title: Molecular diagnostic dilemmas in Rett syndrome.
abstract: Rett syndrome (OMIM 312750) is a progressive, X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene located on chromosome Xq28. The disorder is characterized by a period of normal development during the first 6-18months of life, followed by gradual loss of skills already gained, such as speech and purposeful movement of the hands. The majority of cases are sporadic and represent "de novo" mutations. In this study we summarize the results of diagnostic testing of 30 patients with Rett syndrome (RTT) or mental retardation of unknown etiology using bidirectional sequencing of the open reading frame of the MECP2 gene. Twenty different variants were identified in those patients including 12 missense (R133C, P152R, T158M, V300I, I303M, R306C, T311M, R344W, A358T, P384L, A443T, V481M), four nonsense (R168X, K192X, R255X, R270X), two deletion (E137_L386del, I293_S350del), and two frameshift (S291QfsX26, G343AfsX6) mutations. Seven of the twenty variants identified were novel mutations (E137_L386del, K192X, S291QfsX26, G343AfsX6, I293_S350del, P384L, and A443T). In the cases with novel or non-recurrent missense mutations, family studies were performed to investigate genotype-phenotype correlations. Our results demonstrate the importance of family studies and highlight the complexity of interpretation of MECP2 alterations, which may or may not be disease-associated.
authors.affiliation: Center for Molecular Biology and Pathology, Laboratory Corporation of America, Research Triangle Park, NC 27709, USA. zverefv@labcorp.com
authors.forename: Val
authors.initials: V
authors.lastname: Zvereff
authors.forename: Lori
authors.initials: L
authors.lastname: Carpenter
authors.forename: Dagny
authors.initials: D
authors.lastname: Patton
authors.forename: Huong
authors.initials: H
authors.lastname: Cabral
authors.forename: Debra
authors.initials: D
authors.lastname: Rita
authors.forename: Ashley
authors.initials: A
authors.lastname: Wilson
authors.forename: Kwame
authors.initials: K
authors.lastname: Anyane-Yeboa
authors.forename: Larry
authors.initials: L
authors.lastname: White
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Friedman
mesh_terms: D005192:Family Health; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics*; D057089:Pathology, Molecular / Q000379:methods*; D015518:Rett Syndrome / Q000175:diagnosis* / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2