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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, Clinical Practice Committee 1 Chair, 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 Fragile X Syndrome 3 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. Features 4 Mental impairment Attention deficit/autistic-like Long, thin face - prominent forehead Large ears Flexible joints Low muscle tone Enlarged testicles Jones KL. Smith’s Recognizable Patterns of Human Malformation, 4 th Ed. Chromosome Level Folate-sensitive fragile site at Xq27.3 (FRAXA). Other sites: FRAXD, FRAXE, & FRAXF. 5 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 Molecular Schematic 7 Protein Level Normal – protein widely expressed (nerve, brain, etc.) Pre-mutation – normal protein, increased mRNA Full mutation – no protein produced Protein expression by immunohistochemistry (IHC) 8 RNA binding protein suspected deletions/point mutations in males Transmission Female pre-mutation carriers 50/50 chance of transmitting unstable allele Male pre-mutation carriers Will transmit pre-mutation to all daughters Unlikely to expand Intermediate 9 May stay within pre-mutation range May expand to full mutation (higher pre-mutations more likely to fully expand in one generation) May expand to pre-mutation, but not full mutation, in one generation Risk of Expansion by Pre-mutation Size Number of Maternal Pre-Mutation CGG Repeats Approximate % Risk that a Son Will be Affected with Fragile X Syndrome 56-59 7% 60-69 10% 70-79 29% 80-89 36% 90-99 47% > 100 50% Adapted originally from Warren & Nelson 1994; modified according to Nolin et al. 1996. GENEReviews at www.genetests.org, FMR1-Related Disorders. 10 Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) 11 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 Penetrance is age related Jacquemont, JAMA 2004 Premature Ovarian Failure (POF) Cessation of menses before age 40 21% of females with premutations 180 160 140 120 100 80 60 40 20 0 Full Mutation Premutation Control 18 - 29 30 - 39 40 - 49 50+ Age at Interview Proportion of Subjects Experiencing POF 0.3 Proportion of Subjects Number of Subjects Distribution of Subjects 0.26 0.25 0.22 0.2 0.15 0.11 0.1 0.05 0 0.05 0.02 0 0 0 0 0 0 0 18 - 29 30 - 39 40 - 49 Age at Interview 12 Allingham-Hawkins, AJMG, 1999 50+