Autosomal dominant inheritance 11/11 & 11/13

Unit 4: Single-Gene Disease Inheritance

Autosomal Dominant Inheritance 11/11 & 11/13

Definition of Terms

• Mendelian Trait/Monogenic Trait: A specific genotype at a single locus is the primary determinant of a trait.

• Dominant Disorder (Trait): A human monogenic disorder determined by a nuclear gene manifested in the heterozygote.

• Heterozygosity: A condition in which an individual has two different alleles at a locus, leading to a clear pathological phenotype when one allele is dominant.

• The normal allele alone is insufficient to ensure normal function.

Characteristics of Autosomal Dominant Inheritance

1. Inheritance Pattern:

   • Every affected individual should have at least one affected parent.

   • Successive generations exhibit the trait.

2. Sex Ratio:

   • Males and females are equally affected.

   • Traits follow an autosomal pattern.

3. Phenotype Severity:

   • The phenotype in homozygous dominant individuals (AA) is often more severe than in heterozygous individuals (Aa).

   • Affected individuals are typically heterozygous (Aa) with an homozygous recessive (aa) spouse, leading to a 50% chance that their children will be affected.

4. Generational Appearance:

   • Dominant traits appear in nearly every generation; all affected individuals have an affected parent.

   • Each child of affected parents has a 50% chance of being affected.

Autosomal Dominant and Recurrence Risk

• Affected individuals are usually heterozygous for the dominant allele; homozygous conditions (AA) are less common and can cause severe phenotypes.

• Example: Two affected individuals may have unaffected children when both are heterozygous (Aa).

Frequency and Population Genetics

• In rare autosomal dominant diseases, it is highly unlikely that affected individuals inherit the mutant gene from both parents as they are generally heterozygous.

Incompletely Dominant Inheritance

• Certain conditions display incomplete dominance where homozygosity for a dominant allele results in more severe phenotypes than heterozygosity, characterized by varying degrees of symptoms.

Variable Expressivity

• Variable Expressivity: The degree of phenotype expression among individuals with the same genotype. This can manifest as differing disease severity even among family members.

• Example: Marfan syndrome shows variable expressivity influenced by allelic heterogeneity and various genetic/environmental factors, complicating diagnosis.

Penetrance

• Penetrance: The probability that a person with a specific genotype will express the associated phenotype.

  • Complete Penetrance: 100% of individuals with a specific genotype manifest the disease.

  • Example: Individuals with achondroplasia exhibit 100% penetrance.

  • Reduced Penetrance: Not all individuals with the genotype express the phenotype.

    • Example: BRCA1 mutations related to familial breast cancer show 60-85% penetrance.

    • Retinoblastoma, with 90% penetrance, where 10% of obligate carriers do not show symptoms.

Clinical Examples of Autosomal Dominant Disorders

1. Achondroplasia

2. Marfan Syndrome

3. Neurofibromatosis Type 1 and 2

4. Huntington Disease

Case Study: Marfan Syndrome (MFS)

• An autosomal dominant disorder characterized by multisystem impacts.

  • First described over 100 years ago by Dr. Marfan.

  • Diagnosis is usually based on clinical criteria, including signs like the thumb sign.

  • Connective tissue disorder affecting the skeletal, ocular, pulmonary, skin, and cardiovascular systems.

  • Resulting from mutations in the FBN1 gene, which encodes fibrillin-1.

    • Fibrillin is a glycoprotein in the extracellular matrix of connective tissue.

  • Phenotype: 100% penetrance, variable expressivity of symptoms.

  • Affected individuals have a 50% chance of passing it on to their offspring.

  • ~25% present with a de novo mutation.

De Novo Mutation in Marfan Syndrome

• Spontaneous mutations in the MFS gene occurring during gamete formation.

• Higher incidence associated with advanced paternal age.

Neurofibromatosis

• Autosomal dominant condition affecting the nervous system, eye, and skin, characterized by benign tumors.

  • This condition also shows variable expressivity and 100% penetrance.

  • About half of cases arise from de novo mutations.

Huntington Disease

• Autosomal dominant disorder affecting neurological functions with symptoms of progressive dementia and movement disturbances.

  • Inherited through mutations in the HD gene marked by an abnormal expansion of CAG repeats, encoding polyglutamine repeats.

  • Normal HD gene contains 9-35 CAG repeats, while affected individuals have 40 or more.

  • Onset varies greatly, typically between ages 30-50, with most cases presenting around 45.

  • Transmitted features of Huntington Disease can lead to anticipation, with symptoms appearing earlier and becoming more severe in subsequent generations due to expanded repeats.

  • Anticipation: Notably associated with disorders characterized by trinucleotide repeat expansions.