Phenotypic and Genotypic Variability in Four Males With MECP2 Gene Sequence Aberrations Including a Novel Deletion

Abstract

ABSTRACT:The MECP2 gene mutations cause Rett syndrome (RTT) (OMIM: 312750), an X-linked dominant disorder primarily affecting girls. Until RTT was considered lethal in males, although now approximately 60 cases have been reported. Males with MECP2 mutations present with a broad spectrum of phenotypes ranging from neonatal encephalopathy to nonsyndromic mental retardation (MR). Four boys (aged, 3-11 y) were evaluated for MR. Patient 1 had autistic features. Patients 2 and 3 were brothers both presenting with psychomotor delay. Patient 4 showed dysmorphic features and behavioral problems reminiscent of FXS. All patients had a normal 46, XY karyotype and three were tested for FXS with negative results. MECP2 gene analysis of exons 3 and 4 was performed using methods based on the PCR, including Enzymatic Cleavage Mismatched Analysis (ECMA) and direct sequencing. Patient 1 presented somatic mosaicism for the classic RTT p.R106W mutation and patient 4 carried the p.T203M polymorphism. Analysis of the mothers in both cases revealed normal DNA sequences. Patients 2 and 3 had a novel deletion (c.1140del86) inherited from their unaffected mother. MECP2 gene mutations may be considered a rare cause of MR in males although great phenotypic variation hinders genotype-phenotype correlation. (Pediatr Res 67: 551-556, 2010) R ett syndrome (RTT) (OMIM: 312750) is a severe Xlinked dominant neurodevelopmental disorder, typically affecting females. It is characterized by apparently normal psychomotor development during the first 6 months of life, followed by gradual loss of acquired skills, deceleration of head growth, initiation of stereotypic hand movements, and autistic behavior by the age of 3-4 y (1). During the course of the disease multiple clinical problems emerge such as seizures, scoliosis, breathing abnormalities, and severe mental retardation (MR) (1). The prevalence of RTT is 1:10 -15.000 live births per year and 99% of the cases are considered sporadic (1).Although the diagnosis of classic RTT is based on welldefined criteria, several atypical RTT forms also exist (2). In the majority of cases, the syndrome is caused by heterozygous mutations in the MECP2 gene, which is located on chromosome X (Xq28) and encodes a methyl-CpG binding protein 2 (MeCP2). The protein is thought to selectively bind methyl-CpG islands in the mammalian genome, functioning as a regulator (mostly a repressor) of gene expression. Mutations of the MECP2 gene have been reported in a broad phenotypic spectrum of mentally retarded individuals (3). The first case was molecularly documented in 1999 after the discovery of the MECP2 gene. Generally, males were considered not to survive due to the X-linked mode of inheritance of the disease (4), but to date, more than 60 male patients with MECP2 mutations have been reported (5), suggesting that mutations in this gene may be included among the causes of MR in males. Recent data show that the frequency of MECP2 mutations among mentally retarded males is approximately 1.3 to 1.7% (5).The clinical phenotype...

Correlation between clinical features and MECP2 gene mutations in patients with Rett syndrome

“…Also, within our cohort, 8 cases had preserved speech (25%) within whom, 3 cases showed MECP2 mutations. In our study, the more severe impairment of hand use and the earlier onset of respiratory rhythm dysfunction were associated with MECP2 mutations, which is in accordance with reports by Downs et al 14 and Psoni et al 12 The incidence of epilepsy among our cases was 81.3%, which is in agreement with other reports. 15 Microcephaly was present in most of the cases with epilepsy 20/24 (83.3%), and was more frequent among patients with generalized tonic-clonic cases.…”

“…No correlation was noted amongst the various groups regarding the brain MRI and EEG findings, which is similar to the results by Ponsi et al 12 However, in females with MECP2 mutations the non specific neuro-imaging findings may reflect the absolute volumic brain reduction due to late neuronal maturation and delayed dendritic arborization resulting clinically in microcephaly as described by Mahmood et al 17 …”

“…However, a reasonable number of affected males, with varying disease phenotype, have been reported in recent years indicating that MECP2 mutations are responsible for some cases of mental retardation in males. 12 MECP2 comprises 4 exons and has 2 isoforms as a result of using 2 alternative start codons and alternative splicing of exon 2. Most mutations are single nucleotide substitutions and small insertions and deletions.…”

Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions

“…In 2008, when the original guidelines were written, no males with MECP2 abnormalities and autism had been reported. Since then, two publications 59,60 have identified males with MECP2 duplications and an ASD phenotype. Among the four studies, 22 males with known MECP2 mutations were evaluated.…”

Epigenetic Impacts on Neurodevelopment: Pathophysiological Mechanisms and Genetic Modes of Action

“…Genes implicated in MR/ID syndromes are also being found to be pathogenic for ASD (e.g. the MECP2 gene was thought to be lethal if deleted in males; however, there is now evidence of milder phenotypes including ASD behavioral phenotypes manifesting in males with deficient MECP2 (Table 1) (40).…”