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