Autosomal Dominant Disorders

Autosomal Dominant Traits

• Traits or diseases are common in the pedigree and found in every generation
• Affected individuals are often heterozygote
• Autosomal dominant disorders may manifest during childhood or adolescence
• Each affected individual transmits the disease to half of their offspring, independent of sex
• The probability of transmission is independent of each child

Variability in Autosomal Dominant Inheritance

• The manifestation of autosomal dominant diseases in different individuals is usually variable
• Variations may be due to:
  • Variable Expressivity
  • Incomplete Penetrance

Incomplete Penetrance

• An individual who has the genotype for a disease may not exhibit the disease phenotype at all, even though they can transmit the disease gene to the next generation
• Penetrance rates are estimated by examining a large number of families to determine what proportion of obligate carriers develop the disease phenotype

Treacher-Collins Syndrome

• Clinical characteristics:
  • Small mandible
  • Downward palpebral fissures
  • Defect of the lower eyelid (coloboma)
  • Microtia
  • Hearing impairment

Causes of Incomplete Penetrance

• Genotypes do not act in isolation
  • Interaction with the wild-type allele
  • Interaction with other loci
  • Interaction with the environment
  • Just chance

Variable Expression

• Even when penetrance of a condition is complete, the severity of the disease may vary greatly
• Possible causes:
  • Genotypes do not act in isolation
    • Interaction with the wild-type allele
    • Interaction with other loci
    • Interaction with the environment or just chance

Anticipation

• The tendency of some dominant conditions to become more severe (or have earlier onset) in successive generations
• Caused by unstable expanding nucleotide repeats
• Example: Huntington disease - expansion of a polyglutamine repeat in the huntingtin gene on chromosome 4

Mosaicism

• When an individual has two or more genetically different cell lines derived from a single zygote
• Caused by a new mutation
• Mosaicism can be:
  • Somatic
  • Germ-line

Huntington's Disease

• Caused by a mutation in the Huntingtin gene on chromosome 4
• Responsible for producing the protein Huntingtin
• CAG expansion on exon 1 of the Huntingtin gene
• Autosomal Dominant disease, not sex-linked
• HD onset is found generally in adults around the age of 40
• Paternal Anticipation is seen in HD due to high number of mitoses during gametogenesis and selection against oocytes with large expansions
• Age of onset varies based on the number of repeats
• Juvenile HD is a rare form of HD that initiates before the age of 20, usually with 80-100 CAG repeats

Neurofibromatosis

• Type I (NF1) is caused by a mutation in the neurofibromin gene
• Also known as von Recklinghausen disease or Watson disease
• Autosomal Dominant neurogenetic disorder
• Characterized by the presence of multiple benign neurofibromas
• Affects the bone, nervous system, soft tissue, and skin
• Clinical symptoms increase over time
• Neurologic problems and malignancy may develop
• 50% inherited, 50% spontaneous mutations
• Autosomal Dominant, does not "skip" generations
• If a person has the NF gene mutation, they will have NF (100% penetrance by the age of 5 years)