Explain what is meant by anticipation and give examples

1
Explain what is meant by anticipation and give
examples

• Richard Barber
• Richard.Barber_at_bwhct.nhs.uk
• 15th November
• Patterns of Inheritance session II

2
What is Anticipation?

• A phenomenon in which a genetic disease appears
  earlier and possibly with increased severity in
  succeeding generation
• Anticipation was once thought not to exist but
  due to statistical artefacts
• Severely affected individuals are less likely to
  have children but more likely to be seen by
  clinical genetics and be diagnosed and family
  followed up
• However, anticipation has now been proven to
  occur in a large number of important genetic
  disorders, including Huntington disease and
  myotonic dystrophy

3
Huntington Disease

• Caused by CAG coding repeat sequence
• There is a inverse correlation between CAG repeat
  size and age of onset
• Anticipation occurs more commonly in paternal
  transmissions arises from instability of the CAG
  repeat during spermatogenesis
• Adult onset
• 36 50 repeats
• Juvenile onset (under age of 21)
• over 60 repeats
• Caused by toxic build up of polyglutamine tracts

4
Myotonic Dystrophy

• Caused by CTG repeat in 3 UTR of DMPK gene
• There is a inverse correlation between CTG repeat
  size and age of onset
• Anticipation occurs more dramatically in maternal
  transmissions
• Late onset
• 50 - 100 repeats
• Adult onset
• 100 1000 repeats
• Congenital onset
• gt1000 repeats
• Tissue specificity probably caused by different
  rates of expansion
• Caused by sequestering of proteins need for
  splicing of other genes by the expanded CUG tract
  in the mRNA

5
Anticipation and Repeat Expansion in DM
84
late onset
112
205
160
adult onset
congenital
2100
730
Often resulting in congenital myotonic dystrophy
in the later generations
2100
6
Causes of Anticipation

• Most disorders are caused by triplet repeat
  expansions but there are some other types
• tetra (DM2)
• penta (SCA10)
• megasatellite (FSHMD1A)
• Variation in repeat length accounts for variable
  disease severity and age of onset
• Increases in length from one generation to the
  next account for anticipation
• The larger the repeat the larger the subsequent
  expansion
• Repeat instability due to DNA replication
  slippage see
• Diseases of Unstable Repeat Expansion Mechanisms
  and Common Principles Gatchel JR, NRG 6, 743 -
  755
• Repeat instability mechanisms of dynamic
  mutations Pearson CE, NRG 6, 729 - 742

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Gene Discovery

• Once an inherited disease has been shown to have
  anticipation then this is likely to be a triplet
  repeat. Can therefore look for triplet repeat
  expansions in affected individuals and avoid
  lengthy positional cloning techniques to identify
  new genes
• RED (Repeat Expansion Detection)
• Schalling, M., Direct detection of novel expanded
  trinucleotide repeats in the human genome. Nature
  Genet. 4, 135-139 (1993)
• Koob MD 1999 Nat Gen An untranslated CTG
  expansion causes a novel form of spinocerebellar
  ataxia (SCA8)

8
Anticipation by Shortening?

• Anticipation also occurs in diseases caused by
  defects in telomere maintenance
• Mutations in the genes encoding the RNA and the
  protein catalytic subunits of telomerase seen in
  conditions with anticipation
• The telomeres undergo progressive shortening of
  the TTAGGG tract
• After reaching a critical length this triggers
  apoptosis
• Vulliamy T, (2004) Disease anticipation is
  associated with progressive telomere shortening
  in families with dyskeratosis congenita due to
  mutations in TERC. Nature Genetics 36 , 447-449

9
Polygenic Anticipation

• Lies, lies and statistics
• For every claim of anticipation in a polygenic
  disorder there are papers explaining the error in
  the statistics used
• Radstake, Genetic anticipation in rheumatoid
  arthritis in Europe. J Rheumatol. 2001
  May28(5)962-7
• C. Deighton, Ages of onset suggestive of genetic
  anticipation in rheumatoid arthritis multicase
  sibships can be explained by observational bias.
  Rheumatology, January 1, 2007 46(1) 120 123
• Other disorders to have shown anticipation
  include familial intracranial aneurysms,
  diabetes, Crohns disease

10
Anticipation in Single Gene Disorders?

• Studies have been published documenting evidence
  for anticipation in single gene disorders. They
  all state that counselling should reflect this
  risk but have yet to demonstrate a cause and
  effect
• A Peixoto Fam Can, BRCA1 and BRCA2 germline
  mutational spectrum and evidence for genetic
  anticipation in Portuguese breast/ovarian cancer
  families
• Stella A, Germline novel MSH2 deletions and a
  founder MSH2 deletion associated with
  anticipation effects in HNPCC. Clin Genet. 2007
  Feb71(2)130-9.