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
Phenotype – Genotype correlation
Case
Genotype
Phenotype
1
(aCGH,
MLPA)
Dup MECP2 exon 4 –
SLC6A8
+dup FMR-1 (unconfirmed)
+dupRP1-29A6
(unconfirmed)
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
2
(MLPA)
Dup
MECP2 – L1CAM
Severe XLMR, seizures & flapping
hands, recurrent infections
3
(MLPA)
Dup MECP2 ex 1-2
Trip MECP2 ex 3-4, IRAK1
Dup L1CAM – SLC6A8
Severe MR, immobile, recurrent
infections, seizures, severe
hypotonia
4
(MLPA)
Trip MECP2 ex1-(5’)4
Dup MECP2 ex(3’)4 –
SLC6A8
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 NewburyEcob, Frances Elmslie
All Wales Molecular Genetics
Laboratory