Patterns of Inheritance (Part 4)

Question 1

Why do autosomal dominant mutations manifest in the heterozygous state?

Answer 1

• Haplo-insufficiency
• Dominant-negative mutations
• Gain of function mutations

Question 2

What is Haplo-insufficiency?

Answer 2

• One reasons why dominant mutations manifest in the heterozygous state
• Loss-of-function mutation in which half normal levels of gene product result in disorder

– Examples include cell membrane receptors (familial hypercholesterolemia)
– Rarely there is an enzyme deficiency (such as AIP)

Question 3

What are dominant-negative mutations?

Answer 3

• One of the reasons Autosomal dominant diseases manifest in the heterozygous state
• a mutant gene product interferes with the function of the normal gene product

– Examples include collagenopathies such as osteogenesis imperfecta, or Marfan syndrome

Question 4

What are gain-of-function mutations?

Answer 4

• One of the reasons why autosomal dominant disorders manifest in the heterozygous state.
• result from increased levels of gene expression or the development of a new function of the gene product

– Examples include Huntington disease and achondroplasia

Question 5

Unless it is clearly indicated, always assume a person with an AD disorder is a heterozygote

Answer 5

Unless it is clearly indicated, always assume a person with an AD disorder is a heterozygote

Question 6

Molecular basis for autosomal recessive disorders

Answer 6

• Loss-of function mutations: result in either reduced activity (hypomorph) or complete loss of gene product (null allele or amorph); examples include enzyme deficiencies
• The protein produced from the normal allele in a carrier is sufficient to carry out the normal functions of the gene in the carrier state. The carrier usually does not have phenotypic manifestations. A heterozygous carrier has 50% of the normal level of enzyme activity

Question 7

Pseudo-autosomal dominant

Answer 7

An autosomal recessive condition present in individuals in two or more generations of a family, thereby appearing to follow a dominant inheritance pattern.

Question 8

Pseudo-autosomal dominant (common explainations)

Answer 8

– a high carrier frequency
– birth of an affected child to an affected individual
– genetically related (consanguineous) reproductive partner.

Question 9

Pseudodominant Inheritance

Answer 9

When a carrier (Aa) and a affected individual (aa) mate then 1⁄2 the offspring will be affected. The other half will be carriers.

Question 10

Factors that can increase incidence of an autosomal recessive trait in a population

Answer 10

1) Consanguinity
2) Heterozygote advantage
3) Genetic isolation
- geographic, such as outports in Newfoundland
- religious, such as Amish, Hutterites, etc.
- cultural (language), such as some Asian populations in UK
4) Assortative mating
- people associate and marry with “like” e.g deaf or visually impaired individuals

Question 11

Example of Co-dominance?

Answer 11

Blood types