Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males.
OBJECTIVE
Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome.


METHODS
Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number.


RESULTS
Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination.


CONCLUSIONS
These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling.
del Gaudio
Daniela
D
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Fang
Ping
P
Scaglia
Fernando
F
Ward
Patricia A
PA
Craigen
William J
WJ
Glaze
Daniel G
DG
Neul
Jeffrey L
JL
Patel
Ankita
A
Lee
Jennifer A
JA
Irons
Mira
M
Berry
Susan A
SA
Pursley
Amber A
AA
Grebe
Theresa A
TA
Freedenberg
Debra
D
Martin
Rick A
RA
Hsich
Gary E
GE
Khera
Jena R
JR
Friedman
Neil R
NR
Zoghbi
Huda Y
HY
Eng
Christine M
CM
Lupski
James R
JR
Beaudet
Arthur L
AL
Cheung
Sau Wai
SW
Roa
Benjamin B
BB
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D041321:Chromosomes, Human, X; D002658:Developmental Disabilities / Q000235:genetics*; D018628:Gene Dosage; D020440:Gene Duplication; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2