Genetics

Question 1

Function of KRAS gene and clinical manifestations associated with its mutation?

Answer 1

KRAS encodes for GTPase and is an important component in many signal transduction pathways, including those driving cell-growth.

80-90% pancreatic adenocarcinomas ave mutations in the KRAS2 gene.

Colon cancers

Leukaemia

Ichthyosis (skin lesions)

Question 2

Features of homocystinuria?

Answer 2

Marfanoid habitus
Learning difficulties (normal intelligence in 1/3)
Thromboembolic disease
Lens dislocation
Hypotonia
Livedo-type skin appearance

Question 3

Diagnostic test for homocystinuria?

Answer 3

Elevated urinary homocysteine levels.

Question 4

Treatment of homocystinuria?

Answer 4

Methionine-restricted, cysteine-supplemented diet
Pharmacologocial doses of pyridoxine or folic acid

Question 5

Mutations involved in Marfan syndrome?

Answer 5

Autosomal dominant syndrome caused by mutations in the fibrillin-1 gene (FBN1) on chromosome 15q21

Incidence of 1–2 per 10 000

Some 25% are new mutations and the gene is large and polymorphic, which makes diagnostic genetic testing problematic; the diagnosis is therefore currently made on clinical criteria

Question 6

Diagnostic criteria for Marfan’s?

Answer 6

At least two major criteria or on major + 2 minor criteria must be present:

Major skeletal criteria includes:
1) Pectus carinatum
2) Pectus excavatum (marked)
3) Reduced upper-to-lower segment ratio of less than 0.85
4) Increase arm span to height ratio (normal ratio is 1:1)
5) Positive thumb sign and wrist sign, also known as Steinberg sign and Walker–Murdoch sign
6) Thoracolumbar scoliosis (more than 20 degrees)
7) PCFD (progressive collapsing foot deformity)
8) Protrusio acetabula ( it is the migration of the femoral head along the femoral neck axis, medially and proximally, through the medial acetabular wall into the pelvis)

Minor skeletal criteria include:
1) Moderate pectus excavatum
2) Hyper flexible joints
3) High vaulted palate (unusually high and narrow palate)
4) Specific facial appearance for example: hypoplasia, enophthalmos, retroganthia and malar hypoplasia etc.

Question 7

What Murmur is associated with Marfan’s?

Answer 7

early diastolic murmur
(indicates aortic valve incompetence which is likely to be secondary to aortic root dilatation).

Question 8

Is hereditary haemorrhagic telangectasia a recessive or dominant disease?

Answer 8

Autosomal dominant

Question 9

Common presentations of HHT?

Answer 9

Easy bruising of the skin
Nose bleeds that often present at the start of puberty
GI bleeding beginning in 40s-50s
Catastrophic cerebral haemorrhage due to AV malformation

Question 10

Treatment of HHT?

Answer 10

Oestrogen therapy in women
Laser therapy to vascular lesions

Question 11

Mode of inheritance of Prader-Willi syndrome?

Answer 11

Non-mendelian: 70% occur because of deletion or disruption of genes on the proximal arm of the paternal copy of chromosome 15 (15q11-13).

28% due to maternal disomy

An example of genetic imprinting (genes expressed differently based on which parent they come from).

Question 12

Features of Prader-Willi?

Answer 12

Morbid obesity, hyperphagia, hypogonadism, mental impairment, elevated ghrelin

Question 13

What is Fabry’s disease?

Answer 13

an inherited lysosomal storage disorder caused by mutations in the GLA gene, which encodes the enzyme alpha-galactosidase A.

Question 14

Inheritance pattern of Fabry’s?

Answer 14

X-linked recessive

Question 15

Features of Fabry’s?

Answer 15

Stroke
Burning pain in extremities (acroparesthesia)
Angiokeratomas
GI issues
Renal failure

Question 16

Inheritance of Wilson’s disease?

Answer 16

Autosomal recessive

Question 17

How to work out the risk of someone passing on a certain disease to their offspring if it is not known if they are a carrier or not?

Answer 17

Carrier frequency within population x chance of passing on the abnormal gene if they are a carrier.

E.g Father has Wilson’s, unkown if mother is a carrier. Carrier frequency of Wilson’s in British population is 1 in 100.

It is an autosomal recessive disease = 50% chance of passing on abnormal gene if mother is a carrier.

Dad is affected so 100% chance he will pass it on.

So, 1 in 100 x 50% x 100% = 1 in 200 chance of child being affected.

Question 18

Inheritence pattern of phenylketonuria?

Answer 18

Autosomal recessive

Question 19

Inheritance pattern of BRCA1and BRCA2 genes?

Answer 19

Mainly autosomal dominant

Question 20

Genetics of Kearns-Sayre syndrome?

Answer 20

mitochondrial disorder characterised by rearrangements of mitochondrial DNA, including deletions and duplications.

Question 21

Clinical features suggesting a mitochondrial disorder?

Answer 21

Affects tissues that depend heavily on oxidative phosphorylation for energy production.

Sensorineural hearing loss
Retinitis pigmentosa
Muscle weakness
Ataxia
Recurrent stroke
Cardiomyopathy
Insulin-depended DM
Complete heart block
Lactic acidosis

Question 22

Inheritance of Huntington’s?

Answer 22

Autosomal dominant

Question 23

How many CAG repeats will cause patients to develop symptoms in Huntington’s disease?

Answer 23

Over 40

Question 24

Most common enzyme implicated in homocystinuria in patients of celtic origin?

Answer 24

Cystathionine beta-synthase (CBS) deficiency

Question 25

Most common enzyme implicated in homocystinuria in patients of Mexican origin?

Answer 25

5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency

Question 26

Inheritance of sickle cell disease?

Answer 26

Autosomal recessive- caused by substitution by the amino acid valine for glutamic acid on position 6

Question 27

Mutation implicated in psuedohypoparathyroidism?

Answer 27

a loss-of-function mutation affecting the G-protein-linked receptor for PTH

Question 28

Mutation involved in Von Hippel Lindau Syndrome?

Answer 28

an autosomal dominant mutation in a tumour suppressor gene

Question 29

clinical features of Von Hippel Lindau Syndrome?

Answer 29

Phaeochromocytomas Renal cell carcinoma Pancreatic cysts Bilateral epididymal cystadenomas in men Cystadenomas of the broad ligament in women Haemangiomas

Question 30

Gold-standard diagnostic test for myotonic dystrophy type 1?

Answer 30

Genetic testing >50 CTG repeats in the DMPK gene confirms disease

Question 31

Role of helicase?

Answer 31

Separates DNA strands. Plays a role in DNA repair, replication and transcription

Question 32

Function of nuclease?

Answer 32

to remove a sequence of DNA which aids the DNA repair process and can, indirectly contribute to replicationn.

Question 33

Function of restriction endonuclease?

Answer 33

These are a subset of nucleases that cut DNA molecules at a limited number of specific nucleotide sequences.

Question 34

Function of telomerase?

Answer 34

responsible for telomere repair to prevent progressive shortening during replication.

Question 35

In which phenotype of alpha-1-antitrypisn deficiency is smoking particularly implicated in the development of COPD?

Answer 35

The PiSZ phenotype

Question 37

What is the Amsterdam Criteria for Lynch syndrome?

Answer 37

At least three relatives have a cancer linked to Lynch syndrome One of the relatives is a first-degree relative of the other two At least two generations are affected At least one relative was diagnosed with cancer before age 50 Familial Adenomatous Polyposis (FAP) should be excluded Tumors must be verified by pathological examination

Question 38

Genetics and pathophysiology of Von Wilebrand Disease?

Answer 38

A gene on chromosome 12 encodes the VW factor, a large multimeric molecule. VW factor is stored in Weibel–Palade bodies in endothelial cells and platelet α-granules. This protein is involved in platelet adhesion and is the carrier molecule for factor VIII, thereby preventing its premature destruction. Inheritance is autosomal dominant. Point mutations and major deletions of the gene have been described.

Question 39

Treatment of a patient with Von-Willebrand undergoing surgery?

Answer 39

desmopressin (DDAVP®), which may boost factor VIII as well as VW factor levels factor VIII concentrates (Haemate P®), which contains significant amounts of VW factor- *Don't use in patients who have not been exposed to blood products in the past (as Haemate, and FFP, are from large donor pools)* antifibrinolytics, e.g. tranexamic acid

Question 40

Clinical features of acute intermittent porphyria?

Answer 40

Episodes of anxiety, sympathetic overactivity (hypertension and tachycardia), central abdominal pain and bilious vomiting. Attacks are intermittent, more common in women and may be precipitated by a number of drugs, including a number of analgesics, anti-epileptics and antibiotic agents. There are no skin manifestations of AIP.

Question 41

Pathophysiology of acute intermittent porphyria?

Answer 41

Occurs due to absence of porphobilinogen (PBG) deaminase and leads to elevated levels of 8-ALA and PBG.

Question 42

Clinical features of Wolfram syndrome?

Answer 42

a rare and progressive neurodegenerative disorder characterised by diabetes insipidus, diabetes mellitus, optic atrophy and sensorineural deafness (DIDMOAD); patients may also suffer from red-green colour blindness.

Question 43

Inheritence pattern of Wolfram syndrome?

Answer 43

Autosomal recessive