Single Gene Disorders Overview

Single Gene Disorders

• Genetic Basis: Single-gene disorders, also known as Mendelian or unifactorial disorders, arise from mutations affecting a single gene.
• Prevalence: More than 5,000 such disorders are identified, accounting for 1% of adult hospital admissions and 6-8% of pediatric admissions.
• Mutation Types: Mutations encompass changes in the DNA sequence, including:
  • Chromosome Mutations: Structural alterations (e.g., translocations, deletions) or gain/loss of whole chromosomes (e.g., monosomy, trisomy).
  • Gene Mutations: Changes at the level of individual genes, affecting the nucleotide sequence.
    • Germ Cell Mutations: Inherited and cause hereditary diseases.
    • Somatic Cell Mutations: Do not cause hereditary diseases but may lead to cancers or congenital malformations.

Gene Mutations

• Point Mutations: Single base substitutions within a DNA sequence:

  • Missense Mutation: Replaces one amino acid with another.
    • Conservative: Substituted amino acid is similar to the original, often minimal impact on protein function.
    • Non-Conservative: Substitutes with a biochemically different amino acid, potentially significant consequences for protein function. Example: Sickle cell anemia (mutation in β-globin gene).
  • Nonsense Mutation: Converts a codon for an amino acid into a stop codon, leading to premature protein termination. Example: β0-thalassemia (mutation affects glutamine codon, creating a stop codon).
  • Silent Mutation: Alters a base pair but does not change the encoded amino acid; often located in non-coding regions and has no impact on protein function.

• Frameshift Mutation: Insertion or deletion of nucleotides shifts the reading frame during translation, resulting in a drastically altered protein sequence downstream of the mutation, often leading to non-functional proteins.

• Trinucleotide Repeat Mutations: Expansion of a three-nucleotide sequence. Example: Fragile X syndrome (expansion of CGG repeat within the FMR1 gene).

Inheritance Patterns of Single-Gene Disorders

• Autosomal Dominant:

  • Affected Allele: Manifests with one mutated allele.
  • Parent Involvement: Usually, at least one parent is affected.
  • Sibling Risk: Siblings have a 50% chance of inheriting the trait.
  • New Mutations: Some affected individuals may have unaffected parents due to new mutations.
  • Incomplete Penetrance: Individuals may inherit the mutated gene but not exhibit the phenotype.
  • Variable Expressivity: The disorder can present differently in individuals carrying the same mutation.
  • Late Onset: Symptoms often appear in adulthood.
  • Heterozygous Manifestation: The disorder is primarily expressed in heterozygotes.
  • Equal Gender Effect: Both males and females are affected equally.

• Autosomal Recessive:

  • Affected Alleles: Manifests with two mutated alleles.

  • Parent Involvement: Parents are typically unaffected carriers.

  • Sibling Risk: Siblings have a 25% chance of inheriting the trait.

  • Consanguinity: Affected individuals may be the result of consanguineous marriages, especially for rare mutations.

  • Uniform Expression: More uniform expression of the disorder compared to dominant disorders.

  • Complete Penetrance: High likelihood of individuals with the mutation expressing the disorder.

  • Early Onset: Symptoms usually appear early in life.

  • Rare New Mutations: New mutations are uncommon.

  • Enzyme-Encoding Genes: Many mutated genes in autosomal recessive disorders encode enzymes.

  • Inborn Errors of Metabolism: Autosomal recessive disorders include many inborn errors of metabolism.

  • X-Linked Disorders:

  • No Father-Son Transmission: Fathers cannot transmit the disorder to their sons.

  • Obligate Carriers: All daughters of affected males are obligate carriers.

  • Hemizygous Males: Males are hemizygous for X-linked genes, meaning they have only one copy.

  • Predominantly Recessive: Most X-linked disorders are recessive.

  • Sex Distribution: Females are typically carriers, while males are affected.

  • Maternal Transmission: Carrier females transmit the disorder to their sons.

  • No Paternal Transmission to Sons: Affected males cannot transmit the disease to their sons.

  • Rare X-Linked Dominant Disorders: Examples include vitamin D-resistant rickets, Alport's syndrome, Goltz syndrome, and X-linked dominant porphyria.