Identification of a novel epigenetic marker for typical and mosaic presentations of Fragile X syndrome.

Background: Fragile X syndrome (FXS) is primarily due to CGG repeat expansions in the gene. alleles are classified as normal (N), intermediate (I), premutation (PM), and full mutation (FM). FXS patients often carry an FM, but size mosaicism can occur.

Molecular and clinical insights into complex genomic rearrangements related to MECP2 duplication syndrome.

MECP2 duplication syndrome (MDS) is caused by copy number variation (CNV) spanning the MECP2 gene at Xq28 and is a major cause of intellectual disability (ID) in males. Herein, we describe two unrelated males harboring non-recurrent complex Xq28 rearrangements associated with MDS. Copy number gains were initially detected by quantitative real-time polymerase chain reaction and further delineated by high-resolution array comparative genomic hybridization, familial segregation, expression analysis and X-chromosome inactivation (XCI) evaluation in a carrier mother.

Understanding the Landscape of X-linked Variants Causing Intellectual Disability in Females Through Extreme X Chromosome Inactivation Skewing.

Intellectual disability (ID) affects 30% more males than females. This sex bias can be attributed to the enrichment of genes on the X chromosome playing essential roles in the central nervous system and their hemizygous state on males. Moreover, as a result of X chromosome inactivation (XCI), most genes on one of the X chromosomes in female somatic cells are epigenetically silenced, so that females carrying X-linked variants are not expected to be so severely affected as males.

Network Profiling of Brain-Expressed X-Chromosomal MicroRNA Genes Implicates Shared Key MicroRNAs in Intellectual Disability.

MicroRNAs are endogenous non-protein-coding RNA molecules that regulate post-transcriptional gene expression. The majority of human miRNAs are brain-expressed and chromosome X is enriched in miRNA genes. We analyzed the genomic regions of 12 brain-expressed pre-miRNAs located on chromosome X coding for 18 mature miRNAs, aiming to investigate the involvement of miRNA sequence variants on X-linked intellectual disability (XLID).

rs3851179 Polymorphism at 5' to the PICALM Gene is Associated with Alzheimer and Parkinson Diseases in Brazilian Population.

Alzheimer's (AD) and Parkinson's diseases (PD) share clinical and pathological features, suggesting that they could have common pathogenic mechanisms, as well as overlapping genetic modifiers. Here, we performed a case-control study in a Brazilian population to clarify whether the risk of AD and PD might be influenced by shared polymorphisms at PICALM (rs3851179), CR1 (rs6656401) and CLU (rs11136000) genes, which were previously identified as AD risk factors by genome-wide association studies. For this purpose, 174 late-onset AD patients, 166 PD patients and 176 matched controls were genotyped using TaqMan assays.

Influence of low frequency PSEN1 variants on familial Alzheimer's disease risk in Brazil.

About 30-70% of familial Alzheimer's disease (AD) cases are related to mutations in presenilin-1 gene (PSEN1). Although the role of mutations and common variants in AD had been extensively investigated, the contribution of rare or low frequency PSEN1 variants on AD risk remains unclear. In the current study, we performed a mutational screening of PSEN1 coding exons and flanking intronic sequences among 53 index cases with familial history of AD from Rio de Janeiro (Brazil).

Finding FMR1 mosaicism in Fragile X syndrome.

Objective: Almost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (FMR1). Here, the authors report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism.

Methods: Mutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR).

Novel microduplications at Xp11.22 including HUWE1: clinical and molecular insights into these genomic rearrangements associated with intellectual disability.

Recently, we defined a minimal overlapping region for causal Xp11.22 copy number gains in males with intellectual disability (ID), and identified HECT, UBA and WWE domain-containing protein-1 (HUWE1) as the primary dosage-sensitive gene, whose overexpression leads to ID. In the present study, we used this minimal interval to search for HUWE1 copy number variations by quantitative polymerase chain reaction in a large cohort of Brazilian males with idiopathic ID.

KDM5C mutational screening among males with intellectual disability suggestive of X-Linked inheritance and review of the literature.

An increasing number of neurodevelopmental diseases have been associated with disruption of chromatin remodeling in eukaryotes. Lysine(K)-specific demethylase 5C (KDM5C) is a versatile epigenetic regulator that removes di- and tri-methyl groups of lysine 4 on histone H3 (H3K4) from transcriptional targets and is essential for neuronal survival and dendritic growth. Mutations in KDM5C gene, located at Xp11.

A MECP2 missense mutation within the MBD domain in a Brazilian male with autistic disorder.

Point mutations and genomic rearrangements in the MECP2 gene are the major cause of Rett syndrome (RTT), a pervasive developmental disorder affecting almost exclusively females. MECP2 mutations were also identified in patients with autism without RTT. In this study, we present a mutational and gene dosage analysis of the MECP2 in a cohort of 60 Brazilian males with autistic features but not RTT.

Mutational analysis of GIGYF2, ATP13A2 and GBA genes in Brazilian patients with early-onset Parkinson's disease.

In the last decade, several genes have been linked to Parkinson's disease (PD), including GIGYF2, ATP13A2 and GBA. To explore whether mutations in these genes contribute to development of PD in the Brazilian population, we screened 110 patients with early-onset PD. No clearly pathogenic mutations were identified in ATP13A2 and GIGYF2.

LRRK2 p.G2019S mutation is not common among Alzheimer's disease patients in Brazil.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have emerged as a potential common cause for both sporadic and familial Parkinson's Disease (PD) in different populations. The pleomorphic features exhibited by LRRK2 mutation carriers and the central role of Lrrk2 protein in the proper functioning of central nervous system suggest that mutations in this protein might be involved in multiple cellular processes leading to other neurodegenerative disorders than PD. The location of LRRK2 gene on chromosome 12, close to a linkage peak for familial late-onset Alzheimer's Disease (AD), highlights that LRRK2 mutations might be involved in AD pathogenesis.

A MECP2 mutation in a highly conserved aminoacid causing mental retardation in a male.

MeCP2 is a protein that functions as a key factor in epigenetic transcriptional regulation. Mutations in MECP2 gene have been reported as being the major cause of Rett syndrome. These mutations may also cause a wide spectrum of neurological disorders in males.

A study of LRRK2 mutations and Parkinson's disease in Brazil.

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are known as a common cause of Parkinson's disease (PD) among patients from different geographic origins. In this study, we evaluated the prevalence of LRRK2 mutations in exons 31 and 41 in a cohort of 154 consecutive, unrelated Brazilian patients with familial or sporadic PD, including early and late onset patients. The LRRK2 p.

Low significance of MECP2 mutations as a cause of mental retardation in Brazilian males.

MeCP2 is a protein that selectively binds to methylated cytosines through its methyl-CpG-binding domain (MBD) and connects DNA methylation to transcriptional repression. Mutations in MECP2 gene, located in Xq28, have been reported as being the major cause of Rett syndrome and are also associated with some cases of X-linked mental retardation in both males and females. In this study, we present the first screening in the MECP2 gene in a Brazilian cohort of 239 unrelated males with idiopathic mental retardation.

The A140V mutation in the MECP2 gene is not a common etiological factor among Brazilian mentally retarded males.

In mammals, methyl-CpG binding proteins play a significant role in the control of gene expression through their association with chromatin-remodeling complexes. Mutations in the gene coding for methyl-CpG-binding protein 2 (MECP2) cause Rett syndrome and have also been reported in a number of X-linked mental retardation diseases. In this study, DNA samples from 363 male individuals with syndromic and non-syndromic mental retardation and other psychiatric diseases were screened for A140V (419C>T) mutation in the MECP2 gene, considered the most frequent MECP2 mutation in males.