Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Five decades ago, Tijo and Levan (1956) first recognized the correct chromosome number in man to be 46. Shortly thereafter, several chromosome aneuploid syndromes were identified. In the early 1970s, various chromosomal-banding techniques were developed that allowed the recognition of individual chromosomes and deletions and duplications as etiologies for numerous chromosome syndromes. Slightly more than 10 years ago, fluorescence in situ hybridization (FISH) procedures, using fluorescent-labeled DNA sequences were developed and clinical use of this technique allowed for the identification of cryptic chromosome abnormalities associated with microdeletions and microduplications. The use of subtelomere region-specific FISH probes further led to the identification of deletions and other unbalanced rearrangements in individuals with mental retardation with an apparently normal karyotype. More recently, microarray comparative genomic hybridization was developed, and the technique has recently become incorporated into the clinical cytogenetics laboratory for the identification of submicrosopic deletions and duplications that are associated with developmental delay. The intent of this article is to review the cytogenetic and molecular cytogenetic techniques currently available for the diagnosis of individuals with neurologic disease and genetic imbalances that result in neurologic disturbances and to summarize the most efficient and appropriate use of these techniques in clinical practice.
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PMID:Role of cytogenetics and molecular cytogenetics in the diagnosis of genetic imbalances. 1733 78

The human chromosome X is closely associated with congenital disorders and mental retardation (MR), because it contains a significantly higher number of genes than estimated from the proportion in the human genome. We constructed a high-density and high-resolution human chromosome X array (X-tiling array) for comparative genomic hybridization (CGH). The array contains a total of 1,001 bacterial artificial chromosome (BACs) throughout chromosome X except pseudoautosomal regions and two BACs specific for Y. In four hybridizations using DNA samples from healthy males, the ratio of each spotted DNA was scattered between -3SD and 3SD, corresponding to a log(2) ratio of -0.35 and 0.35, respectively. Using DNA samples from patients with known congenital disorders, our X-tiling array was proven to discriminate one-copy losses and gains together with their physical sizes, and also to estimate the percentage of a mosaicism in a patient with mos 45,X[13]/46,X,r(X)[7]. Furthermore, array-CGH in a patient with atypical Schinzel-Giedion syndrome disclosed a 1.1-Mb duplication at Xq22.3 including a part of the IL1RAPL2 gene as a likely causative aberration. The results indicate our in-house X-tiling array to be useful for the identification of cryptic copy-number aberrations containing novel genes responsible for diseases such as congenital disorders and X-linked MR.
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PMID:Construction of a high-density and high-resolution human chromosome X array for comparative genomic hybridization analysis. 1740 83

An example of familial mental retardation is described in which there is a distinctive phenotype. It consists of IQ in the 30-50 range, microcephaly, short stature, narrow skull, prominent ears and nose and a cryptic subtelomeric translocation resulting in del 14qter and dup 9qter. Variable features include congenital heart disease, peripheral neuropathy and epilepsy. The phenotype was described in 1965 by Anyon.
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PMID:Familial mental retardation due to a cryptic subtelomeric translocation -del 14qter and dup 9qter (the Anyon phenotype). 1778 13

Supernumerary marker chromosomes (SMCs) have a reported frequency in the prenatal and newborn population ranging from 0.04% to 0.08% and about 37% of diagnosed SMCs are associated with an abnormal phenotype. Around 7.5% of them are derived from chromosome 22. SMCs(22) that result in tri- or tetrasomy of band 22q11.2 are associated with Cat-eye syndrome (CES), a syndrome of variable penetrance and affectation. CES-like phenotype has been also related to 22q11.2 interstitial duplications and der(22) syndrome. The 22q11.2 region, also involved in the velocardiofacial microdeletional syndrome, presents high susceptibility to chromosomal rearrangements due to the presence of low-copy repeats sequences (LCR22). Another region in the genome rich in LCR is 17p and five recurrent disorders have been mapped on the region 17p11-p13. Some chromosomal imbalances affecting the 17p13.3 subtelomeric region have been reported, related to cryptic unbalanced translocations and associated, in most cases, to mental retardation and dysmorphic features. We report on a healthy male carrier of a SMC that was identified as a +der(22)t(17;22)(p13.3;q11.2) consequence of an abnormal 3:1 segregation of the paternal t(17;22) and we have determined the approximate size of the trisomic regions, comparing the obtained results with other reported imbalances involving 22q11.2 and 17pter.
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PMID:Trisomy of 19.4 Mb region of chromosome 22 and subtelomeric 17p identified in a male without clinical affectation. 1785 59

It has been 15 years since we proposed that assays of telomere integrity might reveal cryptic translocations and deletions as a significant cause of mental retardation (MR) in patients with normal G-banded karyotypes. Development of unique genomic probes adjacent to the subtelomeric repeats of each chromosome arm allowed multiplex FISH analyses that confirmed such cryptic telomeric imbalances in 3-6% of all unexplained MR. Although such "telomere FISH" analysis quickly became standard of care, limitations of this technology platform included a lack of information on the size and gene content of the deleted/duplicated segments and the failure to detect interstitial deletions not involving the most distal unique clone. The development of "molecular ruler" clone sets for every human telomere provided the foundation for accurate determination of size and gene content of each imbalance, as well as the detection of interstitial deletions within these regions. Array comparative genomic hybridization (aCGH) has emerged as a powerful technology to assess single copy changes (monosomy or trisomy) at targeted loci such as telomeres or across the whole genome. This technology now replaces multiplex FISH for the assessment of telomere integrity in unexplained MR and has the advantage of efficiently determining the size and gene content of the imbalance, as well as detecting interstitial deletions near telomeres or anywhere else in the genome covered by the array design. The application of aCGH in several studies of unexplained MR has confirmed that telomere imbalances are overrepresented compared to "average" chromosomal regions, although this is likely due to random chromosome breakage rather than specific molecular mechanisms associated with the genomic architecture of human telomeres. Telomere imbalances are significantly larger than initially envisioned ( approximately 40% are >5 Mb in size), and indicate the analytic sensitivity of the G-banded karyotype is much lower than previously thought. Finally, experience with smaller benign variants compared to larger pathogenic imbalances at telomeres serves as a model for approaching whole-genome aCGH in a clinical setting.
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PMID:Cryptic telomere imbalance: a 15-year update. 1791 73

Complex chromosome rearrangements (CCRs) are rare structural abnormalities that involve at least two chromosomes and more than two breakpoints and are often associated with developmental delay, mental retardation, and congenital anomalies. We report on a de novo, apparently balanced translocation t(1;5;7)(p32.1;q14.3;p21.3) involving three chromosomes in a 7-year-old boy with severe psychomotor retardation, neonatal muscular hypertonia, congenital heart defect, polysyndactyly of hands and feet, and dysmorphic features resembling Greig cephalopolysyndactyly syndrome. Analysis of the chromosome breakpoints using fluorescence in situ hybridization (FISH) with locus-specific BAC clones and long-range PCR products did not identify chromosome imbalance at any of the interrogated regions. High-resolution comparative genomic hybridization (HR-CGH) and array CGH (aCGH) revealed two additional cryptic de novo deletions, del(1)(p31.1p31.1) and del(7)(p14.1p14.1), respectively, that are not associated with the translocation breakpoints. FISH and polymorphic marker analyses showed that the deletion on derivative chromosome 1 is between 4.2 and 6.1 Mb, and the deletion on derivative chromosome 7 is approximately 5.1 Mb, and that both are paternal in origin. The deletion on chromosome 7p encompasses the GLI3 gene that is causative for the Greig cephalopolysyndactyly, Pallister-Hall and some cases of Acrocallosal syndromes. We discuss the potential mechanisms of formation of the described CCR.
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PMID:Complex balanced translocation t(1;5;7)(p32.1;q14.3;p21.3) and two microdeletions del(1)(p31.1p31.1) and del(7)(p14.1p14.1) in a patient with features of Greig cephalopolysyndactyly and mental retardation. 1793 35

In idiopathic or nonspecific mental retardation, the overall rate of cryptic subtelomeric rearrangements is estimated to be about 5%. Development of cost-effective screening for subtelomeric deletions would help clinical geneticists to make specific diagnoses in children with idiopathic mental retardation. Current screening modalities include fluorescence in situ hybridization (FISH) using subtelomeric probes and PCR-based quantitative analyses. Reductions in the cost and turnaround time will make the complete screening of subtelomeric rearrangements more widely used in clinical settings. Recently, a versatile method, called the multiplex PCR/liquid chromatography assay (MP/LC), was developed to assess copy numbers in this assay. Multiple genomic regions are amplified using unlabeled primers, then separated by ion-pair reversed-phase high-performance liquid chromatography. In the present study, we developed an MP/LC-based subtelomeric screening system that involves 21 multiple reactions and validated the protocol by analyzing 16 publicly available cell lines with known cytogenetic abnormalities involving at least one subtelomere per patient. To confirm the validity of the MP/LC method, we analyzed these cell lines concurrently with array-based comparative genomic hybridization (array-CGH), which gives higher resolution than the conventional G-banding technique. Among those 16 samples, the results from MP/LC and array-CGH agreed with each other perfectly. In 2 of the 16 samples, MP/LC correctly revealed subtelomeric duplications that were detected by array-CGH but were undetected by conventional cytogenetics, demonstrating the sensitivity of the MP/LC assay. This system is expected to be useful for making specific diagnoses and in genetic counseling for children with idiopathic mental retardation, a sizable fraction of whom have subtelomeric rearrangements.
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PMID:Multiplex PCR/liquid chromatography assay for screening of subtelomeric rearrangements. 1794 85

This study was designed to increase the diagnostic detection rate for subtelomeric unbalanced chromosomal rearrangements (UCRs) that are believed to cause 3-5% of all cases of mental retardation (MR), but often remain undetected by routine karyotyping because of limited resolution in light microscopy. Increased detection of such cryptic UCRs may be achieved by CGH- or SNP-array technology adapted for genome wide screening but these techniques are labor-intensive and expensive. We have implemented subtelomeric Multiplex Ligation-dependant Probe Amplification (MLPA), a relatively low cost and technically uncomplicated molecular approach, as a high throughput prospective screening tool for UCRs in MR patients. We prospectively studied a cohort of 466 MR patients and detected 53 aberrant MLPA signals. After exclusion of false-positives, potential familial polymorphisms and of non-cryptic UCRs also found in routine chromosome analysis, 18 cases or 3.9% of total could be confirmed as true cryptic subtelomeric UCRs. These were 6 terminal deletions, 8 unbalanced translocations, 3 Prader-Willi deletions and 1 subtelomeric interstitial deletion. This result increases our laboratory's detection rate in this patient cohort from 8.3% (without MLPA) to 12.2% (with MLPA), representing a 47% improvement. This study demonstrates that when applying MLPA in a routine cytogenetic diagnostic setting, a major increase of the diagnostic yield can be achieved.
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PMID:Prospective screening of patients with unexplained mental retardation using subtelomeric MLPA strongly increases the detection rate of cryptic unbalanced chromosomal rearrangements. 1803 23

Genome-wide analysis of DNA copy-number changes using microarray-based technologies has enabled the detection of de novo cryptic chromosome imbalances in approximately 10% of individuals with mental retardation. So far, the majority of these submicroscopic microdeletions/duplications appear to be unique, hampering clinical interpretation and genetic counselling. We hypothesised that the genomic regions involved in these de novo submicroscopic aberrations would be candidates for recurrent copy-number changes in individuals with mental retardation. To test this hypothesis, we used multiplex ligation-dependent probe amplification (MLPA) to screen for copy number changes at eight genomic candidate regions in a European cohort of 710 individuals with idiopathic mental retardation. By doing so, we failed to detect additional submicroscopic rearrangements, indicating that the anomalies tested are non-recurrent in this cohort of patients. The break points flanking the candidate regions did not contain low copy repeats and/or sequence similarities, thus providing an explanation for its non-recurrent nature. On the basis of these data, we propose that the use of genome-wide microarrays is indicated when testing for copy-number changes in individuals with idiopathic mental retardation.
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PMID:Identification of non-recurrent submicroscopic genome imbalances: the advantage of genome-wide microarrays over targeted approaches. 1815 13

Chromosomal aberrations are typically associated with primordial growth retardation, psychomotoric constrictions, and dysmorphisms. Since these features may be present in patients with Silver-Russell syndrome (SRS) and chromosomal disturbances are also detected in a subgroup of SRS patients, we screened a cohort of 45 SRS patients for cryptic subtelomeric imbalances. Submicroscopic deletions/duplications in the telomere regions are meanwhile well known to cause a broad spectrum of conspicuous phenotypes, characterized by mental retardation and multiple further congenital anomalies. We hypothesize that SRS might represent at the mild end of the broad phenotypic range of subtelomeric imbalances. Screening of the patients was performed by multiplex ligation-dependent probe amplification (MLPA), a technique that has already been shown to be effective and reliable for measuring copy numbers. We excluded pathogenetically relevant copy number variations in the subtelomeres in our SRS patient cohort, but one patient carried an apathogenic polymorphic Yq deletion. It can therefore be concluded that this type of chromosomal aberration does not belong to the genetic causes of SRS and it is not necessary to include this test in the diagnostic algorithm of the disease.
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PMID:Search for subtelomeric imbalances by multiplex ligation-dependent probe amplification in Silver-Russell syndrome. 1830 83


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