How can autosomal dominant inheritance be explained?

Explaining Autosomal Dominant Transmission

Autosomal dominant inheritance means that a single mutated copy of a gene on a non-sex chromosome is sufficient to cause disease, with an affected individual having a 50% chance of passing the condition to each child, regardless of the child's sex. 1

Core Principles of Autosomal Dominant Inheritance

Basic Transmission Pattern

• An affected individual typically has one affected parent, demonstrating vertical transmission through generations 2
• Males and females are affected in approximately equal numbers, as the gene is located on an autosome (chromosomes 1-22) rather than sex chromosomes 2
• Each child of an affected parent has a 50% risk of inheriting the mutant gene and developing the disorder 2

Genetic Mechanism

• Only one copy of the mutated gene is required to manifest disease—the individual is heterozygous for the mutation 1
• The affected individual carries one normal allele and one mutant allele 1
• The mutant allele is "dominant" because it overrides the normal allele's function 1

Key Features That Complicate Simple Inheritance Patterns

Variable Expressivity

• The same mutation can cause different severity of disease among affected family members 2
• In neurofibromatosis, for example, while 50% of children inherit the gene, only one-fourth to one-third experience serious consequences due to variable expressivity 2
• This variability can make identification of mildly affected individuals challenging 2

Incomplete Penetrance

• Not all individuals who inherit the mutation will develop clinical manifestations, though this is rare in most autosomal dominant conditions 1
• Penetrance may be reduced in some families, affecting risk calculations 1

Variable Age of Onset

• Some autosomal dominant conditions manifest late in life, such as Huntington's disease, which creates challenges for reproductive decision-making 2
• In LMNA-related dilated cardiomyopathy, presentation typically occurs in early to mid-adulthood 1

Recognizing Autosomal Dominant Patterns in Clinical Practice

Family History Characteristics

• Disease appears in at least three individuals across two or more generations, with two being first-degree relatives of the third (e.g., grandparent, parent, child) 1
• Vertical transmission pattern—disease passes from generation to generation without skipping 1
• Male-to-male transmission definitively excludes X-linked inheritance and confirms autosomal transmission 3

Patterns That May Obscure Recognition

• Small family size can mask the inheritance pattern 1
• Premature death from other causes may prevent manifestation 1
• De novo mutations can present as isolated cases without family history 1
• Missed diagnoses in other family members may falsely suggest sporadic disease 1

Special Considerations in Genetic Counseling

Risk Communication

• Each pregnancy carries an independent 50% risk—previous unaffected children do not reduce risk for subsequent pregnancies 2
• Both affected and unaffected offspring can occur in the same family due to chance 1
• Unaffected individuals do not carry the mutation and cannot transmit it to their children (assuming complete penetrance) 1

Exceptions and Variants

• Sex-limited autosomal dominant inheritance exists where the gene is on an autosome but manifests only in one sex, such as male-limited precocious puberty 4
• This should not be confused with X-linked inheritance, as the gene location remains autosomal 4

Testing Implications for Family Members

• When a causative mutation is identified in an affected individual, at-risk family members can undergo predictive testing 1
• For potential kidney donors in families with autosomal dominant kidney disease, genetic testing should be mandatory if a mutation is known 1
• Testing of minors is generally not recommended unless specific therapeutic interventions are available, though decisions require individualization 1

Common Clinical Pitfalls to Avoid

• Do not assume sporadic cases exclude autosomal dominant inheritance—they may represent de novo mutations or unrecognized affected family members 1
• Do not equate autosomal dominant with 100% penetrance—some conditions show reduced penetrance, affecting risk calculations 1
• Do not overlook variable expressivity—mildly affected family members may be missed, leading to underestimation of genetic risk 2
• Do not confuse sex-limited autosomal dominant inheritance with X-linked patterns—male-to-male transmission confirms autosomal location 4, 3