What are autosomal dominant conditions?

Autosomal Dominant Conditions

Autosomal dominant conditions are genetic disorders where only one mutated copy of a gene (from either parent) is sufficient to cause disease, meaning affected individuals typically have a 50% chance of passing the condition to each child. 1, 2

Core Inheritance Principles

Autosomal dominant inheritance follows predictable patterns:

• An affected individual typically has one affected parent (vertical transmission through generations) 2
• Males and females are affected in approximately equal numbers 2
• Each child of an affected parent has a 50% risk of inheriting the disease-causing mutation 1, 2
• The condition can affect multiple generations consecutively 2

Important Exceptions and Complexities

De novo mutations occur and complicate family history assessment:

• New mutations can arise spontaneously, resulting in affected individuals with no family history 3, 4
• Negative family history does not exclude autosomal dominant inheritance 3
• This is particularly relevant in conditions like autosomal dominant non-syndromic hearing loss and childhood-onset spinal muscular atrophy 3, 4

Penetrance and expressivity create clinical variability:

• Complete penetrance means all individuals with the mutation will eventually develop disease (as in Huntington disease) 1
• Variable expressivity causes different severity levels among affected family members, making identification difficult 2
• Neurofibromatosis demonstrates extreme variable expressivity—while 50% inherit the gene, only 25-33% experience serious consequences 2

Age of onset varies significantly:

• Late-onset conditions (like Huntington disease with average onset 35-45 years) create reproductive counseling challenges 1, 2
• Affected individuals may have children before knowing their own disease status 2
• Early-onset forms exist in some conditions, particularly with anticipation 1

Genetic Phenomena in Autosomal Dominant Disorders

Anticipation—worsening across generations:

• Progressive increase in mutation severity (such as CAG repeat expansion) occurs in successive generations 1
• Results in earlier symptom onset and potentially more severe disease in offspring 1
• Classic example: Huntington disease with expanding trinucleotide repeats 1

Genetic heterogeneity complicates diagnosis:

• Multiple different genes can cause clinically similar autosomal dominant phenotypes 5, 6
• Autosomal dominant polycystic kidney disease results from mutations in PKD1 or PKD2 6
• Autosomal dominant tubulointerstitial kidney disease has at least four causative genes (UMOD, MUC1, REN, HNF1B) 5

Clinical Examples Across Organ Systems

Neurological conditions:

• Huntington disease: CAG repeat expansion >38 in huntingtin gene, complete penetrance 1
• Autosomal dominant striatonigral degeneration: onset in second-fourth decade with parkinsonian features 7
• Myotonic dystrophy: variable onset and expressivity 2

Renal conditions:

• Autosomal dominant polycystic kidney disease (ADPKD): significant cause of ESRD 6
• Autosomal dominant tubulointerstitial kidney disease (ADTKD): progressive kidney function loss with bland urinary sediment 5

Cardiac conditions:

• Autosomal dominant dilated cardiomyopathy: most common inherited form, often with conduction disease 5
• LMNA-related cardiomyopathy: presents with arrhythmias and conduction abnormalities preceding heart failure 5

Sensory conditions:

• Autosomal dominant non-syndromic hearing loss: typically bilateral, post-lingual, high-frequency, progressive 3

Diagnostic Approach

Genetic testing is increasingly the diagnostic standard:

• Commercially available for many conditions (Huntington disease, ADPKD) 1, 6
• Genetic counseling should precede testing 1
• Some genes remain technically challenging to sequence (MUC1 in ADTKD) 5

Clinical diagnosis requires:

• Detailed three-generation family pedigree documenting affected individuals 5
• Recognition that absence of family history doesn't exclude diagnosis due to de novo mutations 5, 3
• Phenotypic characterization including age of onset, progression pattern, and associated features 5

Critical Counseling Considerations

Reproductive risks are straightforward but emotionally complex:

• 50% transmission risk to each offspring regardless of sex 1, 2
• Late-onset conditions create uncertainty about reproductive decisions 2
• Predictive testing in asymptomatic at-risk individuals requires careful counseling 5

Testing minors requires individualized assessment:

• Generally not recommended when no childhood treatment exists 5
• Should be considered when early intervention improves outcomes (HNF1B-related ADTKD) 5
• Family preferences must be balanced against medical benefit 5