Phenotypic variability

Question 1

Examples of Autosomal dominant Osteogenesis Imperfecta?

example of subtype classification

Answer 1

Types I, II, III, IV

Due to the Col1A1 gene - collagen problem

All have different characteristics and symptoms due to a secondary gene ( Col1A2 )or a missing gene

I : mild. null + Col1A1

II : severe and usually lethal in perinatal period
Col1A1. Col1A2

III : progressive and deforming Col1A1 + Col1A2

IV : deforming but with normal sclerae most of the time. Col1A1. + Col1A2

Question 2

Examples of Autosomal Recessive Osteogenesis Imperfecta?

Answer 2

Types V, VI, VII, VIII

All have differing genes causing an effect from mild, deforming to lethal

V : same clinical features as type IV, but has unique histology (mesh like). IFITM5

VI : shares the same clinical features as type IV, but has unique histology (fish scales). SERPINF1

VII : associated with cartilage associated protein. CRTAP

VIII. :severe to lethal. P3H1

Question 3

Characteristics of Multiple endocrine neoplasia Type 1 as an example of Environmental effect

Answer 3

Increases the chance of adenomas in tissue

Autosomal D

• Not all will have phenotype, need a 2nd event to continue course of disease

Question 4

Characteristics of Hereditary Haemochromatosis as an example of environmental effect?

Answer 4

Autosomal R

HFE gene mutation = excess iron absorption

Organ damage from iron build up

• Dietary load of iron can very considerably

Question 5

Characteristics of Hereditary Haemochromatosis as an example of sex affect?

Answer 5

Autosomal R

Iron build up

Different time course in men and women, women develop after menopause

Men also have severe phenotypes

Question 6

Congenital long-QT syndrome as an example of sex affect?

Answer 6

Cardiac disorder due to KCNQ1/KCNH2 mutations

Prolonged Q-T

Female diagnosis more common.

Higher risk of mutation in girls and mothers tend to pass it to girls rather than boys

Question 7

Cystic Fibrosis as an example of Interaction with other genes?

Answer 7

Can be modified by following :

Homozygous delF508 can have severe or mild lung disease.

TGFB1 gene encodes growth factor B-1. Severe lung disease

Risk of developing infections can be modified -Immunoglobulin FC-gamma receptor 2. Can increase chance of chronic pseudomonas aeruginosa.

Question 8

Von Hippel- Lindau syndrome as an example interactions with other genes?

Answer 8

Dominant familial cancer syndrome.

Cyclin D1 variation alters phenotype of VHL.

Question 9

Muscular dystrophy as an example of same mutation different phenotype?

Answer 9

Dystrophin gene. -muscle wasting and weakness

Causes Duchenne and Becker muscular dystrophy ( milder )

due to mutation effect

DMD the deletion causes a frame shift

BMD the deletion doesn’t

Question 10

Huntington’s disease as an example of same mutation different phenotype?

Answer 10

Caused by expansion of CAG repeats = Poly Q tract.

As repeats pass 27 phenotype shows, past 35 shows more. Past 40 this results in huntington’s

CAG - glutamine - chain of glutamine = polyglutamine tract / poly Q tract

Question 11

What are trinucleotide repeat disorders?

Answer 11

mutation in which region of three repeated nucleotides increases in number. greater number of repeats = more severe phenotype : earlier onset of disease and greater severity of symptoms in each succeeding generation