What are examples of autosomal recessive and dominant diseases and how do they differ?

Autosomal Recessive and Dominant Diseases: Examples and Key Differences

Autosomal recessive diseases require two mutated gene copies (one from each parent) for disease expression, while autosomal dominant diseases manifest with just one mutated copy, fundamentally differing in their inheritance patterns, penetrance, and clinical presentation.

Examples of Autosomal Recessive Diseases

Immunodeficiency Disorders

• DOCK8 deficiency (Hyper-IgE Syndrome Type 2): Characterized by severe allergic manifestations, eosinophilia, disseminated cutaneous viral infections (molluscum contagiosum, HSV, HPV), and autoimmune vasculopathy with CNS involvement 1
• Cartilage-Hair Hypoplasia (CHH): Presents with short-limbed dwarfism, hypoplastic hair, defective immunity with frequent infections, and anemia, caused by mutations in the RMRP gene 1

Metabolic and Systemic Disorders

• Phenylketonuria (PKU): An inborn error of metabolism with phenylalanine hydroxylase (PAH) enzyme deficiency leading to plasma phenylalanine accumulation 2
• Classical homocystinuria, galactosemia, and Usher syndrome: Additional examples of autosomal recessive metabolic conditions 2
• Cystic fibrosis: A common treatable autosomal recessive disorder amenable to carrier screening 3, 4
• Sickle cell disease: A hemoglobinopathy common in certain ethnic backgrounds 4

Cardiac Conditions

• Naxos disease: A cardiocutaneous condition caused by JUP gene mutations, presenting with arrhythmogenic cardiomyopathy 1
• Carvajal syndrome: Associated with DSP gene mutations 1

Hearing Loss

• Approximately 77% of nonsyndromic hearing impairment (NSHI) follows autosomal recessive inheritance, typically presenting as profound prelingual deafness 1

Examples of Autosomal Dominant Diseases

Kidney Diseases

• Autosomal Dominant Tubulointerstitial Kidney Disease (ADTKD): A group of conditions including ADTKD-UMOD (uromodulin mutations), ADTKD-MUC1 (mucin-1 mutations), ADTKD-REN (renin mutations), and ADTKD-HNF1B 1
• Autosomal dominant polycystic kidney disease: Associated with approximately 8% risk of developing intracranial aneurysms 5

Immunodeficiency Disorders

• STAT3-related Hyper-IgE Syndrome (Type 1): Characterized by recurrent infections, eczema, elevated IgE, skeletal abnormalities (hyperextensible joints, bone fragility, delayed tooth shedding), and characteristic coarse facial features 1

Cardiac Conditions

• Arrhythmogenic cardiomyopathy (ACM): Most commonly inherited as autosomal dominant with age-related reduced penetrance and variable expressivity, though inheritance patterns can be complex 1
• LMNA-related dilated cardiomyopathy: Presents with LV enlargement, reduced systolic function, and significant conduction system disease or arrhythmias 1
• Left ventricular noncompaction (LVNC): In the majority of adult patients with isolated LVNC, it follows autosomal dominant inheritance 1

Neurological Conditions

• Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): Caused by NOTCH3 gene mutations, presenting with subcortical infarcts, dementia, migraine headaches, and white matter changes 1
• COL4A1-related conditions: Can cause leukoaraiosis, microbleeds, and hereditary angiopathy with nephropathy, aneurysm, and muscle cramps syndrome 1

Connective Tissue Disorders

• Ehlers-Danlos syndrome type IV: Associated with aneurysms affecting the intracranial portion of the internal carotid artery 5

Hearing Loss

• Approximately 22% of nonsyndromic hearing impairment follows autosomal dominant inheritance, typically with more variable phenotype and later onset 1

Fundamental Differences Between Inheritance Patterns

Genetic Mechanism

• Autosomal recessive: Requires two mutated alleles (one from each parent) for disease expression; the dominant wildtype allele typically suppresses disease presentation in carriers 2
• Autosomal dominant: Only one mutated allele is needed for disease manifestation, often through haploinsufficiency, dominant-negative effects, or gain-of-function mechanisms 6

Penetrance and Expression

• Autosomal recessive: Typically shows complete penetrance when both alleles are mutated; 90% of children with congenital profound autosomal recessive hearing loss are born to parents with normal hearing 1
• Autosomal dominant: Often demonstrates reduced penetrance and variable expressivity; for example, only 34-41% of genotype-positive first-degree relatives with desmosomal variants meet diagnostic criteria for arrhythmogenic cardiomyopathy 1

Clinical Presentation

• Autosomal recessive: Generally presents with more severe, earlier-onset disease; for instance, autosomal recessive NSHI typically causes profound prelingual deafness 1
• Autosomal dominant: Often shows more variable phenotype with later onset; family members sharing the same STAT3 mutation can present with different severity of clinical symptoms 1

Carrier Status Implications

• Autosomal recessive carriers: Traditionally considered "unaffected," but emerging evidence suggests they may display attenuated symptoms; PKU carriers exhibit impaired enzymatic activity and elevated plasma phenylalanine levels, with possible compromised cognitive and mental health outcomes 2
• Autosomal dominant: Heterozygotes are typically affected, though severity varies 6

Special Considerations and Pitfalls

Dual Inheritance Genes

• Some genes demonstrate both AD and AR inheritance patterns (AD/AR genes), with pathogenic variants leading to distinct or similar phenotypes depending on the molecular mechanism 6
• AD/AR genes exhibit unique bioinformatic properties including intermediate constraint scores, greater average number of exons, and elevated propensity to form homomeric/heteromeric proteins 6

Complex Inheritance Patterns

• Oligogenic inheritance: Many cases of arrhythmogenic cardiomyopathy may be oligogenic or multifactorial with both genomic and environmental factors contributing to pathogenesis 1
• X-linked and mitochondrial: Additional inheritance patterns exist; X-linked accounts for 1% of NSHI, while mitochondrial inheritance may account for less than 1% overall but 10-20% in some populations 1

Screening and Genetic Counseling

• Expanded carrier screening (ECS) can detect whether individuals carry gene variants for common autosomal recessive conditions like cystic fibrosis 4
• When both partners carry a variant in the same gene, there is a 25% chance their child will have the genetic disease 4
• Not all expanded carrier screens analyze the same genes, and understanding results requires support from appropriately trained professionals 4

DNA Damage Processing Defects

• Both autosomal recessive and autosomal dominant modes of inheritance are represented in DNA damage processing defects, characterized by genomic instability with eventual cancer appearance 7
• Distinct diseases may arise from different mutations in one gene, with clinical phenotypes reflecting the loss of different partial functions 7