Screening for MECP2 mutations in Spanish patients with an unexplained mental retardation

Abstract

Rett syndrome (RTT) is an X-linked progressive encephalopathy. Mutations in the MECP2 (methyl-CpG-binding protein) gene have been found to cause RTT. In the past few years, the role of MECP2 mutations in patients with mental disorders other than RTT has been studied, finding that mutations in MECP2 also contribute to non-syndromic entities. More recently, it has been demonstrated that RTT shares clinical features with those of Angelman syndrome, another neurodevelopmental disorder. These observations must be confirmed in a large series, to better understand the criteria needed for justifying a molecular test. Consequently, we have searched for MECP2 mutations in 294 patients (43 Angelman and Prader-Willi like included) with mental retardation (MR) of unknown aetiology. We found six polymorphisms (three novel, three previously reported) in 10 patients, one novel unclassified silent change (p.V222V) in a man, and one causative mutation in a girl with MR. Once this case was clinically reviewed, the girl presented symptoms of atypical RTT. The mutation (p.Y141C) lies within the methyl-binding domain, and has only been reported once in another atypical RTT. Our results show that the MECP2 mutations account for a low frequency (1/416 chromosomes = 0.24%) among mentally retarded individuals, which imply that it is necessary to perform an exhaustive clinical examination of patients before determining whether analysis of MECP2 is required or not.

The array of clinical phenotypes of males with mutations in Methyl‐CpG binding protein 2

“…Even when males with MECP2 have some of the distinctive features of RTT, such as loss of spoken language, loss of hand skills, or hand stereotypies, these features may be significantly subtler than those seen in females with RTT, further limiting specific clinical identification. This notion is borne out by MECP2 mutation studies of groups with neurodevelopmental delay that revealed mutations in 1.3–1.7% of males [Orrico, A. et al 2000, Couvert, P. et al 2001, Moncla, A.et al 2002, Yntema, H. G.et al 2002, Yntema, H. G.et al 2002, Bourdon, V.et al 2003, Kammoun, F.et al 2004, dos Santos, J. M.et al 2005, Ylisaukko-Oja, T.et al 2005, Donzel-Javouhey, A.et al 2006, Moog, U.et al 2006, Tejada, M. I.et al 2006], whereas few of these individuals were suspected as having MECP2 mutations. We expect that as whole exome or genome sequencing becomes commonly used to characterize males with neurodevelopmental disorders, it is likely that the identification of MECP2 mutations in these males will increase.…”

MECP2 mutations in males

“…Direct sequencing was used most often because MECP2 is a small gene (1.5 kb of coding sequence). Denaturing gradient gel electrophoresis, 12 denaturing highperformance liquid chromatography 47 or single-strand conformation polymorphism screening 52 were also used to screen large series of patients. These different techniques yield different mutation detection rates (between 0 and 3%).…”

Rett Syndrome and MeCP2

“…Similarly, known RTT-causing MECP2 mutations are found in patients who do not show classical RTT phenotypes (Suter et al 2013). Other than RTT, MECP2 mutations have been found in association with neurological/neuropsychiatric disorders such as, schizophrenia (Cohen et al 2002), FASD (Zoll et al 2004), PPM-X syndrome , autism , Prader-Willi syndrome (Tejada et al 2006) and Angelman syndrome (Watson et al 2001). These reports emphasize that the diagnosis of RTT as well as other MeCP2-related neurological disorders should not be limited to the detection of MECP2 mutations, but rather should be carried out in conjunction with clinical features.…”