title: Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location.
abstract: Mutations in the methyl-CpG-binding protein gene MECP2 at Xq28 cause Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder characterized by a period of stagnation followed by regression in the development of young girls. Mutations were sought in MECP2 in 48 females with classical sporadic RTT, seven families with possible familial RTT and five sporadic females with features suggestive, but not diagnostic of RTT. Long distance PCR coupled with long-read direct sequencing was employed to sequence the entire MECP2 gene coding region in all cases. Mutations were identified in 44/55 (80%) unrelated classical sporadic and familial RTT patients, but only 1/5 (20%) sporadic cases with suggestive but non-diagnostic features of RTT. Twenty-one different mutations were identified (12 missense, four nonsense and five frame-shift mutations); 14 of these were novel. All missense mutations were located either in the methyl-CpG-binding domain or in the transcription repression domain. Nine recurrent mutations were characterized in a total of 33 unrelated cases (73% of all cases with MECP2 mutations). Significantly milder disease was noted in patients carrying missense mutations as compared with those with truncating mutations ( P = 0. 0023), and milder disease was associated with late as compared with early truncating mutations ( P = 0.0190).
authors.affiliation: Institute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK.
authors.forename: J P
authors.initials: JP
authors.lastname: Cheadle
authors.forename: H
authors.initials: H
authors.lastname: Gill
authors.forename: N
authors.initials: N
authors.lastname: Fleming
authors.forename: J
authors.initials: J
authors.lastname: Maynard
authors.forename: A
authors.initials: A
authors.lastname: Kerr
authors.forename: H
authors.initials: H
authors.lastname: Leonard
authors.forename: M
authors.initials: M
authors.lastname: Krawczak
authors.forename: D N
authors.initials: DN
authors.lastname: Cooper
authors.forename: S
authors.initials: S
authors.lastname: Lynch
authors.forename: N
authors.initials: N
authors.lastname: Thomas
authors.forename: H
authors.initials: H
authors.lastname: Hughes
authors.forename: M
authors.initials: M
authors.lastname: Hulten
authors.forename: D
authors.initials: D
authors.lastname: Ravine
authors.forename: J R
authors.initials: JR
authors.lastname: Sampson
authors.forename: A
authors.initials: A
authors.lastname: Clarke
mesh_terms: D000595:Amino Acid Sequence; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins / Q000235:genetics*; D004200:Diseases in Twins; D005091:Exons; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012097:Repressor Proteins; D015518:Rett Syndrome / Q000235:genetics*; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid
chemical_list: D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2; D012097:Repressor Proteins