Clinical Genetics Basics

Single-Gene Disorders

• Single-gene disorders originate from mutations at a single genetic locus on a chromosome.
• A locus refers to the specific position of a gene; alleles are different forms of a gene at the same locus on homologous chromosomes.
• Normal alleles are called wild type, while abnormal forms are termed mutant alleles.
• Distinction exists between genotype (genetic constitution) and phenotype (observable traits).
• Homozygotes have identical alleles, heterozygotes possess different alleles, and hemizygotes have only one allele at a locus (common in X-linked traits in males).
• Traits may be dominant (expressed in heterozygotes and homozygotes) or recessive (expressed in homozygotes for autosomes and hemizygotes for X-linked traits).

Pedigree Analysis

• Pedigrees illustrate family structures and patterns of single-gene inheritance.
• The proband is the first affected family member seeking medical attention.
• Siblings are referred to as sibs, and their collective relationship is called sibship.
• Relatives are classified based on degree of allele sharing, determined by intervening relatives in the pedigree.
• Consanguineous relationships involve couples who are second cousins or closer.

Genetic Heterogeneity

• Genetic heterogeneity occurs when the same phenotype results from different genetic abnormalities.
• Allelic heterogeneity is when variations at the same locus lead to the same abnormal phenotype (e.g., cystic fibrosis).
• Locus or nonallelic heterogeneity describes situations where mutations at different loci can produce the same phenotype (e.g., congenital sensorineural deafness).

Autosomal Dominant Inheritance

• Expressed in both heterozygotes and homozygotes; features include:
  • Phenotype appears in every generation.
  • Each child of an affected parent has a 50% chance of inheriting the trait.
  • Phenotypically normal family members do not transmit the trait.
  • Both genders transmit the phenotype equally.

X-Linked Inheritance

• Female somatic cells have one active X chromosome; the other is condensed as a Barr body.
• X-inactivation happens early in embryonic development and can involve either paternal or maternal X.
• Lyon hypothesis explains dosage compensation, ensuring females express one allele of X-linked genes.
• In X-linked recessive inheritance, a carrier female has a 50% chance of having an affected son and a 50% chance of having a carrier daughter.

Hemophilia A

• An X-linked disorder characterized by factor VIII deficiency.
• Carrier females exhibit approximately 50% factor VIII activity compared to non-carriers.
• Affected males transmit the normal allele to sons and the mutant allele to daughters.

Duchenne Muscular Dystrophy (DMD)

• An X-linked recessive disorder caused by mutations in the dystrophin gene, known for being particularly large.
• Affected males do not reproduce, resulting in a genetic fitness of 0, leading to new mutations as a source for one-third of DMD cases.

X-Linked Dominant Inheritance

• Regularly expressed in heterozygotes, with criteria including:
  • Affected males have no affected sons but only affected daughters.
  • Offspring of heterozygous females have a 50% chance of being affected.
  • Affected females typically exhibit milder symptoms and are more prevalent due to skewed sex ratios in affected offspring.

Test your understanding of single-gene disorders and the concepts related to genetic loci and alleles. This quiz will cover the definitions and distinctions between wild type and mutant alleles, as well as how these genetic elements are inherited. Dive into the fascinating world of genetics and assess your knowledge!