Genetic Flashcards
What are telomers
Region of repetitive nucleotide sequence at the end of each chromosome which protects the chromosome from deterioration and fusion
Which are purines and which are pyrimidines
-Adenine
-Thymine
-Cytosine
-Guanine
-Purine: Adenine, Guanine
-Pyrimidine: Thymine, Cytosine
What are the purpose of these enzymes
-DNA polymerase
-Helices
-Ligase
-DNA polymerase: creases DNA molecules by assembling nucleotides
-Helicase: disrupts the DNA double bond to allow replication
-Ligase: DNA repair enzyme
How do you calculate carrier incidence and carrier frequency
Carrier Incidence: carrier frequency x carrier frequency x4
Carrier frequency: square root (carrier incidence/4)
“Incidence = frequency squared x 4
What is the difference between allelic and locus heterogeneity
-Allelic: more than one mutation in a gene (e.g. CF)
-Locus: mutations of more than one gene (e.g. TS)
What is the difference in these mutations
-missense
-silent point mutation
-nonsense mutation
-splicing mutation
-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
Describe the concept of Anticipation
More triplet repeats occur in successive generations = increased severity of disease
What is penetrance
The presence/absence of a disease or trait. Must have both the phenotype and genotype
What is the difference between expressivity and penetrance
Penetrance= genotype + phenotype. Presence of disease both on person and in genome
Expressivity= variation in the clinical features of a mutation e.g. NF1
In consanguinity what is the risk of having a major problem
-Background risk
-Incest
-1st degree cousins
-2nd degree cousins
-3%
-50%
-6% (double)
-4%
Describe splice site mutation
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
Describe anticipation
Seen in triple repeat disorders. More aggressive and earlier disease in subsequent generations
What type of disorder is Myotonic muscular dystrophy
What is the genetic defect
What are the symptoms
Triplet repeat disorder
-CTG expansion mutation
-SX: facial hypotonia with V shaped lip, muscle weakness, heart condition issues, IQ/Behavioural issues
What type of mutation causes Fredrick ataxia
What is the gene
What age of onset
What are the symptoms
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
What condition does a mutation in FMR1 gene cause
Fragile X
“Fragile Mother Related 1”
What does a mutation in FXN cause
Fredrick Ataxia
“Fredirick ataXiaN gene”
What study to do you use to check for Beckwith-Weidmann
Methylation specific multiple ligand probe analysis
What conditions will a microarray detect vs not
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
What test would be used for NF1 or Marfans
Sanger sequencing- will detect a mutation on a nucleotide level
What test is used for analysis of myotonic muscular dystrophy
triple repeat analysis - PCR reaction that is then analysed with southern blot to see the length of triplet repeats
What is the difference between western and southern blot
Western blot- protein analysis
Southern blot- DNA analysis
Describe the phases of mitosis
-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
What is the gamete result if you have non-dysjunction in meiosis I vs meiosis II
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
What is a Robertsonian chromosome and which are they
Contain an non central centromere. The DNA in the short arm (p arm) is redundant
Chromsomes 13, 14, 15, 21 and 22
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%
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
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
You see a baby with puffy hands and feet and consider the diagnosis of congenital lymphoedema.
What condition should you screen for
Turners syndrome
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
In Turners syndrome, when on growth hormone, what blood test is used to titrate effect
IGF-1
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
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.
What mutation causes Achondroplasia
FGF3- fibroblast growth factor 3
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
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”
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
What condition is due to a mutation in COL5A1 and COL5A2
EHLOS DANLOS- think “COL= COLLAGEN”
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
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
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
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
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
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
In an optic glioma affecting vision, what is the treatment
Carboplatin
What is the diagnostic criteria for NF2
Bilateral vestibular Schwannoma
OR
Family history AND
-unilateral vestibular
-brain tumour e/g. glioma, Schwannoma, meningioma
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
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
A child has a mutation at COL1A1- what condition does it cause
Collagen Type 1
Result in osteogenesis imperfecta
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
What are the side effects of bisphosphonates given for OI
-Flu like illness
-Hypocalcaemia
-Jaw necrosis
What pathway is activated in Tuberous sclerosis
What is a medication that blocks this pathway
mTOR pathway
Sirolimus
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
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
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
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
An accumulation of methionine is associated with what disorder
Homocysteinuria
What co-factor + enzyme is involved converted homocysteine –> cysteine
cystathionine-B-synthetase
Vitamin B6 (pyroxidine)
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
What is used in sickle cell disease to increased HbF production and reduce HbS production
Hydroxurea
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
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
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
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
What is associated with
-ATP7A
-ATP7B
-ATP7A: Menkes kinky hair
-ATP7B: Wilsons disease
both are disorders of copper transport
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
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
SERPINA1 gene is mutated in what disease
A-1-antitrypsin
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
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
What condition gives you Heinz bodies in RBC
G-6-P-D deficiency
which medications do you avoid in g-6-pd
-pain
-antibiotics
-cardiovascular
-food
-aspirn
-cotrimoxazole, nitrofurantoin, chloramphenicol
-sulfonamides
-procainamide
-methyldopa
-fava beans
