title: The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome.
abstract: Missense MECP2 variants can have various phenotypic effects ranging from a normal phenotype to typical Rett syndrome (RTT). In females, the phenotype can also be influenced by the X-inactivation pattern. In this study, we present detailed clinical descriptions of six patients with a rare base-pair substitution affecting Arg309 at the C-terminal end of the transcriptional repression domain (TRD). All patients have intellectual disability and present with some RTT features, but they do not fulfill the clinical criteria for typical or atypical RTT. Most of the patients also have mild facial dysmorphism. Intriguingly, the mother of an affected male patient is an asymptomatic carrier of this variant. It is therefore likely that the p.(Arg309Trp) variation does not necessarily lead to male lethality, and it results in a wide range of clinical features in females, probably influenced by different X-inactivation patterns in target tissues.
authors.affiliation: Center for Rett Syndrome, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.|Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: B
authors.initials: B
authors.lastname: Schönewolf-Greulich
authors.affiliation: Genetics Service, Cruces University Hospital, BioCruces Health Research Institute, Clinical group affiliated with the Centre for Biomedical Research on Rare Diseases (CIBERER), Barakaldo, Bizkaia, Spain.
authors.forename: M-I
authors.identifier: 0000-0002-7334-1864
authors.initials: MI
authors.lastname: Tejada
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals, Manchester, UK.
authors.forename: K
authors.initials: K
authors.lastname: Stephens
authors.affiliation: Department of Medical Genetics, University of Pécs, Pécs, Hungary.
authors.forename: K
authors.initials: K
authors.lastname: Hadzsiev
authors.affiliation: Molecular Diagnostic Laboratory and Division of Medical Genetics, CHU Sainte-Justine, Montreal, Quebec, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Gauthier
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Brøndum-Nielsen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: K
authors.initials: K
authors.lastname: Ravn
authors.affiliation: Genetics Service, Cruces University Hospital, BioCruces Health Research Institute, Clinical group affiliated with the Centre for Biomedical Research on Rare Diseases (CIBERER), Barakaldo, Bizkaia, Spain.
authors.forename: H
authors.initials: H
authors.lastname: Maortua
authors.affiliation: Genetics Service, Cruces University Hospital, BioCruces Health Research Institute, Clinical group affiliated with the Centre for Biomedical Research on Rare Diseases (CIBERER), Barakaldo, Bizkaia, Spain.
authors.forename: B
authors.initials: B
authors.lastname: Gener
authors.affiliation: Genetics Service, Cruces University Hospital, BioCruces Health Research Institute, Clinical group affiliated with the Centre for Biomedical Research on Rare Diseases (CIBERER), Barakaldo, Bizkaia, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Martínez-Bouzas
authors.affiliation: Department of Translational Medicine and Neurogenetics, IGBMC, CNRS UMR 7104/INSERM U964/Strasbourg University, Strasbourg, France.|Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg Cedex, France.
authors.forename: A
authors.initials: A
authors.lastname: Piton
authors.affiliation: Department of Human Genetics, McGill University, Montréal, Quebec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Rouleau
authors.affiliation: Manchester Centre for Genomic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals, Manchester, UK.
authors.forename: J
authors.initials: J
authors.lastname: Clayton-Smith
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Center for Rett Syndrome, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: A-M
authors.initials: AM
authors.lastname: Bisgaard
authors.affiliation: Applied Human Molecular Genetics, Kennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Glostrup, Denmark.
authors.forename: Z
authors.initials: Z
authors.lastname: Tümer
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D015518:Rett Syndrome / Q000235:genetics / Q000473:pathology; D017386:Sequence Homology, Amino Acid
chemical_list: D051783:Methyl-CpG-Binding Protein 2
keywords: MECP2; Rett syndrome; X-inactivation; clinical criteria; missense mutations; p.(Arg309Trp)