What is autosomal dominant (Autosomal Dominant) transmission?

Autosomal Dominant Transmission

Autosomal dominant transmission is a pattern of genetic inheritance where a single mutated copy of a gene on a non-sex chromosome (autosome) is sufficient to cause disease, meaning an affected individual has a 50% chance of passing the condition to each offspring. 1

Core Principles of Inheritance

• One affected parent is typically present in the family pedigree, with disease appearing across multiple generations 1
• Males and females are affected in approximately equal numbers, as the gene is located on an autosome rather than a sex chromosome 2
• Each child of an affected parent has a 50% risk of inheriting the mutant gene and developing the condition 2
• Vertical transmission pattern is characteristic, with at least one affected individual in at least two generations when family history is positive 1

Molecular Mechanisms

Autosomal dominant diseases typically arise through three main mechanisms:

• Haploinsufficiency: A single functional copy of the gene is insufficient to maintain normal function 3
• Dominant-negative effects: The mutant protein interferes with the function of the normal protein produced by the wild-type allele 3
• Gain-of-function mutations: The mutant gene product acquires a new, harmful function 3

Important Clinical Considerations

Penetrance and Expressivity

• Penetrance approaches 100% in many autosomal dominant conditions when patients are followed long enough, though age of onset varies widely 1
• Variable expressivity can complicate identification of affected individuals, as disease severity may differ substantially even within the same family 2
• In conditions like neurofibromatosis, only one-fourth to one-third of gene carriers experience serious clinical consequences despite inheriting the mutation 2

De Novo Mutations

• New mutations can occur without a positive family history, particularly in genes like HNF1B where de novo mutations are well-documented 1
• Absence of family history does not exclude autosomal dominant disease, as the condition may represent a new mutation or missed diagnoses in other family members 1

Late-Onset Diseases

• Age of disease manifestation varies widely, with some autosomal dominant conditions like Huntington's disease presenting late in life, creating challenges for reproductive decision-making 2
• In autosomal dominant tubulointerstitial kidney disease, renal replacement therapy is typically required between ages 30-50 years, though the range extends from 20-80 years 1

Common Pitfalls

• Father-to-son transmission definitively confirms autosomal dominant inheritance and excludes X-linked patterns 4
• Filtering genetic variants by inheritance pattern alone is insufficient, as some genes demonstrate both autosomal dominant and recessive inheritance patterns depending on the specific mutation 3
• Cystic changes or other imaging findings may not be pathognomonic for specific autosomal dominant conditions; for example, renal cysts in ADTKD occur no more frequently than in other kidney diseases 1