title: Analysis of Hungarian patients with Rett syndrome phenotype for MECP2, CDKL5 and FOXG1 gene mutations.
abstract: Rett syndrome (RTT) is characterized by a relatively specific clinical phenotype. We screened 152 individuals with RTT phenotype. A total of 22 different known MECP2 mutations were identified in 42 subjects (27.6%). Of the 22 mutations, we identified 7 (31.8%) frameshift-causing deletions, 4 (18.2%) nonsense, 10 (45.5%) missense mutations and one insertion (4.5%). The most frequent pathologic changes were: p.Thr158Met (14.2%) and p.Arg133Cys (11.9%) missense, and p.Arg255Stop (9.5%) and p.Arg294Stop (9.5%) nonsense mutations. We also detected the c.925C >T (p.Arg309Trp) mutation in an affected patient, whose role in RTT pathogenesis is still unknown. Patients without detectable MECP2 defects were screened for mutations of cyclin-dependent kinase-like 5 (CDKL5) gene, responsible for the early-onset variant of RTT. We discovered two novel mutations: c.607G >T resulting in a termination codon at aa203, disrupting the catalytic domain, and c.1708G >T leading to a stop at aa570 of the C terminus. Both patients with CDKL5 mutation presented therapy-resistant epilepsy and a phenotype fitting with the diagnosis of early-onset variant of RTT. No FOXG1 mutation was detected in any of the remaining patients. A total of 110 (72.5%) patients remained without molecular genetic diagnosis that necessitates further search for novel gene mutations in this phenotype. Our results also suggest the need of screening for CDKL5 mutations in patients with Rett phenotype tested negative for MECP2 mutations.
authors.affiliation: Department of Medical Genetics, Faculty of Medicine, University of Pécs, Pecs, Hungary.
authors.forename: Kinga
authors.initials: K
authors.lastname: Hadzsiev
authors.forename: Noemi
authors.initials: N
authors.lastname: Polgar
authors.forename: Judit
authors.initials: J
authors.lastname: Bene
authors.forename: Katalin
authors.initials: K
authors.lastname: Komlosi
authors.forename: Judit
authors.initials: J
authors.lastname: Karteszi
authors.forename: Katalin
authors.initials: K
authors.lastname: Hollody
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Kosztolanyi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Renieri
authors.forename: Bela
authors.initials: B
authors.lastname: Melegh
mesh_terms: D002648:Child; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics*; D006801:Humans; D006814:Hungary; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D015518:Rett Syndrome / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D051783:Methyl-CpG-Binding Protein 2; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; C114482:CDKL5 protein, human