGln tract

Question 2

Repeat size categories for Myotonic Dystrophy?

Repeat and gene?

Answer 2

Normal: 5-34, stable, no phenotype
Premutation: 35-49, may be unstable, no phenotype
Mild/carrier: 50-100, unstable, no or mild phenotype
Adult: 100-700, unstable, classical adult onset
Congenital: 700-4000, unstable, Congenital or juvenile onset

CTG in 3’UTR of DMPK

Question 3

Repeat size categories for Fragile X?

Repeat and gene?

Answer 3

Normal: - 45, stable, no phenotype
Intermediate: 46-58, unstable, no phenotype
Premutation: 59-200, unmethylated, unstable, risk of FXTAS (mostly makes) and females: FXPOI, offspring with FRX
Full: 200, methylated, unstable, FRX in males and 50% of females, males only have premutation in sperm

CGG in 5’UTR of FMR1 gene

Question 4

Common t(8;21) translocation seen in AML

Answer 4

t(8;21) RUNX1-RUNX1T1 fusion (RQ-PCR), usually younger patients, >70% show additional abnormalities (-X, - Y, del9q), good prognosis, 20-25% show KIT mutations

Question 5

Common inv(16) translocation seen in AML

Answer 5

inv(16) incl. centromer, CBFB-MYH11 fusion (RQ-PCR), consider FISH (subtle), additional abnormalities include +22, usually only with inv(16), good prognosis, 30% have KIT mutations

Question 6

Common t(15;17) translocation seen in AML

Answer 6

t(15;17), PML-RARA fusion (RQ-PCR), APML, risk of blood clotting, very urgent, good prognosis due to ATRA, additional abnormalities in 40%, +8,

Question 7

Common t(9;11) translocation seen in AML

Answer 7

t(9;11), MLLT3-KMT2A, break-apart FISH probe, many fusion partners for KMT2A, intermediate prognosis in adult and paediatric (in adult depends on KMT2A partner)

Question 8

Common inv(3) translocation seen in AML

Answer 8

inv(3), RPN1-EVI1break-apart FISH probe, EVI1 breakage involved in many 3q abnormalities, poor prognosis for any EVI1 rearrangement

Question 9

Common t(12;21) translocation seen in AML

Answer 9

t(12;21) ETV6-RUNX1, RUNX1 FISH probe detects t(12;21), iAMP21 and hyperdiploidy,

Question 10

Favourable prognosis karyotype in ALL

Answer 10

High hyperdiploidy

t(12;21) ETV6-RUNX1

Question 11

Intermediate prognosis karyotype in ALL (examples)

Answer 11

Normal karyotype

t(1;19) TCF3-PBX1

Question 12

Poor prognosis karyotype in ALL (examples)

Answer 12

Low hypodiploidy
Near haploidy
t(9;22) BCR-ABL1 fusion
KMT2A rearrangements esp. t(4;11) fusion
iAMP21
t(17;19) TCF3 break-apart 
IGH rearrangements

Question 13

Presentation samples of ?ALL - what do you do?

Answer 13

Direct culture (ALL cells apoptose)
FISH:
BRC-ABL1 (poor prognosis)
KMT2A (chromosome 11 - esp. t(4;11) poor prognosis)
ETV6-RUNX1 (t(12;21), good prognosis - also detects iAMP (poor prognosis) and hyperdiploidy (good prognosis))

G-banding

Question 14

Presentation samples of ?AML - what do you do?

Answer 14

G-banding - consider FISH if unsure of inv(16) (+22 or immunology type (M2/M4) may indicate inv(16))

If ?APML then direct FISH for PML-RARA (t(15;17))

RNA for gene fusion monitoring (base-line), (RUNX1-RUNX1T1, CBFB-MYH11, PML-RARA)
RNA for FLT3 and NPM1 mutations

DNA for myeloid panel and AID13 studies depending on FLT3-itd ratio (>0.25)

DNA: If CBF (RUNX1-RUNX1T1 and CBFB-MYH11) then test for KIT mutations.