1 / 12

Duplications of the MECP2 gene region and severe mental retardation in males

Duplications of the MECP2 gene region and severe mental retardation in males. All Wales Molecular Genetics Laboratory. Classical Rett syndrome. X-dominant condition (Originally thought to be) Lethal in hemizygous males MECP2 mutations in males

wilmer
Download Presentation

Duplications of the MECP2 gene region and severe mental retardation in males

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Duplications of the MECP2 gene region and severe mental retardation in males All Wales Molecular Genetics Laboratory All Wales Molecular Genetics Laboratory

  2. Classical Rett syndrome • X-dominant condition • (Originally thought to be) Lethal in hemizygous males • MECP2 mutations in males • Aneuploidy of X chromosome, mosaics for MECP2 mutations • Lethal neonatal encephalopathy born to asymptomatic or mildly affected carrier mothers with mutations that usually cause the Rett phenotype in females • MECP2 mutations that cause a milder Rett phenotype in females, and classic or atypical Rett in males • Milder male cases with MECP2 mutations that do not result in classical Rett in female carriers (XLMR) All Wales Molecular Genetics Laboratory

  3. Gene dossier: Expanding the testing criteria Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: All Wales Molecular Genetics Laboratory

  4. Gene map of duplicated region > 60 duplications (0.2Mb – large dups;Xq28-ter) All Wales Molecular Genetics Laboratory

  5. Duplication pathogenicity • Phenotypic severity does not correlate with duplication size (flanking genes could play a role) • LICAM (spastic paraplegia) • Critical region – MECP2 & IRAK1 • Gene dosage influences phenotype (triplication – more severe) • Transgenic mice over-expressing Mecp2: Normal at birth but develop Rett-like progressive neurologic problems and die prematurely • Female carriers are asymptomatic if skewing is favourable • ?Due to LCRs All Wales Molecular Genetics Laboratory

  6. Cardiff samples • 25 male samples now tested by MLPA • 12 rearrangements detected in 4 families All Wales Molecular Genetics Laboratory

  7. Cardiff case 1: aCGH partial dup RP1-29A6 (unconfirmed) FMR-1 (unconfirmed) MECP2 (confirmed by MLPA, partial dup exon 4 only) All Wales Molecular Genetics Laboratory

  8. Cardiff case 2: MLPA dup All Wales Molecular Genetics Laboratory

  9. Cardiff case 3: MLPA dup / triplication All Wales Molecular Genetics Laboratory

  10. Phenotype – Genotype correlation All Wales Molecular Genetics Laboratory

  11. Phenotype of “duplicated” males • Severe MR • Initial hypotonia (floppiness) • Progressive spasticity • Recurrent infections (linked to IRAK1?) • Absent speech • Dysmorphic appearance • Undescended testicles • Constipation • Seizures • Severity increases with copy number of MECP2 • Need to expand MECP2 testing criteria to include Xq28 MR All Wales Molecular Genetics Laboratory

  12. Thanks to Cardiff team: Ruth Lewis, Laz Lazarou, Sian Morgan, Hayley Archer, Angus Clarke, Referring clinicians: Sally Davies, Emma Baple, Ruth Newbury-Ecob, Frances Elmslie All Wales Molecular Genetics Laboratory

More Related