AUTOSOMAL RECESSIVE PHENOTYPES

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AUTOSOMAL RECESSIVE PHENOTYPES

• expressed only in homozygote - aa
• (AA or Aa are the normal phenotype)
• mutant allele must have been inherited from
  each parent i.e. parents are both carriers -
  Aa
• carriers are not usually detectable
• ? birth of first affected child usually
  completely unexpected
• BUT, recurrence risk is then 1 in 4, or 25

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AUTOSOMAL RECESSIVE PHENOTYPES (cont.)

• -Frequencies of AR disorders are dependent on
  carrier frequencies
• (very different for different
  diseases)
• -Many AR diseases are the result of an enzymatic
  defect
• (i.e. Inborn errors of metabolism)

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Relationship of Carrier Frequency to Disease
Frequency
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CHARACTERISTICS OF AUTOSOMAL RECESSIVE
INHERITANCE

• - Both males and females affected
• - Typically seen in only one sibship of a family
  (not in parents, offspring or other relatives)
• -- Horizontal Inheritance Pattern
• - Both parents of an affected person must be
  carriers.

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CHARACTERISTICS OF AUTOSOMAL RECESSIVE
INHERITANCE (cont.)

• - Recurrence risk for each sib of a proband is 1
  in 4 (25)
• - Parents of an affected person may be
  consanguineous (particularly if condition is
  rare)

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Punnett square AR inheritance
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CONSANGUINITY

• 1. Relative risk of any disorder is increased but
  only slightly
• Risk of abnormal offspring
• unrelated parents - 3
• first cousins - 4.5 - 5
• 2. Relative risk of specific disorder (already
  identified in family), is significantly
  increased.
• Risk of PKU in child of first cousins, where one
  parents sibling has PKU
• 1/24 instead of 1/10,0000

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Exceptions

• Only one sex affected (eg sex-limited trait such
  as vaginal atresia)
• Affected individual has affected children
  (pseudodominance)
• -consanguinity (common ancestor)
• -assortative mating --like marries like
• -genetic isolate (increased carrier
  frequency in sub-population)

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ASSORTATIVE MATING

• like marries like
• e.g. hearing impaired, visually
  impaired

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GENETIC ISOLATES

• Geographic
• - small island, isolated valley
• - Newfoundland outport
• Language/Cultural
• - Pakistani or Cypriot population in Great
  Britain
• Religious
• - Amish, Hutterite, Ashkenazi Jewish

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One gene, one enzyme concept

• A specific gene directs the synthesis of each
  enzyme
• Mutation of a gene leads to deficiency of the
  enzyme
• ? block in biochemical pathway
• RESULT
• i) for biosynthetic pathway
• -toxic accumulation of substrate e.g. PKU
• -deficiency of product e.g. Albinism
• ii) for degradative pathway
• -Accumulation of substances within cell e.g.
  Tay Sachs
• (eg, partially degraded cell membrane)

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