Genetic inheritance

• What is the purpose of discussing inheritance models in genetic disease?

  To interpret pedigrees and understand genetic inheritance patterns
• What is a genetic pedigree?

  • A diagram that shows the occurrence of a genetic trait across generations
  • Used to analyze inheritance patterns in families
• What type of inheritance is characterized by traits expressed in heterozygotes?

  Autosomal dominant inheritance
• What is the typical genetic makeup of most cases of autosomal dominant disease?

  Most cases are heterozygous
• What is familial hypercholesterolemia associated with?

  Heterozygous mutations in the LDL receptor
• What are the consequences of familial hypercholesterolemia?

  High levels of cholesterol and increased risk of myocardial infarctions
• How much higher are plasma LDL levels in homozygous individuals with familial hypercholesterolemia?

  10 times normal blood LDL level
• What is the probability of receiving a normal or mutative gene in autosomal dominant inheritance?

  There is a 50/50 chance
• What are exceptions to the autosomal dominant inheritance pattern?

  • Mutation: sporadic cases may arise by de-novo mutation
  • Reduced penetrance: no clinical symptoms of the disease
  • Variable expressivity: nature & severity of phenotype varies among individuals
• What is haploinsufficiency?

  When normal physiology requires more than 50% of gene product
• What is the dominant negative effect?

  When an abnormal protein interferes with the function of the normal allele's product
• What is gain of function in genetic mutations?

  When the function of the mutant protein is enhanced
• Which conditions are examples of gain of function mutations?

  Achondroplasia and Huntington disease
• What does loss of heterozygosity refer to?

  Associated with inherited sites of cancers where the normal allele is lost
• In autosomal recessive inheritance, who shows symptoms?

  Only recessive homozygotes
• What are carriers in autosomal recessive inheritance?

  Heterozygotes who do not show symptoms
• Why are autosomal recessive diseases more common than autosomal dominant diseases?

  Because carriers are not at a selective disadvantage
• What is the typical pedigree pattern for autosomal recessive inheritance?

  • Horizontal pattern
  • Often shows consanguinity
• What is the most common mating type for autosomal recessive inheritance?

  Unaffected carrier father and unaffected carrier mother
• What is the chance of producing an affected child from two carrier parents in autosomal recessive inheritance?

  1 in 4 chance
• What is X chromosome inactivation?

  A process that equalizes protein production from X chromosomes in males and females
• Why are males considered hemizygous for the X chromosome?

  Because they have only one X chromosome
• What are the differences between X-linked recessive and X-linked dominant diseases?

  • X-linked recessive: rarely expressed in females
  • X-linked dominant: expressed in many females
• What are examples of X-linked recessive diseases?

  Haemophilia A and Duchenne muscular dystrophy
• What are examples of X-linked dominant diseases?

  Hypophosphatasemia (rickets)
• What are the symptoms of hypophosphatasemia?

  Short stature, bone deformities, low blood phosphate, and high urinary phosphate levels
• What is a key characteristic of X-linked dominant inheritance?

  Absence of male-to-male transmission
• What does extranuclear inheritance refer to?

  Mitochondrial DNA defects
• What is the structure of mitochondrial DNA (mtDNA)?

  It contains a small circular DNA genome
• How is mtDNA transmitted?

  It is maternally transmitted via the ovum
• What are the concepts of homoplasmy and heteroplasmy in mitochondrial DNA?

  • Homoplasmy: every mt genome contains mutations
  • Heteroplasmy: mixed population of normal and mutant mt genome
• What does population genetics study?

  Genetic differences within and between populations
• What is genetic drift?

  The change in frequency of a gene variant due to random chance
• What is gene migration?

  The movement of genes between populations
• What is selection in population genetics?

  The change in gene frequency under selective advantage
• What are examples of autosomal recessive inheritance diseases?

  • Sickle cell anemia
  • Cystic fibrosis