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Unusual Fragile X case

Unusual Fragile X case. Catharina Yearwood St George’s Hospital, London. Fragile X Background. Mental retardation syndrome ~ 1in 5000 males Macrocephaly, large ears, macro-orchidism Caused by loss of FMR1 gene expression no FMRP protein produced

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Unusual Fragile X case

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  1. Unusual Fragile X case Catharina Yearwood St George’s Hospital, London

  2. Fragile X Background • Mental retardation syndrome ~ 1in 5000 males • Macrocephaly, large ears, macro-orchidism • Caused by loss of FMR1 gene expression no FMRP protein produced • X-linked dominant with reduced penetrance • >99% of cases caused by a large hypermethylated expansion of CGG triplet repeat in 5’UTR. Known as a Fragile X full mutation.

  3. Repeat sizes and Testing strategy • Normal<50 Intermediate/grey zone 50-58 repeats Premutation 59 to ~200 (unmethylated) Full>200 (methylated) • PCR exclusion test (1 normal allele male, 2 normal alleles females). • Southern blot to pick up large expansions in patients not excluded by PCR.

  4. FMR1 deletions • <1% of Fragile X cases caused by an FMR1 deletion -same phenotype as a full mutation • Several cases of deletions reported in the literature -large deletions encompassing all or a large part of the gene -microdeletions in the region in and around the CGG repeat (often disrupt the promoter and/or the start codon in exon 1, located either side of the repeat) • Often found in combination with full mutations and/ or premutations - mosaics

  5. Fragile X Family

  6. Original blot

  7. Alternative enzyme blot

  8. Initial report

  9. Narrowing down breakpoints

  10. Deletion of entire CGG repeat as well as 73-75bp 5’ and 39-41bp 3’ Sequencing

  11. What does this mean for the patient? • Deletion restricted to 5’UTR - both transcription start site and translation initiation codon intact • Three reports in literature of 5’UTR deletions, all shown not to impair FMR1 expression. • Largest 63-67bp 5’ and 30-34bp 3’ to CGG repeat – slightly smaller than our deletion. • Is the extra sequence deleted in our patient required for FMR1 expression? Unknown • Patient may still be at risk of having a child affected by Fragile X syndrome. This child could be affected either by inheriting the deletion if pathogenic, or by inheriting a full mutation if PJ is mosaic for the familial expansion not detectable in her blood.

  12. Further report

  13. Possible further testing (immunocytochemistry) If patient were to require prenatal testing - CVS FMRP expression No FMRP expression Testing of male child – blood smears FMRP expression No FMRP expression

  14. X-inactivation results

  15. Conclusions • Potentially non-pathogenic small deletion found • Would be useful to test father to check that deletion has not been inherited from him • Immunocytochemistry (ICC) may give rough idea of pathogenicity in female patient • Prenatal and diagnostic ICC testing available for any male offspring

  16. References • Coffee et al (2008). Am J Med Genet Part A 146A: 1358-1367 • Gronskov et al (1997). Am J Hum Genet 61: 961-967

  17. Acknowledgements • Louise Kiely • Sandra Ramos • Sally Cottrell

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