Clinical Genetics (2)

Question 1

Classification of genetic disorders

Answer 1

• Multifactorial/complex
• Single gene
• Chromosomal
• Mitochondrial
• Somatic mutations

Question 2

Single gene modes of inheritance

Answer 2

Autosomal dominant, Autosomal recessive, X-linked, Mitochondrial

Question 3

Autosomal Dominant Inheritance

Answer 3

• Males and females equally affected

- Offspring 1 in 2 change inheriting mutation

Question 4

Examples of AD inheritance

Answer 4

• Myotonic dystrophy
• Marfan syndrome
• Huntington disease
• 22q11 deletion syndrome

Question 5

Penetrance

Answer 5

The frequency with which a specific genotype is expressed by those individuals that possess it, usually given as a percentage

Question 6

By what age is Huntington disease 100% penetrance?

Answer 6

80

Question 7

Incomplete penetrance

Answer 7

Not all relatives who inherited the mutation develop the disorder e.g. BRAC1 80%

Question 8

Expressivity

Answer 8

Variation in expression, the extent to which a heritable trait is manifested by an individual

Question 9

Anticipation

Answer 9

Symptoms of a genetic disorder become apparent at an earlier age as it passes from one generation to the next and normally increases in severity

Question 10

Examples of anticipation illnesses

Answer 10

Myotonic dystrophy and Huntington’s disease

Question 11

New dominant/de novo mutation

Answer 11

New mutation that has occurred during gametogenesis/early embryonic development

Question 12

Examples of AR inheritance

Answer 12

• Cystic fibrosis
• Many metabolic disorders
• Haemachromatosis
• Sickle cell disease

Question 13

Do males are females suffer more from X-linked?

Answer 13

Males, females are variably affected

Question 14

Cannot have male to …. transmission

Answer 14

male

Question 15

What influences XL expression in females?

Answer 15

X inactivation and XL dominant (rare) vs XL recessive

Question 16

Can you predict female phenotype on prenatal testing?

Answer 16

No

Question 17

What is lyonisation?

Answer 17

Random inactivation of one of the X chromosomes (X-inactivation)

Question 18

When does X-inactivation occur?

Answer 18

Early embryogenesis and once activated remains inactive throughout and descendants

Question 19

Are all the genes switched off in an inactivated X?

Answer 19

Most but not all

Question 20

Barr body

Answer 20

Condensed X

Question 21

Skewed X-inactivation

Answer 21

Random preference for ‘normal’ X chromosome to be inactivated

Question 22

Tissue variability

Answer 22

Random preference for X with mutation to be active in crucial tissue group

Question 23

Example of tissue variability

Answer 23

Muscles in Duchenne muscular dystrophy

Question 24

XL dominant examples

Answer 24

• Rett syndrome (lethal in males)

- Fragile X syndrome

Question 25

XL recessive examples

Answer 25

• Red-green colour blindness
• Haemophilia
• Duchenne muscular dystrophy
• Carrier girls affected if X-inactivation switches normal X off

Question 26

Examples of mitochondrial inheritance

Answer 26

Maternally inherited diabetes and deafness

Question 27

Is mitochondrial inheritance from your father or mother?

Answer 27

Mother, as sperm head has no mitochondria (give all her children the mutation)

Question 28

How many genes in mitochondrial DNA?

Answer 28

27

Question 29

Is mitochondrial inheritance rare or common?

Answer 29

Rare

Question 30

Expressivity of mitochondrial inheritance

Answer 30

is variable

Question 31

Consanguinity

Answer 31

Couples who are ‘blood’ relatives (5-6% risk of congenital birth defect)