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Fragile X Laboratory Testing: Background and Quality Improvement Opportunities (part 1 of 2)

Fragile X Laboratory Testing: Background and Quality Improvement Opportunities (part 1 of 2). Elaine Lyon, Ph.D. University of Utah/ARUP Laboratories Association for Molecular Pathology, Chair, Clinical Practice Committee. 1. Outline.

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Fragile X Laboratory Testing: Background and Quality Improvement Opportunities (part 1 of 2)

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  1. Fragile X Laboratory Testing:Background and Quality Improvement Opportunities(part 1 of 2) Elaine Lyon, Ph.D. University of Utah/ARUP Laboratories Association for Molecular Pathology, Chair, Clinical Practice Committee 1

  2. Outline • Clinical Features of Fragile X • Molecular Basis of Disease • Molecular Testing/Interpretation • Opportunities for Improvement • Quality control material • Interlaboratory study (AMP, CDC, NIST) 2

  3. Fragile X Syndrome • Most common inherited form of mental retardation. • Incidence 1:4000 males and 1:8000 females. • Affected males have mental retardation, characteristic physical features and behavior. • Affected females exhibit a less severe phenotype. • Found in all populations. 3

  4. Features • Mental impairment • Attention deficit/autistic-like • Long, thin face - prominent forehead • Large ears • Flexible joints • Low muscle tone • Enlarged testicles 4 Jones KL. Smith’s Recognizable Patterns of Human Malformation, 4th Ed.

  5. Chromosome Level Folate-sensitive fragile site at Xq27.3 (FRAXA). Other sites: FRAXD, FRAXE, & FRAXF. 5

  6. Molecular Level • Tri Nucleotide Repeat (CGG) at the 5' Untranslated Region (UTR). • A small expansion (pre-mutation) associated with increased mRNA • A large expansion associated with methylation, inactivating gene expression. 6

  7. Molecular Schematic 7

  8. Protein Level • Normal – protein widely expressed (nerve, brain, etc.) • RNA binding protein • Pre-mutation – normal protein, increased mRNA • Full mutation – no protein produced • Protein expression by immunohistochemistry (IHC) • suspected deletions/point mutations in males 8

  9. Transmission • Female pre-mutation carriers • 50/50 chance of transmitting unstable allele • May stay within pre-mutation range • May expand to full mutation (higher pre-mutations more likely to fully expand in one generation) • Male pre-mutation carriers • Will transmit pre-mutation to all daughters • Unlikely to expand • Intermediate • May expand to pre-mutation, but not full mutation, in one generation 9

  10. Risk of Expansion byPre-mutation Size Adapted originally from Warren & Nelson 1994; modified according to Nolin et al. 1996. GENEReviews at www.genetests.org, FMR1-Related Disorders. 10

  11. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) • Symptoms • Late-onset, progressive cerebellar ataxia/intention tremor • Short-term memory loss, executive function deficits, cognitive decline • Lower-limb proximal muscle weakness, and autonomic dysfunction • Genetics • FMR1 pre-mutation • mRNA accumulation 11

  12. Premature Ovarian Failure (POF) • Cessation of menses before age 40 • 21% of females with pre-mutations Allingham-Hawkins, AJMG, 1999 12

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