Table of Contents
Overview of Autosomal Genetic Disorders
Autosomal genetic disorders are caused by mutations in genes located on the autosomes—the 22 pairs of non‑sex chromosomes in humans. Unlike X‑linked disorders, these conditions affect males and females equally because both sexes carry the same set of autosomes.
Autosomal disorders can be inherited in different ways, most commonly as autosomal recessive or autosomal dominant traits. They may also arise sporadically through new (de novo) mutations.
Key features:
- Both sexes are usually affected with similar frequency.
- Risk to siblings and offspring depends on the specific mode of inheritance.
- Many disorders show characteristic patterns in pedigrees that allow genetic counseling and risk estimation.
In this chapter, we focus on:
- Distinguishing autosomal dominant and recessive disorders.
- Typical pedigree patterns and recurrence risks.
- Representative examples and their biological consequences.
- Medical and social implications for affected individuals and families.
Autosomal Recessive Disorders
General Features
In autosomal recessive disorders, the disease appears when both copies of the gene (alleles) are mutated: genotype $aa$ (homozygous affected). Individuals with only one mutated allele ($Aa$) are carriers and usually symptom‑free or only mildly affected.
Characteristic points:
- Parents of affected individuals are often healthy carriers.
- The disorder may appear to “skip generations.”
- Increased frequency in consanguineous (related) marriages, because relatives are more likely to carry the same rare mutation.
- Often caused by loss‑of‑function mutations (the gene product is missing or not working).
Pedigree Pattern and Risk
Consider two healthy carrier parents: genotype $Aa \times Aa$.
Punnett square:
- $AA$: unaffected, non‑carrier
- $Aa$: unaffected carrier
- $aA$: unaffected carrier
- $aa$: affected
So, for each child:
- 25 % risk: affected ($aa$)
- 50 % risk: carrier ($Aa$)
- 25 % risk: unaffected non‑carrier ($AA$)
These ratios are probabilities per pregnancy, not guarantees.
In a pedigree:
- Affected individuals usually appear horizontally in a single generation (siblings), while previous generations can be unaffected.
- Men and women affected in similar numbers.
Typical Biological Consequences
Because both gene copies are defective, key cellular functions can be severely impaired. Many recessive disorders involve:
- Enzyme deficiencies in metabolic pathways.
- Transport proteins that are nonfunctional.
- Structural proteins that are absent or unstable (if the normal protein level is halved or less).
As a result, toxic substances may accumulate, essential products may be missing, or certain tissues (e.g., nervous system, blood, liver) may be damaged.
Examples of Autosomal Recessive Disorders
Cystic Fibrosis (CF)
- Gene / Protein: Mutations in the
CFTRgene, encoding a chloride ion channel in epithelial cell membranes. - Main mechanism: Impaired chloride and water transport across cell membranes leads to thick, viscous secretions in various organs.
Clinical Features (Overview)
- Lungs: Thick mucus obstructs airways, recurrent infections, chronic inflammation, progressive lung damage.
- Pancreas: Blockage of exocrine ducts → deficiency of digestive enzymes → poor digestion and malabsorption.
- Sweat glands: Elevated salt (NaCl) in sweat, used diagnostically (“sweat test”).
Genetic Aspects
- Very common autosomal recessive disease in some populations.
- Many different mutations in
CFTR; severity and symptoms can vary. - Heterozygotes (carriers) usually have no symptoms but can be detected via genetic testing.
Phenylketonuria (PKU)
- Gene / Enzyme: Mutations in the gene for phenylalanine hydroxylase.
- Main mechanism: Phenylalanine cannot be efficiently converted to tyrosine → accumulation of phenylalanine and its toxic metabolites.
Consequences
- If untreated in early childhood: severe, irreversible intellectual disability, seizures, behavioral disturbances.
- Tyrosine deficiency can affect pigment synthesis (often lighter hair/skin).
Importance of Early Diagnosis
- Many countries screen newborns using a Guthrie test or related methods.
- Early dietary treatment (restricting phenylalanine intake, supplying safe amino acid mixtures) can prevent most severe symptoms.
- PKU is a classic example of how environmental modification (diet) can largely compensate for a genetic defect.
Sickle Cell Anemia
- Gene / Protein: Mutation in the β‑globin gene of hemoglobin (a single amino acid substitution).
- Main mechanism: Under low oxygen conditions, abnormal hemoglobin polymerizes → red blood cells become sickle‑shaped, rigid, and fragile.
Biological and Clinical Effects
- Blockage of small blood vessels → pain crises, organ damage.
- Increased breakdown of red cells → chronic anemia, jaundice.
- Life‑threatening complications such as stroke, infections, acute chest syndrome.
Heterozygote Advantage
- Carriers (sickle cell trait, $AS$ genotype) are usually healthy.
- In malaria‑endemic regions, carriers have increased resistance to severe malaria, giving the mutant allele a selective advantage.
- This illustrates how evolutionary forces can keep a harmful recessive allele relatively frequent in certain populations.
Autosomal Dominant Disorders
General Features
In autosomal dominant disorders, one altered allele is enough to cause the phenotype. Affected individuals are usually heterozygous ($Aa$). The presence of one normal allele ($A$) does not fully compensate for the mutated one.
Characteristic points:
- An affected person often has one affected parent.
- Affected individuals appear in every generation (“vertical” transmission).
- Males and females are affected equally, and both can transmit the disorder to sons and daughters.
- Caused by various mechanisms:
- Haploinsufficiency: one normal allele does not produce enough functional protein.
- Dominant‑negative effect: mutant protein interferes with normal protein.
- Gain‑of‑function: mutant protein acquires new or overactive function.
Pedigree Pattern and Risk
For a typical cross of affected heterozygote × unaffected:
$Aa \times aa$
- 50 % of children: affected ($Aa$)
- 50 % of children: unaffected ($aa$)
In a pedigree:
- At least one affected individual in each generation (unless a new mutation appears).
- No carriers in the classic sense; if you carry the mutation, you usually show some phenotype (though severity can vary).
Note: Some individuals with an autosomal dominant mutation may be non‑penetrant (genotype present, but no symptoms), making the pedigree appear less clearly dominant.
Examples of Autosomal Dominant Disorders
Huntington’s Disease
- Gene / Protein: Expansion of CAG trinucleotide repeats in the
HTTgene (huntingtin protein). - Main mechanism: Mutant huntingtin is toxic to certain neurons, especially in regions that coordinate movement and behavior.
Key Features
- Late onset: Symptoms typically appear in mid‑adulthood (30–50 years).
- Progressive motor disturbances (involuntary movements, chorea), psychiatric symptoms, and cognitive decline.
- The disease worsens over time and is ultimately fatal.
Anticipation
- The number of CAG repeats can increase when transmitted, especially via the father.
- Longer repeat expansions → earlier onset and often more severe disease.
- This phenomenon is called anticipation (worsening in successive generations).
Genetic Counseling
- If one parent is affected ($Aa$) and the other is healthy ($aa$), each child has a 50 % risk of inheriting the mutation.
- Because of late onset, individuals may have children before symptoms appear, which affects family planning and psychological burden.
- Predictive genetic testing is possible in adults but raises important ethical and psychological questions.
Familial Hypercholesterolemia (FH)
- Gene / Protein: Most often mutations in the LDL receptor gene, but also in other genes of cholesterol metabolism.
- Main mechanism: Impaired removal of LDL (“bad cholesterol”) from the blood → markedly elevated LDL cholesterol.
Consequences
- Early atherosclerosis (fatty deposits in arteries).
- Greatly increased risk of heart attacks and strokes, sometimes already in young adulthood.
- In some cases, visible cholesterol deposits in skin and tendons (xanthomas).
Inheritance Patterns
- In most families, FH behaves as an autosomal dominant trait:
- Heterozygotes: significantly elevated cholesterol, increased cardiovascular risk.
- Rare homozygotes: extremely high cholesterol, severe disease in childhood.
This disorder illustrates how a mutation in a receptor or transport protein can directly influence a common disease risk factor (blood lipids).
Achondroplasia
- Gene / Protein: Specific mutations in the
FGFR3gene (fibroblast growth factor receptor 3). - Main mechanism: Overactive FGFR3 signaling inhibits bone growth in the long bones.
Clinical Features
- Characteristic form of short‑limbed dwarfism:
- Normal trunk length, short arms and legs.
- Typical facial features and spinal curvature.
- Intelligence usually normal.
Genetic Aspects
- Inheritance is autosomal dominant, but ~80 % of cases are due to new (de novo) mutations in sperm.
- Homozygosity for the mutation (two copies) is usually lethal before or shortly after birth.
- Advanced paternal age is associated with an increased risk of new FGFR3 mutations.
Additional Genetic Concepts Relevant to Autosomal Disorders
Penetrance and Expressivity
Even with the same autosomal mutation, the clinical picture may vary:
- Penetrance: Proportion of individuals with the mutation who actually show a recognizable phenotype.
- Incomplete penetrance: Some carriers of the mutant allele remain symptom‑free.
- Expressivity: Degree to which the trait is expressed (mild vs. severe, different organ involvement).
These factors can blur classic Mendelian patterns in families and complicate risk estimation.
De Novo Mutations
Not all autosomal genetic disorders are inherited from parents:
- De novo mutation: A new mutation arises in a germ cell (sperm or egg) or early in embryonic development.
- Parents have normal genotypes in their somatic cells and are usually unaffected.
- Recurrence risk for siblings is generally low but not always zero (e.g., if a parent has germline mosaicism).
Several autosomal dominant disorders, especially those that severely reduce reproductive success, are often caused by de novo mutations (e.g., many cases of achondroplasia, some skeletal dysplasias).
Medical, Ethical, and Social Implications
Diagnosis and Prenatal Testing
For many autosomal genetic disorders, diagnostic tools include:
- Biochemical tests (e.g., enzyme activity, metabolite levels).
- Molecular genetic tests (detection of specific mutations).
- In families with known mutations, prenatal or preimplantation genetic diagnostics may be possible.
The decision to undergo such testing involves:
- Medical considerations (severity, treatability).
- Ethical, cultural, and personal values.
- Potential psychological impact on individuals and families.
Treatment and Management
While many autosomal disorders cannot be “cured” at the DNA level (yet), a range of strategies can significantly improve quality of life:
- Dietary and lifestyle interventions (PKU diet, low‑cholesterol diet in FH).
- Symptomatic therapies (medications, physiotherapy, surgery).
- Enzyme replacement therapy or substrate reduction in some metabolic diseases.
- Gene‑based therapies (still under development or limited use) that aim to correct or bypass the genetic defect.
Autosomal genetic disorders illustrate how molecular changes in single genes can have wide‑ranging effects on the entire organism and how understanding inheritance patterns enables prediction, prevention, and targeted treatment.