title: Delineation of large deletions of the MECP2 gene in Rett syndrome patients, including a familial case with a male proband.
abstract: Comprehensive genetic screening programs have led to the identification of pathogenic methyl-CpG-binding protein 2 (MECP2) mutations in up to 95% of classical Rett syndrome (RTT) patients. This high rate of mutation detection can partly be attributed to specialised techniques that have enabled the detection of large deletions in a substantial fraction of otherwise mutation-negative patients. These cases would normally be missed by the routine PCR-based screening strategies. Here, we have identified large multi-exonic deletions in 12/149 apparently mutation-negative RTT patients using multiplex ligation-dependent probe amplification (MLPA). These deletions were subsequently characterised using real-time quantitative PCR (qPCR) and long-range PCR with the ultimate aim of defining the exact nucleotide positions of the breakpoints and rearrangements. We detected an apparent deletion in one further patient using MLPA; however, this finding was contradicted by subsequent qPCR and long-range PCR results. The patient group includes an affected brother and sister with a large MECP2 deletion also present in their carrier mother. The X chromosome inactivation pattern of all female patients in this study was determined, which, coupled with detailed clinical information, allowed meaningful genotype-phenotype correlations to be drawn. This study reaffirms the view that large MECP2 deletions are an important cause of both classical and atypical RTT syndrome, and cautions that apparent deletions detected using high-throughput diagnostic techniques require further characterisation.
authors: Department of Biological Sciences, Macquarie University, Sydney, Australia.
authors: Simon A
authors: SA
authors: Hardwick
authors: Kirsten
authors: K
authors: Reuter
authors: Sarah L
authors: SL
authors: Williamson
authors: Vidya
authors: V
authors: Vasudevan
authors: Jennifer
authors: J
authors: Donald
authors: Katrina
authors: K
authors: Slater
authors: Bruce
authors: B
authors: Bennetts
authors: Ami
authors: A
authors: Bebbington
authors: Helen
authors: H
authors: Leonard
authors: Simon R
authors: SR
authors: Williams
authors: Robert L
authors: RL
authors: Smith
authors: Desiree
authors: D
authors: Cloosterman
authors: John
authors: J
authors: Christodoulou
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005190:Family; D005260:Female; D017353:Gene Deletion; D015321:Gene Rearrangement; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015518:Rett Syndrome / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: D051783:Methyl-CpG-Binding Protein 2