Nonspecific Mental Retardation Research Articles

一例非特异性精神发育迟滞家系OPHN1基因突变分析并文献复习

一例非特异性精神发育迟滞家系OPHN1基因突变分析并文献复习

Comparative genomic hybridization: its interpretation and use as a diagnostic tool in nonspecific mental retardation and microdeletion/microduplication syndromes

En Colombia el cariotipo por bandeo es todavía la prueba inicial más usada en el estudio de pacientes con retardo mental o con anomalías congénita múltiples. Sin embargo, las técnicas moleculares, particularmente la hibridación genómica comparativa con microarrays, han permitido identiicar un número creciente de síndromes de microduplicación o microdeleción en estos pacientes, de modo que mundialmente esta es hoy en día la tecnología de elección para evaluar alteraciones del número de copias. Se realiza esta revisión de la literatura con el objetivo de brindar al personal médico información actualizada acerca de la interpretación y el papel de la hibridación genómica comparativa con microarrays como herramienta diagnóstica en retardo mental inespecíico, síndromes de microdeleción/ microduplicación y análisis cromosómico prenatal. MÉD.UIS. 2016;29(2):137-44.

Diagnostic value of microRNAs in peripheral venous blood for patients with depressive disorder

Objective To investigate the diagnostic value of microRNA(miRNA) in peripheral venous blood for depressive disorder. Methods Real-time fluorescence quantitative PCR(RT-qPCR) was used to verify expression level of miRNAs in peripheral blood of non-specific mental retardation children, which were aberrantly expressed in depressive disorder patients , and then Receiver Operating Characteristics(ROC)curve was employed to confirm the sensitivity and specificity of abnormal miRNA expression in depressive disorder and non-specific mental retardation. Results MiR-1972, miR-26b, miR-4485, miR-4498 and miR-4743 were upregulated significantly in case group of depressive disorder(P 0.05). The ROC curve of miR-26b in depressive disorder patients and their control group showed that the sensitivity and specificity were 0.609, 0.664 respectively, and the area square under the curve was 0.614(P=0.021). The ROC curve of miR-26b in patients of depressive disorder and non-specific mental retardation indicated that the sensitivity and specificity were 0.784 and 0.471, and area square under the curve was 0.643(P=0.003). Conclusion miR-26b probably have diagnostic value for depressive disorder, which may comorbidity with non-specific mental retardation. But genetic and psychosocial mechanism of comorbidity still needs further exploration. Key words: miRNA; Depressive disorder; Non-specific mental retardation; Diagnosis

Aberrant expression of microRNA in peripheral blood of non-specific mental retardation patients

Objective To explore the differentially expressed miRNAs in peripheral blood from the patients with non-specific mental retardation. Methods The miRNAs expression profilings in peripheral blood of 3 pairs in non-specific mental retardation patients and normal control were analyzed using microRNA array. 10 miRNAs were selected according to the microRNA array results.The expression of these miRNAs were detected by quantitative RT-PCR in 34 non-specific mental retardation patients and 32 healthy individuals. Results There were 27 kinds of microRNA which had statistically different expression(FC≥2.0, P≤0.05), and among the above abnormal expressed miRNAs, 22 were up-expressed (over-expression), 5 were down-expressed (under-expression). The expression levels of miR-664a-5p, miR-1207-5p, miR-3141, miR-1228-5p and miR-4505 in non-specific mental retardation patients group(3.93±3.82, 2.48±3.45, 2.75±3.62, 10.03±3.59, 5.35±3.44, respectively) were significantly up-expressed compared with the control group(5.47±3.59, 3.95±1.3.57, 4.14±3.68, 13.23±5.05, 6.85±3.22, P<0.05-0.01). Conclusion There are many differentially expressed miRNAs between the patients with non-specific mental retardation and healthy controls. Key words: miRNAs; Non-specific mental retardation; Gene chips

Xp22.3 interstitial deletion: A recognizable chromosomal abnormality encompassing VCX3A and STS genes in a patient with X-linked ichthyosis and mental retardation

X-linked ichthyosis is a genetic disorder affecting the skin and caused by a deficit in the steroid sulfatase enzyme (STS), often associated with a recurrent microdeletion at Xp22.31. Most of the STS deleted patients have X-linked ichthyosis as the only clinical feature and it is believed that patients with more complex disorders including mental retardation could be present as a result of contiguous gene deletion. In fact, VCX3A gene, a member of the VCX (variable charge, X chromosome) gene family, was previously proposed as the candidate gene for X-linked non-specific mental retardation in patients with X-linked ichthyosis.We report on a boy with familial ichthyosis, dysmorphic features and moderate mental retardation with approximately 2Mb interstitial deletion on Xp22.3 involving VCX3A and STS genes.

The Genetic variants of IL1RAPL2 gene associated with non-specific mental retardation in Chinese children

The present study investigated the association between the genetic variants of IL1RAPL2 gene and Non-syndromic mental retardation (NSMR) in the children of QinBa region of China. Five common SNPs (rs5962434, rs5916817, rs3764765, and rs5962298 and rs9887672) of IL1RAPL2 were chosen and examined their individual genotype frequencies using the conventional polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) method, and evaluated the association between these genetic polymorphisms and NSMR with the suitable bio-statistic software. Two SNPs (rs5962298 and rs9887672), whose alleles and genotypes distribution showed a significant differences between the control and NSMR groups (alleles: p = 0.020 and 0.017; genotypes: p = 0.025 and 0.053, respectively). Furthermore, the different gender effect was found out, when stratified the data set by the sex. Taken together, we provided substantial evidence that IL1RAPL2 conferred a NSMR susceptibility to children of Qinba region in China, and further work should been done. Key words: Non-syndromic mental retardation, molecular genetics, association analysis, genetic variants

Algorithmic Approach for Methyl-CpG Binding Protein 2 (MECP2) Gene Testing in Patients With Neurodevelopmental Disabilities

Methyl-CpG binding protein 2 gene (MECP2) testing is indicated for patients with numerous clinical presentations, including Rett syndrome (classic and atypical), unexplained neonatal encephalopathy, Angelman syndrome, nonspecific mental retardation, autism (females), and an X-linked family history of developmental delay. Because of this complexity, a gender-specific approach for comprehensive MECP2 gene testing is described. Briefly, sequencing of exons 1 to 4 of MECP2 is recommended for patients with a Rett syndrome phenotype, unexplained neonatal encephalopathy, an Angelman syndrome phenotype (with negative 15q11-13 analysis), nonspecific mental retardation, or autism (females). Additional testing for large-scale MECP2 deletions is recommended for patients with Rett syndrome or Angelman syndrome phenotypes (with negative 15q11-13 analysis) following negative sequencing. Alternatively, testing for large-scale MECP2 duplications is recommended for males presenting with mental retardation, an X-linked family history of developmental delay, and a significant proportion of previously described clinical features (particularly a history of recurrent respiratory infections).

MECP2 mutations and clinical correlations in Greek children with Rett syndrome and associated neurodevelopmental disorders

Background: Mutations in the MECP2 gene (methyl-CpG-binding protein-2) are responsible for 60–95% of cases of Rett syndrome (RTT), an X-linked dominant neurodevelopmental disorder affecting mostly girls. Classic RTT is characterized by normal early development followed by psychomotor regression and onset of microcephaly, although variant forms are also observed. MECP2 has also been implicated in variable mental retardation (MR) phenotypes, including X-linked Mental Retardation (XLMR), Fragile-X-like Syndrome (FXS) and Angelman-like (AS) phenotypes. Aim: The aim of the study was: (a) to evaluate the incidence and spectrum of MECP2 mutations in children with RTT and variant MR; (b) to evaluate phenotype-genotype correlations. Methods: Exons 3–4 were analyzed for mutations in 281 MR patients (aged 13months–27years old, 144 males–137 females) consisting of 88 patients referred for RTT and 193 patients referred for AS-like and FXS-like types of MR. Statistical analysis included correlation between classic MECP2-positive and MECP2-negative and variant RTT patients, and frequency of MECP2 mutations in the various categories. Results: Mutations were detected in ≈70% of classic and ≈21% of variant RTT, respectively. Amongst MR cases, 2.1% carried MECP2 mutations. MECP2-positive females had more problems in ambulation, muscle tone, tremor and ataxia, respiratory disturbances, head growth, hand use and stereotypies. Classic RTT-positive versus negative had significant respiratory and sitting problems and versus variant RTT-positive females ambulatory, hand and stereotypies problems. Conclusion: The analysis of the MECP2 gene could provide a diagnostic tool for RTT and non-specific MR research.

Intragenic deletions of IL1RAPL1: Report of two cases and review of the literature

IL1RAPL1 (interleukin-1 receptor accessory protein-like 1) located at Xp21.3-22.1 has repeatedly been shown to be deleted in patients with a contiguous gene syndrome also affecting neighboring genes, in particular DMD (dystrophin), DAX-1 (NR0B1, nuclear receptor subfamily 0, group B, member 1), and GK (glycerol kinase). In contrast, intragenic deletions of IL1RAPL1 or other mutations or cytogenetic aberrations affecting IL1RAPL1 have only rarely been identified. Up to date, they have mostly been associated with nonspecific mental retardation (MRX). We report on two nonrelated patients with MR and additional dysmorphic features who both show intragenic deletions of IL1RAPL1, one of them being de novo (exon 2) and the other one being inherited from his mother (exons 3-5). Deletions were identified by microarray-based chromosome analysis and confirmed by multiplex PCR and FISH, respectively. These data, along with recent functional studies indicating its role in neuronal development, provide further evidence for the relevance of IL1RAPL1 in the pathogenesis of X-linked MR and add knowledge to the phenotypic spectrum of IL1RAPL1 mutations.

How much change is true change? The smallest detectable difference of the Preschool Imitation and Praxis Scale (PIPS) in preschoolers with intellectual disabilities of heterogeneous aetiology

The teaching of imitation skills is often the first step in interventions for young learners with intellectual disabilities. The main goal of this study was to determine the smallest detectable difference (SDD) at 95% confidence of the Preschool Imitation and Praxis Scale (PIPS) in preschoolers with intellectual disabilities. Two raters independently scored videotapes of the imitation performance of 44 preschoolers (27 with Down syndrome, 10 with Non-Specific Mental Retardation and 7 with Low-functioning Autism) between 13 and 58 months of age (mean age 39.6 months, SD 11.9 months). Results revealed that the PIPS demonstrated acceptable interrater reliability on item level (weighted kappa values ranged from 0.52 to 0.96) and scale level (ICC = 0.986; 95% CI: 0.975–0.993). The SDD of the PIPS was 7.2%, indicating that the change score rated by different raters for an individual child with an intellectual disability is valid and that the PIPS can be used by early interventionists and researchers as an outcome measure to determine children's maturation or improvement.

Is the good-imitator-poor-talker profile syndrome-specific in Down syndrome?: Evidence from standardised imitation and language measures

The emergence of the Down syndrome (DS) behavioural phenotype during early development may be of great importance for early intervention. The main goal of this study was to investigate the good-imitator-poor-talker developmental profile in DS at preschool age. Twenty children with Down syndrome (DS; mean nonverbal mental age NMA 1 y10 m) and 15 children with non-specific mental retardation (NS-MR; mean NMA 1 y11 m) participated in this study. The Preschool Imitation and Praxis Scale (PIPS) and the Dutch version of the MacArthur–Bates Communicative Development Inventories (N-CDI) were used to determine absolute and relative (contrasted to a nonverbal mental age reference) imitation and language abilities. Results revealed that there was clear evidence for a good-imitator-poor-talker profile in preschoolers with DS. However, only the advanced bodily imitation ability seems to be syndrome-specific. Clinical implications of these findings are considered.

FMR2 gene deletion as a cause of non-specific mental retardation and autistic behavior in two brothers

Background: Silencing of the Fragile X Mental Retardation 2 gene (FMR2, Xq28) as a consequence of CCG trinucleotide repeat expansion located upstream of the gene is the cause of non-specific X-linked mental retardation (MRX) in 1/50.000 newborn males. This condition, also known as FRAXE, represents a mild to borderline form of mental retardation (MR) associated with communication deficits, attention problems, hyperactivity, and autistic behavior. Little is known about FMR2 deletions as potential cause of FRAXE in the absence of trinucleotide expansion. Several reports on large deletions including FMR1, FMR2 and other adjacent genes exist. However, reports on alterations affecting only FMR2 are to our knowledge limited to descriptions of a balanced translocation having the breakpoint within the FMR2 gene and two submicroscopic deletions which originally led to the cloning of the FMR2 gene.

An association study between IL1RAPL2 gene and non-specific mental retardation in Chinese children

Non-specific mental retardation (NSMR) is one of common children psychiatric diseases with a high prevalence (1–3%). Here we investigated the association between the genetic variants of IL1RAPL2 gene and NSMR in the children of QinBa region of China. We chose five common SNPs of IL1RAPL2, examined their individual genotype frequencies using the conventional polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) method, and evaluated the association between these genetic polymorphisms and NSMR with the suitable biostatistic software. The allele and genotype distributions of two SNPs (rs5962298 and rs9887672) showed significant differences between the control and NSMR groups (allele: p = 0.020 and 0.017; genotype: p = 0.025 for rs9887672 respectively). The distribution differences became more significant in girls, but disappeared in boys, suggesting a gender effect. Taken together, we provide substantial evidence that IL1RAPL2 conferred a NSMR susceptibility to children of Qinba region in China. In future, further work should be carried out to scan mutations and to investigate the specific-gender effect in this gene.

Mutations of the UPF3B gene, which encodes a protein widely expressed in neurons, are associated with nonspecific mental retardation with or without autism

Mutations in the UPF3B gene, which encodes a protein involved in nonsense-mediated mRNA decay, have recently been described in four families with specific (Lujan-Fryns and FG syndromes), nonspecific X-linked mental retardation (XLMR) and autism. To further elucidate the contribution of UPF3B to mental retardation (MR), we screened its coding sequence in 397 families collected by the EuroMRX consortium. We identified one nonsense mutation, c.1081C>T/p.Arg361(*), in a family with nonspecific MR (MRX62) and two amino-acid substitutions in two other, unrelated families with MR and/or autism (c.1136G>A/p.Arg379His and c.1103G>A/p.Arg368Gln). Functional studies using lymphoblastoid cell lines from affected patients revealed that c.1081C>T mutation resulted in UPF3B mRNA degradation and consequent absence of the UPF3B protein. We also studied the subcellular localization of the wild-type and mutated UPF3B proteins in mouse primary hippocampal neurons. We did not detect any obvious difference in the localization between the wild-type UPF3B and the proteins carrying the two missense changes identified. However, we show that UPF3B is widely expressed in neurons and also presents in dendritic spines, which are essential structures for proper neurotransmission and thus learning and memory processes. Our results demonstrate that in addition to Lujan-Fryns and FG syndromes, UPF3B protein truncation mutations can cause also nonspecific XLMR. We also identify comorbidity of MR and autism in another family with UPF3B mutation. The neuronal localization pattern of the UPF3B protein and its function in mRNA surveillance suggests a potential function in the regulation of the expression and degradation of various mRNAs present at the synapse.

Mental retardation and Xq12–Xq23: candidate loci for nonspecific mental retardation in the male population of the QinBa region

The higher prevalence of nonspecific mental retardation (NSMR) presents an important socioeconomic and medical issue for families and the whole QinBa region in China. The obvious family aggregation and high heritability indicated that genetic causes play a role in the NSMR population in QinBa. This study discusses the relationship between Xq12-Xq23 region and NSMR in the QinBa area. We chose six short tandem repeats--DXS7132, DXS6979, DXS1191, DXS1230, DXS1072, and DXS6804, located in Xq12-Xq23--and analyzed the distribution difference of their alleles between the NSMR and control boys. A significant allele distribution difference was found between NSMR and control boys (all P<0.05) for DXS7132, DXS1191, DXS1230, DXS1072, and DXS6804 but not for DXS6979. Our results suggest that Xq12-Xq23 may be the candidate region where there are one or more loci, linked to NSMR in the QinBa region. Further study needs to be carried out for locating the gene responsible for NSMR in this region and a larger sample size and more genetic markers are needed.

Positive association of neuroligin-4 gene with nonspecific mental retardation in the Qinba Mountains Region of China

Neuroligin-4 is essential for proper brain function. Some studies indicate a close relationship between neuroligin-4 and several human psychiatric conditions. The case-control method was used to study the association between nonspecific mental retardation (NSMR) and genetic variants of neuroligin-4 gene (NLGN4). Five single nucleotide polymorphisms (SNPs: rs5916271, rs7049300, rs6638575, rs3810686, and rs1882260) were genotyped by PCR-RFLP/SSCP method in the NLGN4. Individual SNP analysis shows significant differences at SNPs rs3810686 and rs1882260 for allele frequency when NSMR cases and controls [odds ratio (OR)=1.589, 95% confidence interval (CI)=1.035-2.438, chi2=4.53, df=1, P=0.033; OR=2.050, 95% CI=1.211-3.470, chi2=7.38, df=1, P=0.007, respectively] were compared. Further haplotype analysis indicates that there are two haplotype sets, rs3810686-rs1882260 and rs6638575-rs3810686-rs1882260, which show statistical differences between NSMR cases and controls (chi2=6.79, df=2, global P=0.034; chi2=9.29, df=2, global P=0.0096, respectively). The results suggest a positive association between the genetic variants of the NLGN4 and NSMR in the Chinese children from Qinba Mountains Region.

Rett Syndrome Gene Duplication Associated with Unexplained X-Linked Mental Retardation

The incidence of nonspecific mental retardation is higher in males than in females, and responsible genes on the X chromosome continue to be identified. Xq28 duplications involving the MECP2 gene have recently been described in male patients with severe mental retardation, infantile hypotonia, progressive spasticity, and recurrent infections, but the frequency …

Could autism with mental retardation result from digenism and frequent de novo mutations?

The high concordance for autism symptoms in monozygotic twin-pairs compared to di-zygotic twins and/or non-twin sib-ships suggests a high genetic determinism in autism. Those results have hypothesized multi-factorial determinism in accordance with family studies and mathematical models. However, linkage and association or candidate gene strategies have failed to-date to identify clearly involved mechanisms. Mental retardation (MR) is known as frequently associated to autism. Multiplex XLMR pedigrees have been reported with only one mutated patient having autism and MR: different X-located MR genes have been shown to be involved (NLGN4, MECP2, OPHN1, ZNF674 and FRAXA) which does not suggest that they could be “autism genes”. Tuberous sclerosis studies and report of numerous autosomal domains shown deleted in MR-autistic subjects suggest that several autosomal dominant (AD) genes could be also involved in MR with autism. Whereas multiplex AD-MR families are rare, AD de novo mutations could explain numerous sporadic situations of non-specific MR and of autism with MR, in accordance with twin studies. Finally, we hypothesize that in those autistic subjects with mendelian MR, the XL-MR or AD-MR gene (G1) would pave the way for a second Mendelian factor (G2) responsible for autism symptoms.

Anassociation study between &lt;I&gt;OPHN1&lt;/I&gt; gene rs492933 poly-morphism and mental retardation in children of the Qinba Moun-tain region

The OPHN1 gene encodes a Rho-GTPase activating protein (RhoGAP), and mutations in OPHN1 are responsible for non-specific X-linked mental retardation (NSMR). A SNP located in the 5'-untranslated region (UTRs) of OPHN1 (rs492933) was examined by PCR-RFLP to assess its contribution to cognitive ability in 234 unrelated healthy and MR children in the Qinba Mountain region in Shaanxi. The allelic frequencies of rs492933 were 0.826 for the C allele and 0.174 for the T allele. Genotype frequencies and allelic frequencies were not significantly different between the MR and the controls, or between the borderline group and the controls. In conclusion, there is no association between the OPHN1 gene polymorphism and NSMR in the Qinba Mountain region children.

Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: Efficient identification of known microduplications and identification of a novel microduplication in ASMT

BackgroundIt has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications.MethodsIn the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-PCR) and/or direct DNA sequencing were used to validate potential microdeletions and microduplications. Methylation-sensitive MLPA was used to characterize individuals with duplications in the Prader-Willi/Angelman (PWA) region.ResultsMLPA showed two subjects with typical ASD-associated interstitial duplications of the 15q11-q13 PWA region of maternal origin. Two additional subjects showed smaller, de novo duplications of the PWA region that had not been previously characterized. Genes in these two novel duplications include GABRB3 and ATP10A in one case, and MKRN3, MAGEL2 and NDN in the other. In addition, two subjects showed duplications of the 22q11/DiGeorge syndrome region. One individual was found to carry a 12 kb deletion in one copy of the ASPA gene on 17p13, which when mutated in both alleles leads to Canavan disease. Two subjects showed partial duplication of the TM4SF2 gene on Xp11.4, previously implicated in X-linked non-specific mental retardation, but in our subsequent analyses such variants were also found in controls. A partial duplication in the ASMT gene, located in the pseudoautosomal region 1 (PAR1) of the sex chromosomes and previously suggested to be involved in ASD susceptibility, was observed in 6–7% of the cases but in only 2% of controls (P = 0.003).ConclusionMLPA proves to be an efficient method to screen for chromosomal abnormalities. We identified duplications in 15q11-q13 and in 22q11, including new de novo small duplications, as likely contributing to ASD in the current sample by increasing liability and/or exacerbating symptoms. Our data indicate that duplications in TM4SF2 are not associated with the phenotype given their presence in controls. The results in PAR1/PAR2 are the first large-scale studies of gene dosage in these regions, and the findings at the ASMT locus indicate that further studies of the duplication of the ASMT gene are needed in order to gain insight into its potential involvement in ASD. Our studies also identify some limitations of MLPA, where single base changes in probe binding sequences alter results. In summary, our studies indicate that MLPA, with a focus on accepted medical genetic conditions, may be an inexpensive method for detection of microdeletions and microduplications in ASD patients for purposes of genetic counselling if MLPA-identified deletions are validated by additional methods.