Modes of Inheritance

Autosomal Dominant (AD)

• Genders affected
  • male and female at equal frequency
• Generations affcted
  • does not skip generations
    • if two parents without the AD disease have child with an AD disease
      • possibility is reduced penetrance
        • have mutant gene but phenotypically normal
      • de novo germline mutation
  • an affected child must receive disease from an affected parent
    • a homozygote dominant parent has a 100% of having an affected child
    • two heterotyzgote parents with the AD disease condition have a 75% chance of having a child with the disease phenotype 
• Pathology
  • defects in structural gene
  • Presentation timing
• • usually after puberty
• Other notes
  • often pleiotropic
    • several organ systems affected by single genetic defect
  • only one copy of the defective gene is required to express the disease phenotype 
• Examples  
  • von Willebrand disease (most common)
  • Huntington’s disease
  • osteogenesis imperfecta
  • achondroplasia
  • Marfan syndrome
  • neurofibromatosis type I
• acute intermittent porphyria

Autosomal Recessive (AR)

• Genders affected  
  • male and female
• Generations affected 
  • 1/4 of offspring affected when both parents are carriers 
  • 1/2 of offspring are carriers when both parents are carriers 
    • 2/3 of nonaffected children are carriers
  • usually 1 generation
• Pathology
  • defects in enzymes
• Presentation timing
  • infancy to childhood
• Other notes
  • most often more severe than AD
  • must have 2 defective copies of the gene
  • chances greatly increased with consanguinity
• Examples 
  • cystic fibrosis – deficiency in the chloride channel CFTR
  • inborn errors of metabolism 
    • PKU, von Gierke’s, Pompe’s, glycogen storage diseases, sphingolipidoses (except Fabry’s), and mucopolysaccharidoses (except Hunter’s)
  • sickle cell anemia
  • thalassemias
  • albinism
  • ARPKD
• hemochromatosis

X-linked Recessive (XR)

• Genders affected
  • males must receive defective gene from carrier mother
    • carrier mother’s sons have 50% of having disease 
  • affected males give copy to all of their daughters
• Generations affected
  • skips generations
    • male-to-male transmission not allowed
    • diseases passes through carrier daughters
• Pathology
  • defects in enzymatic genes
    • similar to AR diseases
• Presentation timing
  • usually after puberty
• Other notes
  • only one defective copy necessary for disease in males
    • because males are hemizygous for X chromosome
  • two defective copies necessary for disease in females
    • can be affected with just one defective copy if normal X chromosome is inactivated to Barr body
      • called manifesting heterozygotes
        • phenotype usually milder than affected males
• Examples 
  • hemophilia A and B 
  • Menke’s disease 
  • Duchenne muscular dystrophy 
  • Lesch-Nyhan syndrome
  • Ornithine transcarbamoylase deficiency
• red-green color blindness 

X-linked Dominant (XD)

• Genders affected
  • male and female at equal frequency
• Generations affected
  • does not skip generations
    • only possibility is reduced penetrance
  • females of affected fathers are always affected 
    • male-to-male transmission not seen
  • male or females of affected mothers can be affected
• Pathology
  • defects in structural genes
• Presentation timing
  • usually after puberty
• Examples
  • hypophosphatemic rickets
  • Fragile X syndrome
• Alport syndrome

Mitochondrial Inheritance 

• Genders affected
  • male and females at equal frequency
• Generations affected
  • does not skip generations
  • only transmitted from affected female 
    • gives to all offspring
    • due to the fact that the sperm do not contribute mitochondria to the zygote
• Pathology
  • defects in electron transport/oxidative phosphorylation process
    • presents as neuropathies/myopathies 
      • neurons and muscle cells require high amounts of energy and depend on mitochondria
• Presentation timing
  • usually after puberty
• Other notes
  • variable expression due to heteroplasmy
    • a small percentage of mitochondria within a cell are affected leading to variable severity
• Examples
  • myoclonic epilepsy with ragged red muscle fibers  
  • Leber hereditary optic neuropathy 
• MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes) 

Inheritance Algorithm

• Does offspring with disease have a parent with disease? (Y/N)
  • if YES
    • dominant (does not skip generations)
      • is there male-to-male transmission of disease? (Y/N)
        • if YES
          • autosomal dominant
        • if NO
          • do daughters of affected male have disease? (Y/N)
            • if YES
              • X-linked dominant
            • if NO
              • mitochondrial
  • if NO
    • recessive (can skip generations)
      • predominantly males with disease? (Y/N)
        • if YES
          • X-linked recessive
        • if NO
• autosomal recessive