Transcript Rachel Butler
Duplications of the MECP2 gene region and severe mental retardation in males
All Wales Molecular Genetics Laboratory All Wales Molecular Genetics Laboratory
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
Gene dossier: Expanding the testing criteria
Minimum criteria required for testing to be appropriate as stated in the Gene Dossier: Criteria Tick if this patient meets criteria
X-linked or sporadic inheritance
Females
Normal development for first 6-18 months followed by period of regression Deceleration in head growth Mental retardation Loss of purposeful hand use, repetitive stereotypic hand movements
Males
Neonatal encephalopathy All Wales Molecular Genetics Laboratory
Gene map of duplicated region
> 60 duplications (0.2Mb – large dups;Xq28-ter) All Wales Molecular Genetics Laboratory
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
Cardiff samples
• 25 male samples now tested by MLPA • 12 rearrangements detected in 4 families All Wales Molecular Genetics Laboratory
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
Cardiff case 2: MLPA dup All Wales Molecular Genetics Laboratory
Cardiff case 3: MLPA dup / triplication All Wales Molecular Genetics Laboratory
Case 1 (aCGH, MLPA) 2 (MLPA) 3 (MLPA) 4 (MLPA) Phenotype – Genotype correlation Genotype Dup
MECP2
exon 4 – SLC6A8 +dup FMR-1 (unconfirmed) +dupRP1-29A6 (unconfirmed) Dup MECP2 – L1CAM Dup
MECP2
ex 1-2 Trip
MECP2
ex 3-4
, IRAK1
Dup L1CAM – SLC6A8 Trip
MECP2
ex1 (5’)4 Dup
MECP2
ex(3’)4 – SLC6A8 Phenotype Severe MR, delayed motor development, behaviour problems, overeating, micropenis N.B. phenotype may be due to additional duplicated regions on X chromosome and not to partial duplication of
MECP2
Severe XLMR, seizures & flapping hands, recurrent infections Severe MR, immobile, recurrent infections, seizures, severe hypotonia Severe MR, floppy, recurrent infections All Wales Molecular Genetics Laboratory
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
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