Disease Inheritance Patterns: Comprehensive Study Notes

Introduction to Disease Inheritance

• Key Concepts:

  • Dominant (A): An allele that expresses its phenotype even in the presence of a recessive allele.

  • Recessive (a): An allele that expresses its phenotype only when two copies are present (homozygous recessive).

  • Sex-linked: Genes located on sex chromosomes (X or Y).

• Pedigree Symbols:

  • Female: Circle.

  • Male: Square.

  • Healthy/Unaffected: Unfilled shape.

  • Carrier: Half-filled shape (or a dot inside).

  • Diseased/Affected: Fully filled shape.

Autosomal Dominant Inheritance

• Allele Definitions:

  • Dominant (A): The 'affected' allele.

  • Recessive (a): The 'unaffected' or 'normal' allele.

  • Phenotype Expression: If an individual inherits the dominant allele (A), they will express the dominant phenotype, meaning they are affected.

• Rules of Inheritance:

  • Affects males and females equally.

  • Every affected person has an affected parent (vertical transmission).

  • In families, the ratio of affected to unaffected offspring is typically 1:1.

  • If both parents are unaffected (aa imes aa), all their children will be unaffected.

• Pedigree Example: Shows affected individuals in every generation, with affected offspring having at least one affected parent. Often a parent with the condition passes it to half their children. (Refer to provided pedigree on Page 5).

• Risks and Genetic Crosses:

  • Due to the rarity of dominant disease alleles, most affected individuals are heterozygotes (Aa).

  • Affected (heterozygote) x Normal (Aa imes aa):

    • Outcome: Aa:aa in a 1:1 ratio.

    • Result: 50\% affected, 50\% unaffected.

    • Punnett Square:

| | A | a |
|---|---|---|
| a | Aa | aa |
| a | Aa | aa |

* **Affected (heterozygote) x Affected (heterozygote) (Aa imes Aa)**:
* Outcome: AA:Aa:aa in a 1:2:1 ratio.
* Result: 75\% affected (AA, Aa), 25\% unaffected (aa).
* Note: Homozygotes (AA) are often more severe, potentially lethal.
* Punnett Square:

| | A | a |
|---|---|---|
| A | AA | Aa |
| a | Aa | aa |

• Examples:

  • Achondroplasia:

    • Symptoms: Shortening of limbs, macrocephaly, respiratory problems.

    • Frequency: 1/1000 births.

    • Map location: 4p16 (gene: FGFR3).

  • Familial Hypercholesterolaemia:

    • Symptoms: High cholesterol, atherosclerosis, coronary heart disease.

    • Frequency: 1/500 individuals.

    • Map location: 19p (gene: LDL receptor).

Autosomal Recessive Inheritance

• Allele Definitions:

  • Dominant (A): The 'unaffected/normal' allele.

  • Recessive (a): The 'affected' allele.

  • Phenotype Expression: To display a recessive phenotype (i.e., be affected), an individual must have two copies of the recessive allele (aa). Individuals with AA or Aa are unaffected, but Aa are carriers.

• Rules of Inheritance:

  • Affects males and females equally.

  • Pedigrees often show "breaks" in transmission, meaning affected individuals may appear in a lineage where parents are unaffected (but are carriers).

  • When both parents are affected (aa imes aa), all children will be affected.

  • Affected children can be born to unaffected parents (if both parents are carriers, Aa).

  • Note: This pattern is often revealed by consanguineous (related) matings, as relatives have a higher chance of sharing rare recessive alleles.

• Pedigree Example: Shows affected individuals often skipping generations, with unaffected parents having affected offspring. (Refer to provided pedigree on Page 10).

• Risks and Genetic Crosses:

  • Most affected individuals are produced from the mating of two normal carriers.

  • Carrier x Carrier (Aa imes Aa):

    • Outcome: AA:Aa:aa in a 1:2:1 ratio.

    • Result: 25\% affected (aa), 50\% carriers (Aa), 25\% unaffected non-carriers (AA).

    • Punnett Square:

| A | a |
| A | AA | Aa |
| a | Aa | aa |

* **Affected x Affected (aa imes aa)**:
* Outcome: All aa
* Result: 100\% affected.
* **Affected x Normal (carrier) (aa imes Aa)**:
* Outcome: Aa:aa in a 1:1 ratio.
* Result: 50\% affected (aa), 50\% carriers (Aa).
* Punnett Square:

| | a | a |
|---|---|---|
| A | Aa | Aa |
| a | aa | aa |

• Examples:

  • Cystic Fibrosis:

    • Symptoms: Chronic obstructive airway disease, pancreatic insufficiency, anaemia, failure to thrive.

    • Frequency: 1/2500 births (carriers 1/25).

    • Map location: 7q31 (gene: CFTR).

  • Haemochromatosis:

    • Symptoms: Iron accumulation, cirrhosis, cardiomyopathy.

    • Frequency: 1/400 individuals (carriers 1/10).

    • Map location: 6p (gene: HLA-H).

X-linked Dominant Inheritance

• Allele Definitions:

  • Dominant (X^A): The 'affected' allele.

  • Recessive (X^a): The 'unaffected' or 'normal' allele.

  • Phenotype Expression (Females): If a female receives the dominant allele (X^A), she shows the dominant phenotype (i.e., X^A X^A or X^A X^a are affected).

  • Phenotype Expression (Males): Males have only one X chromosome. If a male receives the dominant allele (X^A), he shows the dominant phenotype (i.e., X^A Y is affected).

• Rules of Inheritance:

  • Expressed and transmitted by both sexes.

  • Occurs approximately twice as frequently in females as in males.

  • Affected males (X^A Y) pass the condition to all of their daughters (X^A X^a if mother is X^a X^a) but none of their sons.

  • Affected females (X^A X^a) pass the condition to half of her children (irrespective of sex).

  • Note: Females are generally less severely affected than males, possibly due to X-inactivation.

• Pedigree Example: Shows vertical transmission, more affected females, and affected fathers passing the trait to all daughters. (Refer to provided pedigree on Page 15).

• Risks and Genetic Crosses:

  • Due to the rarity of dominant disease alleles, most affected individuals are heterozygotes (X^A X^a for females or X^A Y for males).

  • Affected female (X^A X^a) x Normal male (X^a Y):

    • Cross: X^A X^a imes X^a Y

    • Offspring Genotypes: X^A X^a:X^a X^a and X^A Y:X^a Y each in a 1:1 ratio.

    • Result: 50\% affected daughters, 50\% unaffected daughters; 50\% affected sons, 50\% unaffected sons.

    • Overall: 50\% affected offspring.

    • Punnett Square:

| X^A | X^a |
| X^a | X^A X^a | X^a X^a |
| Y | X^A Y | X^a Y |

* **Affected male (X^A Y) x Normal female (X^a X^a)**:
* Cross: X^A Y imes X^a X^a
* Offspring Genotypes: All daughters are X^A X^a, all sons are X^a Y.
* Result: 100\% affected daughters, 0\% affected sons.
* Punnett Square:

| X^A | Y |
| X^a | X^A X^a | X^a Y |
| X^a | X^A X^a | X^a Y |

• Examples:

  • Rett Syndrome:

    • Symptoms: Autism, gait ataxia, breathing irregularities.

    • Frequency: 1/10\,000 - 15\,000 in females (less in males due to embryonic lethality).

    • Map location: X chromosome (gene: MECP2 transcription factor).

X-linked Recessive Inheritance

• Allele Definitions:

  • Dominant (X^A): The 'unaffected/normal' allele.

  • Recessive (X^a): The 'affected' allele.

  • Phenotype Expression (Females): Females need two copies of the recessive allele (X^a X^a) to display the disease. X^A X^A and X^A X^a are unaffected, but X^A X^a is a carrier.

  • Phenotype Expression (Males): Males have only one X chromosome. If a male receives the recessive allele (X^a Y), he will show the disease.

• Rules of Inheritance:

  • Much higher incidence in males than in females.

  • Affected males (X^a Y):

    • Pass the condition to all of their daughters, but the daughters do not express it (they become carriers if the mother contributes an X^A).

    • Never pass the condition to their sons.

  • Affected females (X^a X^a):

    • Pass the condition to all of their daughters (who become carriers if the father contributes an X^A).

    • Pass the condition to all of their sons, who will express it.

  • Carrier females (X^A X^a):

    • Pass the condition to half of their daughters, but those daughters do not express it (half become carriers).

    • Pass the condition to half of their sons, who will express it.

• Pedigree Example: Shows a skipping of generations, primarily affected males, and unaffected carrier mothers having affected sons. (Refer to provided pedigree on Page 20).

• Risks and Genetic Crosses:

  • Affected male (X^a Y) x Unaffected female (X^A X^A):

    • Cross: X^A X^A imes X^a Y

    • Offspring: All daughters are X^A X^a (carriers), all sons are X^A Y (unaffected).

    • Result: 100\% offspring unaffected (all daughters are carriers).

  • Unaffected male (X^A Y) x Carrier female (X^A X^a):

    • Cross: X^A X^a imes X^A Y

    • Offspring: Daughters are X^A X^A:X^A X^a (1:1). Sons are X^A Y:X^a Y (1:1).

    • Result: 100\% daughters unaffected (50\% are carriers); 50\% sons affected, 50\% sons unaffected.

  • Affected male (X^a Y) x Carrier female (X^A X^a):

    • Cross: X^A X^a imes X^a Y

    • Offspring: Daughters are X^A X^a:X^a X^a (1:1). Sons are X^A Y:X^a Y (1:1).

    • Result: 50\% daughters affected (X^a X^a), 50\% daughters are carriers (X^A X^a); 50\% sons affected (X^a Y), 50\% sons unaffected (X^A Y).

  • Unaffected male (X^A Y) x Affected female (X^a X^a):

    • Cross: X^a X^a imes X^A Y

    • Offspring: All daughters are X^A X^a (carriers), all sons are X^a Y (affected).

    • Result: 100\% daughters unaffected (all are carriers); 100\% sons affected.

• Examples:

  • Haemophilia A:

    • Symptoms: Severe bleeding, bruising.

    • Frequency: 1/5000 in males.

    • Map location: Xq28 (gene: Factor VIII clotting factor).

  • Duchenne Muscular Dystrophy:

    • Symptoms: Muscle weakness and degeneration.

    • Frequency: 1/3500 in males.

    • Map location: Xp21 (gene: Dystrophin).

Y-linked Inheritance

• Allele Definitions:

  • Only males possess a Y chromosome. If a male inherits an affected allele on his Y chromosome (Y^D), he will express the disease phenotype.

• Rules of Inheritance:

  • ONLY Males are affected: This inheritance pattern is exclusive to males.

  • Generally follows a dominant mode of inheritance.

  • Expressed in and transmitted only by males to all of their sons.

• Risks and Genetic Crosses:

  • Affected male (X Y^D) x Unaffected female (X X):

    • Cross: X X imes X Y^D

    • Offspring: All daughters are X X (unaffected), all sons are X Y^D (affected).

    • Result: 100\% daughters unaffected; 100\% sons affected.

• Example:

  • Hypertrichosis Pinnae Auris:

    • Symptoms: Excessive ear hair growth.

    • Map location: Y chromosome.

Co-dominance

• Definition:

  • A type of inheritance where different alleles for a gene are both expressed, giving rise to distinct (independent) phenotypes in the heterozygote.

  • Neither allele is dominant nor recessive; both contribute equally to the phenotype.

• Example:

  • ABO Blood Group System:

    • Alleles: I^A, I^B, I^O (often denoted as i for I^O).

    • Genotypes and Phenotypes:

      • I^A I^A or I^A I^O (I^A i) = Type A blood

      • I^B I^B or I^B I^O (I^B i) = Type B blood

      • I^A I^B = Type AB blood (Both A and B antigens expressed simultaneously, demonstrating co-dominance).

      • I^O I^O (ii) = Type O blood