Variant Profile of MECP2 Gene in Sri Lankan Patients with Rett Syndrome.

Rett syndrome (RTT) is a rare monogenic disorder affecting 1 in 10,000 live female births causing severe neurodegenerative symptoms. We analyzed the molecular genetic variants in the gene encoding the methyl-CpG binding protein 2 (MECP2) of 16 girls with RTT. Their mutation profile was as follows; Already described variants: p.R168X in 25% (n = 4), p.T158M in 25% (n = 4), p.R255X in 12.5% (n = 2), p.R133C in 12.5% (n = 2), p.R294X in 6.25% (n = 1), p.K177X in 6.25% (n = 1). Novel variants: a large deletion (c.868_1188del321) in 6.25% (n = 1) and a p.X499L in 6.25% (n = 1). We also looked at the genotype to phenotype correlation of these variants. Most of the mutations were C>T in CpG hot spot as seen in other populations.

Novel MEF2C point mutations in Chinese patients with Rett (-like) syndrome or non-syndromic intellectual disability: insights into genotype-phenotype correlation.

BACKGROUND: MEF2C (Myocyte-specific enhancer factor 2C) has been associated with neurodevelopmental disorders. This study aimed at delineating the clinical profiles of MEF2C gene mutations. METHODS: In total, 112 Chinese patients with intellectual disability (ID) were recruited, including 44 patients presented with Rett syndrome (RTT) or RTT-like syndrome, and 68 patients with non-syndromic ID. Targeted next-generation sequencing (NGS) was performed. Detailed clinical information was collected. RESULTS: Five heterozygous MEF2C gene mutations were identified, of which three were novel. The MEF2C mutant rate was 4.5% (5/112) in total, and 6.8% (3/44) in the RTT (-like) cohort. All patients with MEF2C gene mutation presented with cognitive impairment, gross motor delay, speech disorder and autistic features. Four patients had epilepsy, which responded well to antiepileptic drugs. One female was diagnosed with classical RTT, two females with RTT-like syndrome, and two males with non-syndromic ID. Generally, the phenotype of two males with relatively downstream mutations (c.565C > T, p.Arg 189*; c.766C > T, p.Arg 256*) was milder than that of three females with upstream mutations (c.48C > G, p.Asn16Lys; c.334G > T, p.Glu112* and c.403-1G > T). CONCLUSIONS: Our findings expanded the current understanding of the consequences of MEF2C dysfunctions, especially MEF2C point mutations. MEF2C mutations are associated with a broad clinical spectrum, ranged from classical RTT to non-syndromic ID. Through our study, it can be inferred that there is correlation between the phenotype and MEF2C-genotype, the mutation site. Overall, the MEF2C gene mutational analysis should be performed in ID cohort, especially in patients with features overlapped with RTT.

Novel mutations in cyclin-dependent kinase-like 5 (CDKL5) gene in Indian cases of Rett syndrome.

Rett syndrome is a severe neurodevelopmental disorder, almost exclusively affecting females and characterized by a wide spectrum of clinical manifestations. Both the classic and atypical forms of Rett syndrome are primarily due to mutations in the methyl-CpG-binding protein 2 (MECP2) gene. Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in patients with atypical Rett syndrome, X-linked infantile spasms sharing common features of generally early-onset seizures and mental retardation. CDKL5 is known as serine/threonine protein kinase 9 (STK9) and is mapped to the Xp22 region. It has a conserved serine/threonine kinase domain within its amino terminus and a large C-terminal region. Disease-causing mutations are distributed in both the amino terminal domain and in the large C-terminal domain. We have screened the CDKL5 gene in 44 patients with atypical Rett syndrome who had tested negative for MECP2 gene mutations and have identified 6 sequence variants, out of which three were novel and three known mutations. Two of these novel mutations p.V966I and p.A1011V were missense and p.H589H a silent mutation. Other known mutations identified were p.V999M, p.Q791P and p.T734A. Sequence homology for all the mutations revealed that the two mutations (p.Q791P and p.T734A) were conserved across species. This indicated the importance of these residues in structure and function of the protein. The damaging effects of these mutations were analysed in silico using PolyPhen-2 online software. The PolyPhen-2 scores of p.Q791P and p.T734A were 0.998 and 0.48, revealing that these mutations could be deleterious and might have potential functional effect. All other mutations had a low score suggesting that they might not alter the activity of CDKL5. We have also analysed the position of the mutations in the CDKL5 protein and found that all the mutations were present in the C-terminal domain of the protein. The C-terminal domain is required for cellular localization through protein-protein interaction; any mutations in this domain might alter this function of the protein. This is the first report from India showing the mutation in CDKL5 gene in Indian cases of Rett syndrome. Our study emphasizes the role of CDKL5 mutation screening in cases of atypical Rett syndrome with congenital seizure variant.

Mutational analysis of the MECP2 gene in Tunisian patients with Rett syndrome: a novel double mutation.

Rett syndrome is a severe disorder characterized by loss of acquired skills after a period of normal development in infant girls. It is caused mainly by mutations in the MECP2 gene. In this study, we reported mutations in the MECP2 gene in 7 Tunisian patients with classic Rett syndrome. The results showed the presence of a double mutation in 1 patient: p.R306C and c.1461+98insA, which create a new hypothetical polyadenylation site in the 3(')UTR of the MECP2 gene. We also detected in another patient a new variant c.1461+92C>G in the 3(')UTR located previous to 34 bp from the polyadenylation site with a score of 4.085. This variation is located in a hypothetical splicing enhancer with a score of 1.96277 according to the ESE finder program. In the remaining 5 patients, we found 2 common mutations: p.T158M in 4 individuals and p.R168X in only 1 girl.

MECP2 mutations in Serbian Rett syndrome patients.

BACKGROUND: Rett syndrome is a severe neurodevelopmental X-linked dominant disorder affecting 1/15,000 girls worldwide. Eight years ago, the MECP2 gene was associated with the devastating clinical features observed in Rett syndrome patients. OBJECTIVES: To investigate the spectrum and the frequency of MECP2 mutations in Serbian Rett syndrome patients. PATIENTS AND METHODS: We screened the MECP2 coding region by conventional mutational screening (single-strand conformation polymorphism/sequencing) in 24 patients of Serbian origin and in their 41 unaffected family members. In search for gene dosage alterations in seemingly mutation-negative girls, we developed a new, specific quantitative PCR method. RESULTS: Nineteen patients (79%) carried MECP2 mutations, five of which were novel (one nonsense mutation, one duplication and three deletions). Fourteen previously described disease-causing sequence changes and one polymorphism were also detected. Detailed case reports are given for the carriers of the novel mutations. Large MECP2 rearrangements cause Rett syndrome in a significant number of girls without 'classic' mutations in this gene. Therefore, we developed a specific quantitative PCR method, covering MECP2 exons 3 and 4, which previously has not been used for screening. No dosage alterations of the two exons were found in the four tested mutation-negative girls. CONCLUSIONS: This is the first genetic study of Rett syndrome in Serbian patients describing the MECP2 mutational and phenotypic spectrum in this population. Detailed clinical descriptions of this ethnically homogeneous patient population add to our knowledge of genotype/phenotype correlations in this severe condition.

Mutation analysis of MECP2 and clinical characterization in Korean patients with Rett syndrome.

Rett syndrome is a progressive neurodevelopmental disorder occurring predominantly in females. Recently, mutations in the MECP2 gene on Xq28, which encodes methyl-CpG binding protein 2, were identified as responsible for some cases of Rett syndrome. In the present study, we analyzed the entire coding sequence of the MECP2 gene in 20 sporadic cases of Rett syndrome in Korea. Of the 20 patients, 14 (70%) had pathogenic mutations, which included 10 different mutations. Altogether, there were five missense mutations (D97Y, L100V, R133C, T158M, R306C), four nonsense mutations (R168X, R255X, R270X, R294X), and one frameshift mutation (a 41-bp deletion at 1157-1197). Two of these were novel mutations (D97Y, L100V). Most of the nucleotide substitutions involved C to T transitions at CpG hotspots. We could find no clear phenotype-genotype correlation according to the type of mutation. However, there was a tendency for patients with no MECP2 mutation (30%) to show more severe symptoms and more rapid clinical progression than patients with mutations. Further studies are necessary to identify the other possible genetic causes of Rett syndrome.

Mutation analysis of the MECP2 gene in British and Italian Rett syndrome females.

Rett syndrome is an X-linked dominant neurological disorder, which appears to be the commonest genetic cause of profound combined intellectual and physical disability in Caucasian females. Recently, this syndrome has been associated with mutations of the MECP2 gene, a transcriptional repressor of still unknown target genes. Here we report a detailed mutational analysis of 62 patients from UK and Italian archives, representing the first comparative study among different populations and one of the largest number of cases so far analyzed. We review the literature on MECP2 mutations in Rett syndrome. This analysis has permitted us to produce a map of the recurrent mutations identified in this and previous studies. Bioinformatic analysis of the mutations, taking advantage of structural and evolutionary data, leads us to postulate the existence of a new functional domain in the MeCP2 protein, which is conserved among brain-specific regulatory factors.