Autosomal Dominant Inheritance: Principles and Examples

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Autosomal Dominant Inheritance

Introduction

Autosomal dominant (AD) inheritance is a fundamental pattern in human genetics where a single mutant allele on an autosome is sufficient to express the clinical phenotype. This lecture covers the principles of AD inheritance, its genetic basis, and examples of diseases following this pattern.

Key Concepts of Autosomal Dominant Inheritance

Clinical phenotype is expressed when only one mutant allele is present. The other allele is typically wild-type.
De novo mutations are common in many autosomal dominant diseases.
Mutations often occur in genes coding for non-enzymatic structural proteins or protein components of membranes or receptors.

Single Gene Disorders with Classical Mendelian Inheritance

Single gene disorders can be classified based on the nature of the defect and the inheritance pattern.

	Dominant structural defects	Recessive enzyme defects
Autosomal	Autosomal dominant	Autosomal recessive

Prevalence and Population Distribution

AD diseases are seen in approximately 1 out of every 200 individuals.
Most AD diseases are individually rare, but some are common in specific populations (e.g., Myotonic Dystrophy in Quebec, Familial Hypercholesterolemia in South African Afrikaner population).
Most affected offspring (>98%) are produced by the union of an unaffected parent with an affected heterozygote (genotype Aa).

Pedigree Patterns in Autosomal Dominant Inheritance

AD inheritance is characterized by vertical transmission in pedigrees, with affected individuals in each generation. Both males and females are equally likely to be affected.

Pedigrees show affected individuals in every generation.
Both sexes are affected, indicating autosomal (not sex-linked) inheritance.

Genotype and Phenotype Ratios

Wild-Type x Affected (Heterozygote)

Genotypes: 2 Hh (affected), 2 hh (unaffected)
Phenotypes: 2 affected, 2 wild-type
At each birth, there is a 50% risk of having an affected child.

Affected x Affected (Complete Dominant)

Genotypes: 1 HH (homozygous affected), 2 Hh (heterozygous affected), 1 hh (wild-type)
Phenotypes: 3 affected, 1 wild-type
Risk: 75% affected, 25% wild-type

Affected x Affected (Incomplete Dominant)

Genotypes: 1 HH (severely affected), 2 Hh (affected), 1 hh (unaffected)
Phenotypes: 1 severely affected, 2 affected, 1 unaffected
Risk: 25% severely affected, 50% affected, 25% unaffected

Types of Autosomal Dominant Inheritance

Complete AD Inheritance: The clinical symptoms of Aa individuals are the same as AA individuals.
Incomplete AD Inheritance: The phenotype of Aa individuals is distinct from and often intermediate to the phenotypes of AA individuals.

Characteristics of Autosomal Dominant Inheritance

Phenotype appears in every generation except in cases of new mutations or reduced penetrance.
Each child of an affected parent has a 50% risk of inheriting the mutant gene (in WT x affected (Aa) mating).
Phenotypically normal family members do not transmit the mutant phenotype to children unless reduced penetrance is present.

Examples of Autosomal Dominant Diseases

Familial Hypercholesterolemia
Marfan Syndrome
Huntington Disease

These diseases illustrate the principles of AD inheritance and show how genetic mutations can lead to distinct clinical syndromes.

Summary Table: Autosomal Dominant vs. Autosomal Recessive Inheritance

Inheritance Pattern	Gene Defect Type	Clinical Expression
Autosomal Dominant	Structural protein defects	Phenotype expressed with one mutant allele
Autosomal Recessive	Enzyme defects	Phenotype expressed only with two mutant alleles

Key Terms

Autosome: Any chromosome that is not a sex chromosome.
Dominant allele: An allele that expresses its phenotype even in the presence of a different allele.
Heterozygote: An individual with two different alleles at a locus (e.g., Aa).
Homozygote: An individual with two identical alleles at a locus (e.g., AA or aa).
Penetrance: The proportion of individuals with a particular genotype who express the expected phenotype.

Example: Huntington Disease

Caused by a mutation in the HTT gene.
Progressive neurodegenerative disorder with late onset.
Inheritance follows autosomal dominant pattern.

Example: Marfan Syndrome

Caused by mutations affecting connective tissue proteins.
Clinical features include cardiovascular, ocular, and skeletal abnormalities.
Inheritance is autosomal dominant.

Example: Familial Hypercholesterolemia

Caused by mutations affecting LDL receptor function.
Results in elevated cholesterol levels and increased risk of cardiovascular disease.
Inheritance is autosomal dominant.