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RACP EXAM > Genetic > Flashcards

Genetic Flashcards

1
Q

What are telomers

A

Region of repetitive nucleotide sequence at the end of each chromosome which protects the chromosome from deterioration and fusion

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2
Q

Which are purines and which are pyrimidines
-Adenine
-Thymine
-Cytosine
-Guanine

A

-Purine: Adenine, Guanine
-Pyrimidine: Thymine, Cytosine

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3
Q

What are the purpose of these enzymes
-DNA polymerase
-Helices
-Ligase

A

-DNA polymerase: creases DNA molecules by assembling nucleotides
-Helicase: disrupts the DNA double bond to allow replication
-Ligase: DNA repair enzyme

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4
Q

How do you calculate carrier incidence and carrier frequency

A

Carrier Incidence: carrier frequency x carrier frequency x4

Carrier frequency: square root (carrier incidence/4)

“Incidence = frequency squared x 4

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5
Q

What is the difference between allelic and locus heterogeneity

A

-Allelic: more than one mutation in a gene (e.g. CF)
-Locus: mutations of more than one gene (e.g. TS)

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6
Q

What is the difference in these mutations
-missense
-silent point mutation
-nonsense mutation
-splicing mutation

A

-missense: point mutation results in codon change that causes a amino acid change e.g. sickle cell disease (A instead of T)
-Nonsense mutation: point mutation that results in a stop codon
-Silent mutation: codon change but same amino acid is still encoded for. Natural genetic variability
-Splicing mutation: failure to remove introns from transcripts DNA so intron DNA is left in the RNA molecule causing abnormal protein

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7
Q

Describe the concept of Anticipation

A

More triplet repeats occur in successive generations = increased severity of disease

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8
Q

What is penetrance

A

The presence/absence of a disease or trait. Must have both the phenotype and genotype

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9
Q

What is the difference between expressivity and penetrance

A

Penetrance= genotype + phenotype. Presence of disease both on person and in genome

Expressivity= variation in the clinical features of a mutation e.g. NF1

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10
Q

In consanguinity what is the risk of having a major problem
-Background risk
-Incest
-1st degree cousins
-2nd degree cousins

A

-3%
-50%
-6% (double)
-4%

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11
Q

Describe splice site mutation

A

Splicing- removal of non-coding introns
Mutation is splicing allows this non-coding material to be translated into the RNA. Results in mutation in end protein

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12
Q

Describe anticipation

A

Seen in triple repeat disorders. More aggressive and earlier disease in subsequent generations

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13
Q

What type of disorder is Myotonic muscular dystrophy
What is the genetic defect
What are the symptoms

A

Triplet repeat disorder
-CTG expansion mutation
-SX: facial hypotonia with V shaped lip, muscle weakness, heart condition issues, IQ/Behavioural issues

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14
Q

What type of mutation causes Fredrick ataxia
What is the gene
What age of onset
What are the symptoms

A

Triplet repeat mutation
FXN gene- GAA triplet repeat mutation = results in loss of function mutation
FXN gene encodes a mitochondrial protein that is used to chaperone iron. Mutation - iron accumulation and oxidative damage

Age onset: teenage years
Sx
-Brain: ataxia, peripheral neuropathy, loss of proprioception and vibration, loss deep tendon reflexs
-Muscle: weakness, kyphosis, foot deformity
-Heart: HOCM
-Endo: diabetes mellitus

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15
Q

What condition does a mutation in FMR1 gene cause

A

Fragile X
“Fragile Mother Related 1”

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16
Q

What does a mutation in FXN cause

A

Fredrick Ataxia
“Fredirick ataXiaN gene”

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17
Q

What study to do you use to check for Beckwith-Weidmann

A

Methylation specific multiple ligand probe analysis

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18
Q

What conditions will a microarray detect vs not

A

Detect: micro deletion, micro duplication, aneuploidy, unbalanced translocation, uniparental disomy if SNP analysis used, long stretches of homogeneity (SNP)

Won’t detect: balanced translocation, methylation abnormalities, triple repeat, single nucleotide

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19
Q

What test would be used for NF1 or Marfans

A

Sanger sequencing- will detect a mutation on a nucleotide level

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20
Q

What test is used for analysis of myotonic muscular dystrophy

A

triple repeat analysis - PCR reaction that is then analysed with southern blot to see the length of triplet repeats

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21
Q

What is the difference between western and southern blot

A

Western blot- protein analysis
Southern blot- DNA analysis

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22
Q

Describe the phases of mitosis

A

-interphase: DNA replicates. Go from 46 –> 92 chromatids
-prophase: formation of microtubules. nuclear envelop dissolves. Microspindles attache to each chromosome
-metaphase: chromosomes lined up along the equator (metaphase plate)
-anaphase: chromosomes pulled to separate ends of the cell by the microtubles
-Telophase: nuclear envelope reforms around opposite cluster of DNA
-Cytokinesis: remained of cell and cytoplasm divides to make 2 daughter cells

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23
Q

What is the gamete result if you have non-dysjunction in meiosis I vs meiosis II

A

Meiosis I: all the cell lines affected. 2 cells have N+1, 2 cells have N-1
Meiosis II: happens after the first division, so of the 4 cells produced, 2 won’t be affected. Of the remaining 2, 1 will gain (N+1) and one will loose (N-1)- therefore 4 gametes: 2 normal, 1 N+1, 1N-1

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24
Q

What is a Robertsonian chromosome and which are they

A

Contain an non central centromere. The DNA in the short arm (p arm) is redundant

Chromsomes 13, 14, 15, 21 and 22

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25
In a maternal carrier of a translocation between T14 and T21, what is the hypothetical risk of having an abnormal gamete vs the actual risk
In theory, you only have a 1/6 chance of normal, 1/6 chance balance translocation, 1/6 chance T21 and then a 1/6 chance of T14, 1/6 chance of -21, 1/6 chance of -14 In reality, zygotes except normal, balance and T21 are non-viable so you risk of recurrence is 1%
26
What abnormal results on Quad screening would you expect for the 3 trisomies (21, 18, 13) and Turners Syndrome
T21: "HIgh" High hCG and Inhibin A T18 "HE is low"- hCG and estriol T13: "AFPateau is low" - low AFP Turner: HIgh- high hCG and Inhibin A
27
What is the most consistent features of Turners syndrome and what is it due to
Short stature Loss of the SHOX gene on the short arm of the X chromosome
28
You see a baby with puffy hands and feet and consider the diagnosis of congenital lymphoedema. What condition should you screen for
Turners syndrome
29
Name features of Turner syndrome
-short stature -webbed neck, low posterior hairline -shield shaped chest, widely spaced nipples -wide carry angle with cubits valgus -amenrrhoea, delayed puberty -cardiac: bicuspid aortic valve, coarcation of aorta -renal: horse-shoe kidney, HTN -Autoimmune: coeliac, hashimotos, IBD
30
In Turners syndrome, when on growth hormone, what blood test is used to titrate effect
IGF-1
31
What is the condition called that is due to a deletion in 5p chromosome
Cri du chat- 'cry of the cat' -meow like cry at birth, slanted eyes, hypotonia, hypertelorism
32
What causes the condition Wolf-Hirschhorn syndrome -what gene -what symptoms
Deletion of the WHSC1 gene due to a macro deletion of chromosome 4p 'Greek warrior helmet face' with prominent forehead, wide flat nasal bridge, hypertelorism, microcephaly. Also get seizures and ID.
33
What mutation causes Achondroplasia
FGF3- fibroblast growth factor 3
34
What mutation causes Allagile syndrome and what are the features
JAG1 or NOTCH2 mutation - deletion Triangular face, pointed chin, deep set eyes Cardiac: peripheral pulmonary stenosis Skeleteal: butterfly vertebrae Liver: paucity of bile ducts --> cholestatic jaundice
35
What sx do you get in CHARGE syndrome and what is the mutation
Coloboma- Heart defect- Atresia (choanal), retardation of growth, genitourinary defect, ear abnormalities AND cranial nerve dysfunction, especially of the facial nerve Mutation: CHD7 "C-Harge disease"
36
You see a child with high arched eyebrows, long lashes, a monobrow, long philtrum and short upturned nose What is the disease and mutation
Cornelia de Lange Syndrome NIPBL gene mutation
37
What condition is due to a mutation in COL5A1 and COL5A2
EHLOS DANLOS- think "COL= COLLAGEN"
38
What are the features of Ehlos Danlos syndrome, what is the mutation and what is the scoring system
Mutation: COL5A1 or COLD5A2 SX: joint hypermobility, poor wound healing, hyper extensible skin, mitral valve prolapse, autonomic dysfunction, tendon rupture Scoring system- Beighton score X/9. >4 indicates joint hyper mobility. -thumb hyperextension =2 -5th finger 90 degree hyperextension =2 -hyper extension elbows =2 -hyper extension knees =2 -flexion of hips so palms are on the floor =1
39
What mutation causes Familial adenomatous polyposis What is the management
APC gene on chromosome 5 6-12 monthly colonoscopy until old enough for total colectomy
40
What mutation causes familial hypercholestrolaemia What are the symptoms What is the management
LDLR mutation - LDL receptor mutation SX: increased LDL, normal/low HDL, normal triglycerides -Tendon xanthomata -Corneal acrus -Xanthelmas -Premature CVD -Plantar xanthoma Management: Diet, statin Regular CAD screening and echo Ezetimbe if statin not effective
41
What is second line management after a statin in familiar hypercholesterolaemia and what is the MOA What mutation causes this condition
Ezetimibe Reduces fat absorption LDL-receptor mutation
42
What mutation causes Gilberts syndrome What are the symptoms What is the management What is the homozygous version of this condition called
Uronyltransferase enzyme mutation (UGT1A1) which conjugates bilirubin Sx; severe neonatal jaundice TX: Phototherapy and liver transplan Criggler-Najjar syndrome
43
What is the defect in Neurofibromatosis What is the diagnostic criteria
NF1 gene mutaiton SX: >2 of - Cafe au last spots >6 -Neurofibromas >2 or 1+ plexiform neurofibroma -Auxillary freckling -Lisch nodes 2+ -Osseous lesions- scapula and scoliosis -Optic glioma -Family history of NF1 in 1st degree relative
44
In an optic glioma affecting vision, what is the treatment
Carboplatin
45
What is the diagnostic criteria for NF2
Bilateral vestibular Schwannoma OR Family history AND -unilateral vestibular -brain tumour e/g. glioma, Schwannoma, meningioma
46
What mutation is present in Noonans syndrome What are the symptoms
PTPN1 is gene in 50% of cases Short stature Webbed neck Low posterior hairline Slanted eyes Cardiac: pulmonary valve stenosis Widely spaced nipples Coagulopathy
47
What conditions are caused by these defects -JAG1/NOTCH2 -COL5A1 -FRG3 -APC -CHD7 -PTPN1 -FBN1 -LDLR -COL1A1
-Allagiles -Ehlos Danlos -Achondroplasia -Familal adenomatous polyposis -CHARGe disease -Noonans -Marfans -Familial hypercholesterolaemia -Ostengenesis imperfect
48
A child has a mutation at COL1A1- what condition does it cause
Collagen Type 1 Result in osteogenesis imperfecta
49
What are the symptoms of type 1-4 osteogenesis imperfect
Type 1: 'classical' - blue sclera, variable fractures, normal stature, most get premature conductive hearing loss Type 2: lethal Type 3: severe OI- multiple neonatal and easy fractures, blues sclera, short stature, most don't walk Type 4: mild- normal sclera, variable fractures, normal adult height. Increased conductive hearing loss
50
What are the side effects of bisphosphonates given for OI
-Flu like illness -Hypocalcaemia -Jaw necrosis
51
What pathway is activated in Tuberous sclerosis What is a medication that blocks this pathway
mTOR pathway Sirolimus
52
What are major and minor criteria for tuberous sclerosis
Major Criteria: 1) Skin: a. Facial angiomas (Adenoma sebaceum) – butterfly/malar distribution or forehead plaques b. Ungal/periungal fibroma c. >3hypomalanotic macules d. Shagreen patch e. Multiple retinal nodular hamartomas 2) Brain a. Cortical tubers b. Subependymal nodule c. Subependymal giant cell astrocytoma 3) Other: a. Renal angiomyolipoma b. Cardiac rhabdomyoma c. Lymphangioleiomyomatosis (LAM) i. dilated lymphatic and interstital proliferation. Resultant obstruction and cystic lung disease. Presents with pneumothorax and dyspnoea. Minor Criteria: 1) Cutaneous: confetti skin lesions, dental enamel pits, oral fibromas 2) Brain: cerebral white matter migration lines 3) Other: non renal hamartomas, bony cysts, multiple renal cysts, hamartomatous rectal polpys
53
What is the mutation in Fanconi anaemia What are the symptoms
FANCA or FANCC gene mutation Defect in DNA repair "FANCCONI" -Frizzled blood: loss of haemopoietic stem cell -> pancytopenia -Abnormal bones: absent radii, absent thumbs -Not tall: short stature -Crypoorchidism, hypogonadism, micropenis -Cardiac: VSD, PDA -Other: renal and gut e.g. aplasia, horseshoe kidney, malrotation, duodenal atresia -N --> V = vertebral abnormalities -Increased risk: increased risk of AML and myelodysplastic
54
What is galactosemia What is it due to Mode of inheritance Symptoms
Disorder of galactose metabolism Due to enzyme mutation in Galactose kinase, Galactose-1-phosphate uridyl transferase OR UDP-Galactose-4 epimerise (GAL) Mode: AR Symptoms: Hepatmoegally, E-Coli SEPSIS, poor feeding, hypotonia Eventual neurodevelopment impairment, cataracts, growth delay, ovarian failure
55
What accumulates in homocysteinuria What is it a defect of What is the treatment
Homocysteine and methionine Defect in cystathionine-B-synthetase due to CBS gene defect Sx; -marfanoid appearance -downward displacement of ectopic lentis -seizures, intellectual disability -stroke/PE/clots as homocysteine inflamed endothelium Treatment -B6 vitamin- acts as a co-factor Betanine- reduces homocystein back to methionine which is less harmful
56
An accumulation of methionine is associated with what disorder
Homocysteinuria
57
What co-factor + enzyme is involved converted homocysteine --> cysteine
cystathionine-B-synthetase Vitamin B6 (pyroxidine)
58
What type of mutation is sickle cell disease How is it inherited What are the symptoms What do you seen in RBC that are important What is the treatment
-point mutation of arginine --> thymine -AR SX: vaso-occlusion -Brain: stroke, moyamoya (build collaterals around areas of vaso-occlusion which are fragile and burst easily) -limbs: dactylics -Spleen: vasoocclusion --> pain and infarction -Infection secondary to lack of spleen. Increased risk of encapsulated bacterial infections + osteomyelitis will salmonella -Lungs: acute chest syndrome -Kidneys: proteinuria/ haematuria/ infarction -Aplastic crisis Red cell film: Howell-Jolly bodies Treatment -Hydroxurea- increases production of HbF -Blood transfusion -Folate -May need iron chelation -Stem cell transplant
59
What is used in sickle cell disease to increased HbF production and reduce HbS production
Hydroxurea
60
What causes sickle cell disease
Point mutation in gene causes a defect in the B-globin chain so that it shifts the Hb oxygenation curve right and when deoxygenated crystallises
61
For the below B-thalassamia combinations list the outcome -B0/B0 -B0/B+ -BO/B -B+/B+ -B+/B
B-thallasaemia major B-thalassaemia major -B-thalassaemia minor/trait -B-thalassaemia intermedia -B-thalassaemia trait
62
What symptoms occur in B-thalassaemia major What do you seen on blood film
Anaemia Alternate areas of haemaotopoiesis --> hepatosplenomegaly, frontal bossing, jaw enlargement Iron overload- body absorbs iron as anaemia --> haemochromatosis like syndrome Blood film: -microcytic aneamia -tear drops -a-globin precipitates
63
What are HbH cells and what disease are they associated with
HbH- tetrad of B-globin cells "Bart haemoglobin" Associated with a-thalassaemia as not enough alpha chains produced so the B-chains precipitate
64
What is associated with -ATP7A -ATP7B
-ATP7A: Menkes kinky hair -ATP7B: Wilsons disease both are disorders of copper transport
65
In Wilsons disease -what are the symptoms -what would you see on serum copper and ceruloplasmin
Copper accumulation -Liver: fibrosis -Kidney: CKD -Eyes: kayser--fischer rings -Brain: mostly accumulates in basal ganglia --> Parkinson like symptoms Increased serum copper Low ceruloplasmin -ATP7B defect means copper isn't excreted in bile or incorporated onto ceruloplasmin for transport in the blood, so it is rapidly broken down
66
In Wilsons disease -what is the gene and defect -what is the treatment
-ATP7B defect -Inability to excrete copper into bile or incorporate it into ceruloplasmin so it accumulates Treatment -Low copper diet -Penicilliamine which is copper chelating -Liver transplant
67
SERPINA1 gene is mutated in what disease
A-1-antitrypsin
68
What is the role of a-1-anti trypsin Where is it produced What defect causing a-1-anti-trypsin deficiency What phenotype do you get with these genotypes -M/M -M/S -M/Z -S/S -S/Z -Z/Z -Null: Null
protease inhibitor which protects the lung epithelium against neutrophil elastase and bacterial elastase Produced in the liver. In mutation either not produced (null) , OR misfolded and accumulates in liver (Z) or reduced production (S) MM: normal M/S: carrier M/Z: carrier S/S: mild disease S/Z: severe disease Z/Z: severe disease with misfolding so accumulates in the liver Nul; nil : severe lung disease, nil liver accumulation
69
A child has a genetic condition that results in severe sunburn with minimal exposure. What is the disease and how is it inherited
Xeroderma Pigmentosa AR
70
What condition gives you Heinz bodies in RBC
G-6-P-D deficiency
71
which medications do you avoid in g-6-pd -pain -antibiotics -cardiovascular -food
-aspirn -cotrimoxazole, nitrofurantoin, chloramphenicol -sulfonamides -procainamide -methyldopa -fava beans

RACP EXAM (9 decks)

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