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Explain what is meant by anticipation and give examples

Explain what is meant by anticipation and give examples. Richard Barber Richard.Barber@bwhct.nhs.uk 15 th November Patterns of Inheritance session II. What is Anticipation?. A phenomenon in which a genetic disease appears earlier and possibly with increased severity in succeeding generation

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Explain what is meant by anticipation and give examples

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  1. Explain what is meant by anticipation and give examples Richard Barber Richard.Barber@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 • >1000 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

  7. 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 May;28(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, Crohnsdisease

  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 Feb;71(2):130-9.

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