22. Genetic Diseases

Monogenic vs Polygenic Disease

• Monogenic disease is a disease caused by one mutation: follows mendelian inheritance patterns

• Polygenic disease is a disease caused by the effects of multiple genes and the environment: sporadic and no Mendelian Inheritance. More diseases are polygenic.

What are the pedigree characteristics of Autosomal Dominant Genetic Disease?

• Vertical transmission

• Affects amles and femals equally

• M to M transmission

• Heterozygotes 50% chance of transmitting to offspring

What is variable penetrance?

The proportion of individuals with a specific genotype who actually express the associated phenotype. Complete penetrance: genotype = phenotype. Incomplete penetrance: genotype not equal to phenotype.

What is Phenocopy?

When the phenotype is present without the genotype.

What are the pedigree characteristcs of autosomal recessive disease?

• Horizontal transmission, within a generation

• Phenotype skips generations

• Affects males and females equally

• Carriers: no pheno/slight pheno

What are the epidemiology for autosomal recessive disease?

• Consanguinity: Same blood/mating relatives

• Endogamy: pairings within specific group

• Founder’s effect: lack of genetic variable when few individuals start new population

Example of consanguinity

Egypt’s Ptolemy dynasty with brother-sister and uncle-niece pairing.

What is founder’s effect?

When there is a lack of genetic variable due to few individuals starting a new population.

What are examples of endogamy?

Pairings within a group:

• Religion: Ashkenazim Jew, Muslims, Christens, etc.

• Race

• Social Class

What are the characteristics of X-linked genetic diseases?

• Usually LOF mutation on X chromosme, no Y linked human diseases

• Pedigree pattern of transmission:

  • No male to male transmission

  • Disease phenotype most obvious in males

  • Female carriers can have mild phenotype due to X inactivation

What are the presentation of AD, AR, and XL Retinitis Pigmentosa?

• AD and AR forms: loss of peripheral vision with peripheral pigmentary changes: bony spicules, moves centrally causing loss of central vision

• X-linked RP: black w/ tapetal sheen in XLRP; Severe vision loss; X-linked RP carrier with tigroid appearance

What are the percentages of how Retinitis Pigmentosa is inherited?

• 40% have AD inheritance: slowest progression and best prognosis

• 50% have AR inheritance: moderate prognosis

• 8% have X-L inheritance: Worst prognosis

What does the RPE65 Gene do?

Mutations in the gene can cause AD or AR retinitis pigmentosa, Leber’s congentical amaurosis (LCA) or Usher Syndrome.

How is LCA treated?

Using gene therapy. LCA patients ages 17-23 are reated with RPE65 Adeno-associated Virus, inject 1/3 of 1 eye. The virus then delivers the working RPE65 gene and cells begin producing normal RPE65 enzyme to restore the visual cycle

What is the pedigree pattern of mitochondrial genetic diseases?

Mother to child transmission. Presentation is dependent on the percent of mutant mtDNA in patient.

How is Leber’s Hereditary Optic Neuropathy transmitted (LHON)?

mtDNA.

What are the symptoms of LHON?

• Degeneration of RGC's

  • Enlarged optic disc

  • Temporal pallor

• Loss of central vision