Analysis of IQSEC2 gene variant in a child with X-linked mental retardation / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and genetic variants of a child with X-linked mental retardation caused by IQSEC2 gene mutation, and provide reference for the diagnosis of the disease.@*METHODS@#The child was subjected to next generation sequencing (NGS), and the diagnosis was made by taking consideration of her clinical characteristics.@*RESULTS@#The child has presented with global developmental delay, particularly in fine motor skill and language development, in addition with intellectual disability. Genetic testing revealed that she has harbored a heterozygous c.1861dup variant of the IQSEC2 gene, which was not detected in either parent.@*CONCLUSION@#The de novo c.186ldup variant of the IQSEC2 gene probably underlay the X-linked mental retardation in this child. Above finding has, expanded the spectrum of IQSEC2 gene mutations and provide a basis for the diagnosis of similar cases.

ATR-X syndrome in two siblings with a novel mutation (c.6718C>T mutation in exon 31).

ATR-X syndrome is an X-linked mental retardation syndrome characterized by mental retardation, alpha thalassaemia and distinct facial features which include microcephaly, frontal hair upsweep, epicanthic folds, small triangular nose, midface hypoplasia and carp-shaped mouth. Here we report two brothers with clinical features of ATR-X syndrome, in whom a novel missense (C>T) mutation was identified in exon 31 of the ATRX gene.

Protocolo de estudio del retraso mental de origen genético / Study protocol of genetic mental retardation

El estudio del retraso mental de origen genético es uno de los campos más complejos en genética humana debido a que presenta una heterogeneidad muy elevada, con una gran complejidad de las bases genéticas y factores ambientales que influyen sobre éstas. En estos momentos, casi la mitad de los casos de retraso mental de origen genético quedan sin un diagnóstico. El objetivo de este trabajo es aportar una visión actualizada de las recientes metodologías desarrolladas para alcanzar un diagnóstico molecular de retraso mental de origen genético para poder dar asesoramiento genético y ofrecer un diagnóstico prenatal. El primer paso es la evaluación del paciente con una exploración clínica minuciosa y la obtención de datos sobre antecedentes personales y familiares. Cuando exista una sospecha diagnóstica de un síndrome clínico reconocible que cursa con retraso mental, ésta deberá ser confirmada en el laboratorio con la técnica correspondiente. Ante casos de retraso mental en los que no existe sospecha clínica para ningún síndrome determinado se realizarán tres pruebas de forma rutinaria: cariotipo, estudio molecular de la expansión CGG del gen FMR1 y estudio de las regiones subteloméricas. Hasta hace poco era difícil avanzar más, pero la reciente aparición de nuevas tecnologías de alto rendimiento cada vez más sensibles y con mayor capacidad de análisis como el MLPA o el aCGH (cariotipo molecular) está permitiendo la detección de nuevos reordenamientos crípticos desequilibrados responsables de retraso mental.

O Gene MECP2 e a função neurocognitiva humana: rastreamento de mutações em pacientes com retardo mental de etiologia desconhecida / The MECP2 gene and the human neurocognitive function: mutation screening in patients with mental retardation of unknown etiology

O retardo mental (RM) é uma das doenças humanas mais comuns, com prevalência de aproximadamente 2%. Esta condição pode resultar de inúmeras causas genéticas, dificultando o seu diagnóstico e representando um desafio para os clínicos. Fatores genéticos possuem um papel importante na etiologia desta condição. Mais de 280 genes foram associados ao RM e, dentre eles, destaca-se o MECP2. Mutações pontuais neste gene, localizado em Xq28, são a principal causa da síndrome de Rett, uma desordem neurológica que, com raras exceções, acomete exclusivamente meninas. Em meninos, estas mutações estão associadas ao RM, mas suas frequências não se mostraram significativas para a aplicação no diagnóstico. Recentemente, microduplicações envolvendo o gene MECP2 foram observadas em meninos com RM, revelando um novo mecanismo mutacional associado a este gene. Este projeto teve como objetivo estudar a contribuição de mutações no gene MECP2 na etiologia do RM em amostra de 150 meninos brasileiros com RM idiopático. A análise de mutações pontuais foi realizada por sequenciamento direto dos produtos da PCR. Para o rastreamento de duplicações, estabelecemos um método de PCR quantitativo em tempo real capaz de dosar o número relativo de cópias do gene MECP2. O método foi otimizado e validado em controles saudáveis. Estudos de expressão foram realizados nos indivíduos com duplicações por PCR em tempo real e a extensão das duplicações foi inferida através da dosagem gênica de quatro regiões adicionais flanqueadoras do MECP2. Oito mutações pontuais foram encontradas, sendo uma variante intrônica, três variantes silenciosas e quatro variantes de sentido trocado. Destas, três são não patogênicas e uma (c.1214C>T), nunca descrita, afeta um aninoácido da proteína altamente conservado. Através de estudos de segregação, de amostra controle normal e de bioinformática, inferimos que esta variante é patogênica. A dosagem gênica do MECP2 por PCR quantitativo identificou três pacientes...

Mental retardation (MR) is one of the most common human disorders, with a prevalence of appoximately 2%. This condition may have several genetic causes, which difficults diagnosis, representing a challenge for clinicians. Genetic factors play a major role in the etiology of this condition. More then 280 genes were associated with MR and, among them, the MECP2. Point mutations in this gene, located in Xq28, are the major cause of Rett syndrome, a neurological disorder that, with rare exceptions, affects exclusively women. In males, these mutations are associated with MR, however their frequency is not supportive for diagnosis application. Recently, microduplications envolving the gene MECP2 were observed in males with MR, uncovering a new mutational mechanism associated with this gene. This project has the objective to study the contribution of mutations in the MECP2 gene in the MR etiology of 150 brazilian males with idiopathic MR. The analysis of point mutations was performed by direct sequencing of the PCR method to quantify the relative MECP2 copy number. The method was optimized and validated in normal controls. Expression studies were performed in the individuals with duplications by Real time PCR and the size of the duplications was accessed though the gene dosage of four additional regions flanking the MECP2. Eight point mutations were identifies, one intronic variant, three silent mutations and four misense mutations. From those, three were non-pathogenic and one (c.1214C>T), never described, affects a highly conserved aminoacid. Through segregation studies, control sample screening and bioinformatics analysis we believe that this variant is pathogenic. MECP2 gene dosage by quantitative PCR has identified three patients with duplications involving this gene (~2). The size of these rearranjements varied among the patients, including other genes in the duplication, what may explain the clinical variantions observed in the patients...

X linked mental retardation

Mental retardation [MR] is a group of heterogeneous clinical conditions. There are more than 900 genetic disorders associated with MR and it affects around 3%of the general population. Many MR conditions described are syndromic, fragile X syndrome being the most common clinical entity among them. Xlinked mental retardation [XLMR] is subdivided in two categories: syndromic XLMR [MRXS] when MR is associated with clinical features and non-syndromic XLMR [MRX] when MR is isolated. The aim of this systematic review of the literature was to join together the results of several studies related to X linked mental retardation and to present various genes implicated in this disease. In this review, focus has been given on genes implicated in mental retardation, the clinical data and on phenotype-genotype correlations. An exhaustive electronic and library research of the recent literature was carried out on the Web sites "Science Direct" and "Interscience Wiley". The key words used were "mental retardation", "X chromosome", "gene", "syndromic mental retardation", "non-syndromic mental retardation". In this review a number of X linked genes, the clinical features associated with the gene abnormality, and the prevalence of the disease gene are discussed. We classified these genes by order of their first implication in MR. A table presented on the XLMR Update Web site who list the 82 known XLMR genes is available as XLMR Genes and corresponding proteins

Molecular basis of X-linked non-specific mental retardation.

Mental retardation (MR) is a common disorder, affecting 1-3% of the total population. This condition results from failure to develop cognitive abilities and intelligence level appropriate for the age group. Mental retardation is basically a clinically as well as etiologically heterogeneous type of condition and both genetic and non-genetic factors have been found to be involved. There are more than 1000 entries in Online Mendelian Inheritance in Man (OMIM) database under the name of mental retardation. In recent years 15 genes for X linked non-specific mental retardation have been identified which provide important clues regarding molecular and cellular processes involved in signal transduction cascade in central nervous system. Recent advancements in identification and characterization of X-linked non-specific mental retardation genes have been discussed in this review. Understanding of the molecular pathways of disease causing genes would be helpful in developing effective therapeutic approaches for mental retardation.