Clinical Genetics 1 Intro

Question 1

Give 5 examples of Single Gene Disorders

Answer 1

Choose 5 from:

1. Cystic Fibrosis
2. Neurofibromatosis
3. Marfan Syndrome
4. Haemochromatosis
5. Familial Expansile Osteolysis
6. Familial Breast Cancer

Question 2

Give types of Mendelian Inheritance

Answer 2

• Autosomal Dominant
• Autosomal Recessive
• X linked Recessive
• X linked Dominant

Also

• Y linked
• Mitochondrial Disease
• Imprinted Genes

Question 3

1. How many genes in the human genome?
2. How many pairs of chromosomes? Autosomes and sex chromosomes?
3. How are mitochondria inherited?

Answer 3

1. Approx 23,000
2. 23 chromosome pairs - 22 pairs of autosomes and 1 pair of sex chromosomes (XX female, XY male)
3. Exclusively maternal inheritance

Question 4

What are the mechanisms of Single Gene Disorders?

Answer 4

• Dosage sensitivity (too much/too little)
• Loss of function
• Gain of function
• Activating mutations
• Accumulation of toxic produce
• Interference of abnormal product with normal product
• Effects on developmental timing, cell migration, interaction etc
• ‘Two hit’ effects

Question 5

Give examples of Autosomal Dominant Conditions.

Explain the mode of inheritance.

Answer 5

• HHT
• Tuberous sclerosis
• Marfan Syndrome
• Neurofibromatosis
• Huntington’s Disease
• BRCCA 1/2 breast/ovarian cancer
• FAP

One copy of the diseased allele causes disease in the individual

Question 6

5 points about Neurofibromatosis

Answer 6

Choose from:

• NF1 – 1/3500: Autosomal dominant
• Multiple café au lait spots
• Neurofibromata (usu post-pubertal)
• Plexiform neuromas
• Lisch nodules, optic nerve glioma
• DevDel/LDs / macrocephaly
• Skeletal abnormalities: scoliosis, tibial pseudarthrosis
• High BP (renal artery stenosis)

(NB: NF2 is a completely different condition)

Question 7

Describe the onset, symptoms and mechanism of Huntington’s Disease

Answer 7

• Onset 40s-50s
• Choreiform movements
• Psychiatric disturbance
• Autosomal dominant: 50% risk of transmission
• Huntingtin gene on chromosome 4
• Disease due to unstable trinucleotide repeat (

Question 8

Give possible targets for Huntington Disease Treatment

Answer 8

• Blocking formation of the abnormal protein (need to consider replacing the normal protein)?
• Help cells degrade/excrette polyglutamine (autophagy)?
• Help cells tolerate polyglutamine inclusions?
• Target the apoptosis pathway?
• Stem cells?
• Gene therapy?

Question 9

1. What is the objective of prenatal diagnosis
2. When is amniocentesis performed?
3. When is chorion villus sampling performed?
4. What is free fetal DNA analysis and what is its purpose?

Answer 9

1. Helping families
2. 16 weeks
3. 12 weeks
4. Analysis of fetal DNA in the mother’s bloodstream - non-invasive prenatal genetic diagnosis. Can be used for fetal sexing.

Question 10

1. How is preimplantation genetic diagnosis performed?

2. What is the use of preimplantation genetic diagnosis?

Answer 10

1. IVF technique in which you fertilise the egg, grow to 8 cell embryo star and remove one cell for testing (blastomere biopsy). Only reimplant non-affected embryos.
2. Used for genetic disorders and ‘saviour siblings’ e.g. bone marrow transplant in Fanconi Anaemia

Question 11

What are the features of congenital myotonic dystrophy?

Answer 11

1. Very floppy babies
2. Often require initial ICU care
3. Muscle tone may improve with time
4. Outlook very variable.

Question 12

Describe the mechanism of myotonic dystrophy.

What are the features of myotonic dystrophy?

Answer 12

• Mutation in DMPK gene on chromosome 19
• Shows anticipation
• Mildly affected mothers can have severely affected children
• Cardiac problems in adulthood
• Diabetes
• Male baldness

Question 13

Give 5 examples of single gene cancer disorders

Answer 13

Choose from:

1. Retinoblastoma
2. Familial Adenomatous Polypoptosis (FAP)
3. Hereditary Non-Polypoptosis Colorectal Cancer (HNPCC)
4. Familial breast and ovarian cancer: BRCA 1/2 mutation
5. Multiple endocrine neoplasia 1 and 2
6. Von Hippel Lindau Disease

Question 14

Describe the Knudson 2-hit hypothesis.

Answer 14

See notes

Question 15

1. What mutation is involved in Von Hippel-Lindau Disease?
2. Describe the tumours which present in this condition.
3. Screening?

Answer 15

1. VHL gene on chromosome 2.
   - CNS heamangioblastomas: cerebellum, cerebrum, spinal cord.
   - Retinal angiomas
   - Pheochromocytomas
   - Pancreatic tumours
   - Renal cell carcinoma
2. Cambridge Protocol - asymptomatic patients need screening

Question 16

1. What gene is involved in the adenoma progression sequence?
2. What does a loss of APC lead to?

Answer 16

1. APC gene - ‘gatekeeper’ of the process

2. Cell proliferation, accumulation of more mutations and eventual cancer.

Question 17

Give 5 examples of recessive conditions.

How are recessive conditions inherited?

Answer 17

Choose from:

1. Cystic fibrosis
2. HURLER SYNDROME
3. Phenylketonuria (PKU)
4. Homocystinuria
5. Thalassaemia
6. Sickle cell anaemia
7. Spinal muscular atrophy

The affected individual inherits two copies of the diseased allele.

Question 18

1. Give another name for Hurler Syndrome
2. Epidemiology?
3. Describe the clinical features of Hurler Syndrome
4. What is the disease mechanism?
5. How do you treat Hurler Syndrome?

Answer 18

1. Mucopolysaccharidosis Type 1
2. Common in travellers.
3. Coarse features, developmental delay, respiratory problems
4. Deficiency of the enzyme Alpha-iduronidase
5. With Bone Marrow Transplant/ enzyme therapy (depends on the mutation!)

Question 19

What are the mechanisms of recessive disorders?

Answer 19

• Mainly loss of function: many metabolic disorders
• Loss of critical enzymes may lead to toxic accumulation of by-priducts or an inability to produce an essential product.
• Loss of structural proteins may cause cellular abnormality

Question 20

Describe X linked recessive inheritance.

Answer 20

• An affected mother passes the disease on to all of her sons
• An affected father will have carrier daughters (affected daughters if mother is also carrier/affected)
• NO male-to-male inheritance

Question 21

1. How is Duchenne Muscular Dystrophy diagnosed?
2. Inheritance
3. What is the disease mechanism?
4. How is DMD treated?
5. What is the prognosis?

Answer 21

1. Clinical, CK levels, muscle biopsy, molecular tests
2. X-linked recessive
3. Loss of protein dystrophin because of mutations in DYS1 gene
4. Supportive treatment. (In future stem cell therapy? Gene therapy?)
5. Death in 2nd/3rd decade (improving)

Question 22

1. What is the mode of inheritance of Coffin-Lowry syndrome?
2. What are the features?
3. What is the disease mechanism?

Answer 22

1. X-linked therefore affects mainly males but females may have mild manifestations?
2. Moderate to severe mental retardation, hypertelorism, thick lips, spatulate tapering digits.
3. Mutation in RSK2 gene (Ribosomal S6 Protein Kinase)

Question 23

1. What is the mode of inheritance of Rett syndrome?
2. What is the disease mechanism?
3. Where are rare mutations found?
4. Why is the male phenotype different from the female?

Answer 23

1. X-Linked dominant, male lethal. Mutations found in most girls with Rett syndrome.
   2 . MeCP2 - binds methylated CpG residues and represses genes
2. Males with mental retardation or neonatal encephalopathy.
3. X inactivation.

Question 24

Give examples of mitochondrial diseases.

How are mitochondrial diseases inherited?

What is heteroplasmy?

Answer 24

Choose from:

• MELAS
• MERRF
• LHON
• NARP
• MIDD

Exclusively maternally.

The presence of more than one type of organellar genome in an individual (mitochondria’s own genome). It is common for mutations to only affect some mitochondria leaving the others unaffected.

Question 25

What are some common diseases that genetics are involved in?

Answer 25

- Ischaemic heart disease - Respiratory Disease - Diabetes - Obesity - Epilepsy - MS - Autism and other learning disabilities - Cancer

Question 26

1. Describe Noonan Syndrome. 2. Describe Leopard Syndrome. 3. Describe Costello Syndrome. 4. Describe Cadio-Facia-Cutaneous Syndrome 5. What common pathway do these disease mutations occur along?

Answer 26

1. Autosomal dominant disease. - Short stature, neck webbing, loose skin, downslanting palpebral fissures, ptosis, posteriorly rotated ears, cardiac abnormalities (pulmonary stenosis and cardiomyopathy), feeding problems and bleeding diathesis. 2. Autosomal Dominant - -> Lentigines, ECG abnormalities, Occular hypertelorism, Pulmonary stenosis, Abnormalities of genetilia, Retardation of growth, Deafness 3. Prenatal polyhydramnios and hydrops, failure to thrive, feeding problems, macrocephaly, thick lips, cardiac abnormalities (congenital heart disease, cardiomyopathy), loose skin, tumours (papilloma and rhabdomyosarcoma). 4. De novo dominant mutations, macrocephaly, high birth weight, failure to thrive, cardiac anomalies (pulmonary stenosis, ASD, HCM), ectodermal abnormalities (sparse friable hair, hyperkeratonic skin lesions, ichthyotic-like skin) ``` 5. RAS pathway. Noonan - SHP2 Leopard - SHP2, KRAS Costello - HRAS CFC - KRAS, BRAF, MEK 1/2 ```

Question 27

1. Why is linkage mapping easy in mice species? | 2. How can animal models be used?

Answer 27

1. Short generation time, big litter sizes and easy DNA availability. 2. Homology and synteny - find the disease one in the animal and you automatically have a candidate in the human - limited by difficulties matching the phenotype.

Question 28

1. What is Deciphering Developmental Disorders? | 2. What is its objective?

Answer 28

1. Based at Wellcome Trust Sanger Institute in Cambridge - recruited 12,000 children with severe undiagnosed developmental disorders across the UK and perform microarray analysis to pick up genomic imbalance. Also full exam analysis. 2. To identify genes involved in birth defects and developmental abnormalities.