Genetics 2

Question 1

De novo mutations common in what inheritance mode?

Answer 1

X-linked Recessive and Autosomal Dominant!

Question 2

Consanguinity increases risk of what inheritance?

Answer 2

Autosomal recessive

Question 3

Autosomal recessive Incidence formula?

Autosomal recessive carrier formula?

Answer 3

(Carrier frequency)2 x 4

Square root of (incidence / 4)

Question 4

X-linked Dominant has what prominent feature?

Answer 4

All/Almost all females affected!

Male - fatal for men (male = hemizygous)

Question 5

Imprinting is epigenetic phenomenon - what it means?

Pathogenesis of imprinting

Answer 5

No DNA changes - just modification of the gene function
via

• *Methylation and histone modification**
• methylate CPG islands
• Histone wrapped tightly around DNA - less transcription

Question 6

imprinting occurs - what is expressed?

Answer 6

Monoallelic expression

Question 7

Angelman and Prader-Willi syndrome - where does the imprinting occurs? what region?

Answer 7

Chromosome 15q12

Question 8

3 possible mechanisms imprinting occurs?

Answer 8

Uniparental disomy
Microdeletion of one gene that is important
Imprinting defect - silence the gene that is important

Question 9

Mitochondrial mutation affects what type of cell?

Answer 9

High energy dependent cells! - brain/heart/liver/endocrine

Question 10

Neurofibromatosis-1 diagnostic criteria?

CAFE-SPOT

Answer 10

C-afe-au-lait  = 6 or more
A-xillary/inguinal freckling
F-ibromas-neuro = 2 or more
E-ye - Lisch nodules = 2 or more
S-keletal osseous lesion ( long bone)
P-ositive family history/pedigree
O-ptic Tumor glioma = Carboplatin as tx

Question 11

Neurofibromatosis-2 Treatment?

Answer 11

Surgery +

Bevacizumab - shrinks vestibular swannomas

Question 12

Tuberous sclerosis - which gene more common in family inheritance?
De novo/single person affected?

tuberous sclerosis - more common is family or denovo?

Answer 12

Family - TSC1 - Hamartin

Single - TSC2 - Tuberin

De-Novo accounts for majority of TS

Question 13

Tuberous sclerosis commonly have what complications?

Answer 13

CNS - seizures/ intellectual disability/Tumor- subependymal glial nodules or tubers!

2nd common - renal angiomyolipomata

Question 14

LAM in Tuberous sclerosis?

Answer 14

Bad prognosis

Question 15

In Tuberous Sclerosis

• Sirolimus helps in what?
• Everolimus helps in what?
• Rapamycin helps in what?

Answer 15

Sirolimus = reduce Renal (angiomyolipomata) and Lungs lesion (LAM)

Everolimus - reduce Ependymal astrocytomas size and reduce seizures

Rapamycin - improve the Rupa awak ( your face - facial angiofibromas)

Question 16

premutations mean?

Answer 16

Repeat size is unstable but not having expression (phenotype) of disease

Question 17

Commonest form of inherited intellectual disability?

Key features of this syndrome?

Answer 17

Fragile X

Key features

1. Large ears, long face, large testis
2. Intellectual disability
3. Behavioural problems
4. Mitral valve prolapse!

Question 18

Dystrophin gene found in what organ?

Answer 18

Muscle
Brain
Heart

Question 19

Classical features of DMD syndrome?

Answer 19

Proximal muscle weakness = Gower sign
Calf pseudo-hypertrophy ( fat replaces muscle)
Waddling sign

Question 20

What is strongly found in Down syndrome?

Answer 20

Alzheimers - 1st
Congenital heart disease - 2nd
-VSD! ( ASD = primum ostium)

Hypothyroidism - 3rd

Question 21

Fragile X gene mutation?

Huntington gene mutation?

Fredreich Ataxia gene mutation?

Answer 21

Fragile X - CGG on FMR1

Huntington - CAG on Exon 1 on Huntington gene

Fredreich Ataxia - GAA on Intron 1

Question 22

Tumor suppressor gene function?

How it causes problem?

Eg. of tumor suppressor gene?

Answer 22

Cell cycle check points - detect damage and repair

Loss of function - 2 HITS - both alleles have loss of function

Everything else - inherited, familial cancer

Question 23

Oncogene function?

How it causes problem?

Eg. of oncogene?

Answer 23

Regulate cell growth

Gain of function - gene mutated/over-expressed

RET gene - the only oncogene

Question 24

Most common gene involved with SOMATIC mutation?

Answer 24

TP53

Question 25

Brazilian population commonly has what as part of Li Fraumeni syndrome?

Answer 25

Adrenal carcinoma at young age

Li fraumeni - TP53 MISSENSE mutation

Question 26

Cowden syndrome mutation?

Associated cancers?

Key features?

Answer 26

PTEN

Breast and Follicular thyroid cancer

Large head circumference
Lhermitte-duclos ( mature neuron benign tumors - ganglio-cytoma)
tricho-Lemminomas ( slow growing papules on skin)

Question 27

How to differentiate FAP ( APC gene) from MutYH polyposis?

Answer 27

MutYH doesn’t have Desmoid tumors
Less polyps ~ 1000
Autosomal recessive!

Question 28

MutYH protein does what?

Answer 28

repairs oxidative DNA damage - need 2 hit to form disease

Question 29

Peutz-jegher syndrome mutation?

Clinical features?

Answer 29

STK11 ( Peutz like to sing at karaoke!)

Benign hamartomatous polyposis - becomes intussusception or volvulus = GI cancer

Lip pigmented macules

Question 30

Lynch syndrome diagnostic criteria?

Answer 30

3-2-1 Hate FAP rule!
3 - family members affected - histologically confirmed
2- successive generation
1 - 1 is diagnosed < 50 yrs old

FAP excluded!

Question 31

What gene mutation implicated in paraganglioma and phaechromocytoma?

Answer 31

SDHB gene - makes succinate dehydrogenase enzyme to convert energy from food into one that body can use