Genetics

Question 1

Inheritance of Leders Hereditary Optic Neuropathy

Answer 1

Mitochondrial with Heteroplasmy so variable expression and arises later in life

(Individuals do not experience vision difficulties until adulthood because only some mitochondria have mutant copies of gene
Causes bilateral, painless subacute loss of central vision during young adult life)

Question 2

Gonadal/Germiline mosaicism

Answer 2

where an individuals germline cells develop mutation during embryonic growth but the somatic cells do not this results in the individuals offspring being affected, but not themselves.
Parent will not have mutated somatic cells on testing, but offspring will.

Question 3

Linkage Disequilibrium

Answer 3

Linkage disequilibrium is the non-random association of alleles at two or more loci, not necessarily on the same chromosome. There is associations in populations of alleles more than what would be expected if they were unlinked.

Question 4

Disorders with Trinucleotide repeats

Answer 4

Huntingtons - CAG repeats
Frederich Ataxia - GAA repeats
Myotonic dystrophy - Autosomal dominant with CTG repeats
Fragile X - X linked with CGG repeats

Question 5

Mutations in variants of Muscular Dystrophy

Answer 5

All X-linked recessive
- Duchenne MD - frame-shift mutation (worst)
- Beckers MD - In-frame mutation
- MD Cardiomyopathy - Promoter region mutation (best)

Question 6

Examples of diseases with Frame-shift mutations

Answer 6

• CCR5 receptor in HIV
• Duchennes MD
• Tay-Sachs disease (usually causes death as toddler_

Question 7

What pattern in a pedigree makes autosomal dominant likely?

Answer 7

Father to Son transmission

Question 8

Types of point mutations/single nucleotide variants

Answer 8

Frame-shift due to insertion or deletion that are not multiples of 3

Nonsense results in unwanted stop codon

Missence results in single different amino acid

Splice mutations occur at site of intron and exon splicing which can cause loss of exon or inclusion of intron altering the protein code

Question 9

Imprinting disorders

Answer 9

Has phenotypic effect if Pt has inherited 2 copies of genes from one parent and none from other, then the copies are imprinted

• Prader Willi Syndrome
• Angelmans syndrome
• Beckwith Weidman Syndrome
• Russel Silver Syndrome
• Transient neonatal hypoglycaemia
• matUPD14
• patUPD14
• Pseudohypoparathyroidism

Question 10

X-linked dominant disorder

Answer 10

Rett syndrome - primary females affected, growth and IQ disabilities

Question 10

Autosomal dominant disorders

Answer 10

Cardiac congenital disorder except Fabrys;
- Brugada
- Long QT syndrome
- Arrythmogenic RV cardiomyopathy
- HCM
- Marfans
- Loey Dietz
- Myotonic dystrophy
- Familial Adenomatous Polyposis
- Huntingtons disease
- Neurofibromatosis Type 1
- Familial Hypercholestraemia

Question 11

Trinucleotide disorders

Answer 11

• Huntingtons, autosomal dominant (> 40 CAG repeats)
• Fredreichs Ataxia, autosomal recessive (CGG repeats)
• Myotonic Dystrophy, autosomal dominant (CTG repeats)
• Fragile X , X-linked (mixed recessive and dominant - CGG repeats)
• Spinocerebellar Ataxia, autosomal dominant

Question 12

Mitochondrial disorders

Answer 12

Heterozomy - Leber Optic atrophy with blindness in older age

Homozomy - MELAS, Myoclonic epilepsy with ragged red fibres

Question 13

Uniparental Disomy

Answer 13

2 x chromosomes from ONE parent. Only causes an issue if imprinted chromosomes
i.e. Prader Willi, Angelmans

Question 14

Linkage Disequilibrium

Answer 14

A correlation between nearby alleles at neighboring polymorphs are associated within a population more often than if they were unlinked.

Question 15

Alpha thalassemia

Answer 15

4 genes on Chromosome 16
Autosomal recessive
AAAA - normal
aAAA - silent
aaAA - minor
aaaA - HbH (4 x beta tetramer)
aaaa - hydros fetalis w Barts Hb (gamma tetramer, due to insufficient switching from metal Hb kappa-gamma to alpha-gamma)

Question 16

Beta thalassemia

Answer 16

2 genes on Chromosome 11
Autosomal recessive
AA - normal
aA - minor/intermediate
aa - Major (forms HbA2 - 2 x alpha, 2 x delta chains)

Question 17

Different Hb’s in Thalassemia

Answer 17

HbA - normal - 2 x alpha, 2 x beta

HbF - normal fetal - 2 x alpha, 2 x gamma

HbA2 - 2 x alpha, 2 x delta

HbH - 4 x beta

Barts Hb - 4 x gamma in hydrops fetalis

Question 18

Congenital Heart Disease - Turner syndrome

Answer 18

XO
Bicuspid aortic valve
Less commonly coarctation of aorta

Question 19

Congenital Heart Disease - Downs Syndrome

Answer 19

Trisomy 21
Tetralogy of Fallot

Question 20

Inheritance Prader Willi

Answer 20

Ch 15 q11 deletion or imprinting in context of Uniparental Disomy

Question 21

Inheritance Angelmans

Answer 21

Ch 15 q12 deletion or imprinting in context of Uniparental Disomy

Question 22

Choroid villous sampling Vs. amniocentesis

Answer 22

Choroid;
< 11 weeks with 2% risk

Amnio;
< 16 weeks with 1% risk

Question 23

Pateu Syndrome

Answer 23

Trisomy 13 - characteristic fist clench (along with Trisomy 18)

Question 24

Edwards Syndrome

Answer 24

Trisomy 18 - characteristic fist clench (along with Trisomy 13)

Question 25

Mainfestations DiGeorges Syndrome

Answer 25

CATCH 22 - Cardiac abnormalities - TOF/VSD/Truncus arteriosis - Abnormal facies - Thymic hypoplasia - Cleft palate - HypoCa, HypoPTH - 22q11.2 deletion

Question 26

Huntington Disease Inheritance

Answer 26

Autosomal Dominant Trinucleotide repeats CAG > 40 Juvenile HD CAG > 60 Worse trinucleotide instability if inherited from Father due to spermatogenesis CAG instability

Question 27

Spinocerebellar ataxia

Answer 27

Autosomal dominant SCA gene Repeat expansion Ataxia with spinal and cerebellar degeneration Onset in 30's

Question 28

Myotonic Dystrophy

Answer 28

Autosomal dominant CTG repeats DMPK gene (dystrophin myotonica protein kinase) Worse with maternal inheritance Percussion myotonia Weakness Cataracts Cardiac conduction abnormalities Testicular Atrophy

Question 29

CK rise in Duchennes/Beckers MD

Answer 29

DMD - CK > 10 x ULN Beckers - CK > 5 x ULN

Question 30

Marfans inheritance

Answer 30

Autosomal dominant FBN1 gene (fibrin variants)

Question 31

Diagnosis of Marfans

Answer 31

FBN1 gene Aortopathy/aortic score > 2 Systemic score > 7 Lens dislocation FHx

Question 32

Loey Deitz Syndrome

Answer 32

Aortopathy without lens dislocation - can be more severe than Marfans Due to TGF gene mutations

Question 33

Indications for surgical intervention AAA

Answer 33

Idiopathic/metabolic > 55mm Marfans > 50mm Loey Dietz > 42mm Or increasing > 0.5cm/year

Question 34

Noonans Syndrome

Answer 34

PTPN11 gene mutation Rasopathy Autosomal dominant Pulmonary stenosis HCM P's - PTPN11 - Pulmonary Stenosis - rasoPathy - Predisposed malignancy

Question 35

Inheritance Neurofibromatosis type 1

Answer 35

Autosomal dominant NF1 gene Increased risk malignancy including optic nerve glioma in children

Question 36

Cancers associated with Neurofibromatosis Type 1

Answer 36

Optic glioma in children Breast Cancer Pheochromocytoma Peripheral nerve sheet tumour

Question 37

Tuberous Sclerosis

Answer 37

Autosomal dominant TSC1 (hamartin) and TSC2 (tuberin) gene mutation causing tumours and seizures Associated with Lymphangioleiomyomatosis of lungs (+++ cysts throughout lungs)

Question 38

Pathogenesis of genetic cardiomyopathies

Answer 38

HCM - Sacromere disease ARVC - Desmosomes with fibrofatty infiltration Fabrys - Lyosomes deposition