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Updated: Aug 10 2022

Modes of Inheritance

  • Pedigree Nomenclature
  • Autosomal Dominant (AD)
    • Genders affected
      • male and female at equal frequency
    • Generations affected
      • 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 genes
    • 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
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