Lecture 19: Autosomal dominant and recessive disorders

Question 1

What is a compound heterozygote?

Answer 1

Two recessive mutations that inhibit function

Question 2

What is halpoinsufficiency?

Answer 2

One allele doesnt produce protein therefore overall protein isnt enough -> phenotype

Question 3

What rules apply to autosomal dominance conditions when full penetrance?

Answer 3

• Affects either sex
• Transmitted by either sex
• (vertical transmission)
• 50% kids receive

Question 4

What are the two examples of autosomal dominant conditions?

Answer 4

• Achondroplasia

- Marfan syndrome

Question 5

What is achondroplasia? whats the mutation and presentation?

Answer 5

• Autosomal dominant
• No cartilage formation
• Shortened limbs, prominent forehead, depressed nasal bridge
• Mutation in the fibroblast growth factor receptor 3 (FGFR3)

Question 6

What does the mutation in FGFR3 mutation in achondroplasia result in?

Answer 6

• Mutations result in premature differentiation of chondrocytes into bone (gain of function)
• Wild type allele cannot compensate / reduce the mutant allele activity
• Potential for prenatal diagnosis

Question 7

Whats responsible for 80% of achondroplasia cases?

Answer 7

New mutations in the male germ line are responsible for 80% cases of achondroplasia.

De novo mutation in fathers germ line cells, increased risk with age

Question 8

Why does paternal age impact chances of achondroplasia?

Answer 8

• Possibly germline selection
• Germline cells with FGFR3 mutation may have increased RAS/MAPK and PI3K/AKT pathway activation = weal proliferative advantage

Question 9

What is marfan syndrome?

Answer 9

• Mutation in fibrillin-1, this binds to and disables any normal fibrillin (a dominant negative effect)
  = Excessive elasticity of of fibrin
• Several 100 alleles (allele heterogeneity)
• Different features b/c of variable expressivity

Question 10

What is common gene product of autosomal recessive inheritence?

Answer 10

Usually enzymes, if heterozygotic then usually sufficient protein for adequate function

Question 11

What are some examples of autosomal recessive inheritance?

Answer 11

• Phenylketonuria (PKU)

- Haemochromatosis

Question 12

What is PKU?

Answer 12

Autosomal recessive disorder due to deficiency in phenylalanine hydroxylase (need to convert phenylalanine to tyrosine)

= Phenylalanine accumulates in the blood

Question 13

What are the symptoms of PKU?

Answer 13

Vomiting, convulsions and mental retardation without treatment

Question 14

Whats the management of PKU?

Answer 14

Low phenylalanine diet..

Question 15

Whats screened as part of the NZ newborn metabolic screening program?

Answer 15

• AA disorders including PKU
• CF
• Congenital hypothyroidism

and many more

Question 16

What is hereditary haemochromatosis?

Answer 16

Autosomal recessive disorder of iron metabolism

• Iron overload in tissues
• multi-organ dysfunction due to iron deposition

Note: Locus heterogeneity (many genes can lead to same phenotype)

b/c

• Increased iron absorption
• Excess iron accumulation

Question 17

Whats the rate of heamochromatosis and age of onset?

Answer 17

1 in 10 caucasians

usually 40+

Question 18

Whats the clincal features of heamochromatosis?

Answer 18

• Lethargy
• Organ damage as iron overloads
• Hepatomeagly and cirrhosis
• diabetes
• arthritis
• cardiomyopathy
• hypoganadism and hypothyroidism

Question 19

What mutations lead to haemochromatosis?

Answer 19

Locus heterogeneity leads to hereditary haemochromatosis

Question 20

Whats the impact of HFE gene discovery on clinical practice?

Answer 20

• Diagnosis now based on abnormal iron studies and HFE gene testing
• Liver biopsy only if HFE negative or concern of cirrhosis
• Can facilitate family screening

Question 21

Summarise autosomal dominant disorders;

Answer 21

• 4000+ known
• Most are uncommon
• Tend to be more biologically complex than recessive
• Genetic products usually a non-enzymatic and diffusible protein

Question 22

Summarise autosomal recessive disorders;

Answer 22

• Largest of single gene disorder
• Genes responsible on chromosomes 1-22
• Homozygous i.e both alleles recessive
• Gene product commonly an enzyme or diffusible protein