title: MECP2 deletions and genotype-phenotype correlation in Rett syndrome.
abstract: Rett syndrome is a neurodevelopmental disorder that represents one of the most common genetic causes of mental retardation in girls. MECP2 point mutations in exons 2-4 account for about 80% of classic Rett cases and for a lower percentage of variant patients. We investigated the genetic cause in 77 mutation-negative Rett patients (33 classic, 31 variant, and 13 Rett-like cases) by searching missed MECP2 defects. DHPLC analysis of exon 1 and MLPA analysis allowed us to identify the defect in 17 Rett patients: one exon 1 point mutation (c.47_57del) in a classic case and 16 MECP2 large deletions (15/33 classic and 1/31 variant cases). One identical intragenic MECP2 deletion, probably due to gonadal mosaicism, was found in two sisters with discordant phenotype: one classic and one "highly functioning" preserved speech variant. This result indicates that other epigenetic or genetic factors, beside MECP2, may contribute to phenotype modulation. Three out of 16 MECP2 deletions extend to the adjacent centromeric IRAK1 gene. A putative involvement of the hemizygosity of this gene in the ossification process is discussed. Finally, results reported here clearly indicate that MECP2 large deletions are a common cause of classic Rett, and MLPA analysis is mandatory in MECP2-negative patients, especially in those more severely affected (P = 0.044).
authors.affiliation: Medical Genetics, Molecular Biology Department, University of Siena, Siena, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Scala
authors.forename: Ilaria
authors.initials: I
authors.lastname: Longo
authors.forename: Federica
authors.initials: F
authors.lastname: Ottimo
authors.forename: Caterina
authors.initials: C
authors.lastname: Speciale
authors.forename: Katia
authors.initials: K
authors.lastname: Sampieri
authors.forename: Eleni
authors.initials: E
authors.lastname: Katzaki
authors.forename: Rosangela
authors.initials: R
authors.lastname: Artuso
authors.forename: Maria Antonietta
authors.initials: MA
authors.lastname: Mencarelli
authors.forename: Tatiana
authors.initials: T
authors.lastname: D'Ambrogio
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Vonella
authors.forename: Michele
authors.initials: M
authors.lastname: Zappella
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Hayek
authors.forename: Agatino
authors.initials: A
authors.lastname: Battaglia
authors.forename: Francesca
authors.initials: F
authors.lastname: Mari
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Ariani
mesh_terms: D001483:Base Sequence; D002851:Chromatography, High Pressure Liquid; D017931:DNA Primers; D005091:Exons; D005260:Female; D017353:Gene Deletion; D005838:Genotype; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015518:Rett Syndrome / Q000235:genetics* / Q000503:physiopathology; D049951:X Chromosome Inactivation
chemical_list: D017931:DNA Primers; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2