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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-specific X-linked mental retardation is a heterogeneous group of disorders with an incidence of approximately 1 in 500 males. A recently identified gene in Xq12, encoding a Rho-GTPase-activating protein, was found to be mutated in individuals with mental retardation. We describe here two sisters with a 46,XY karyotype and a microdeletion of the oligophrenin-1 gene and 1.1 Mb of flanking DNA. We have characterised the molecular interval defining this microdeletion syndrome with the fibre-FISH technique. A visual physical map of 1.2 Mb was constructed which spans the oligophrenin-1 gene and the androgen receptor gene. The analysis of the patients revealed a deletion which extended from the 5' end of the AR gene to a region approximately 80 kb proximal to the EPLG2 gene. The clinical manifestations of the two sisters include psychomotor retardation, seizures, ataxia, hypotonia and complete androgen insensitivity. Cranial MRI scans show enlargement of the cerebral ventricles and cerebellar hypoplasia. Our findings give further support for the involvement of the oligophrenin-1 gene in specific morphological abnormalities of the brain which is of importance in the investigation of male patients presenting with mental retardation. In combination with our results from physical mapping we suggest that a region around the oligophrenin-1 locus is relatively bereft of vital genes.
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PMID:Deletion including the oligophrenin-1 gene associated with enlarged cerebral ventricles, cerebellar hypoplasia, seizures and ataxia. 1043 59

Cryptic unbalanced chromosome rearrangements in the telomeric bands of the chromosomes may constitute a significant cause of unexplained mental retardation with or without congenital anomalies. We report on a boy with a terminal deletion of the long arm of chromosome 13, combined with a partial duplication of the short arm of chromosome 20, owing to a cryptic balanced translocation in his father. The karyotype of the father was 46XY,t(13;20)(q34;p13). The propositus presented with severe mental and growth retardation, microcephaly, facial anomalies including ptosis of the right upper eyelid, a high nasal bridge, small palpebral fissures, and bilateral epicanthus, hypospadias, and scoliosis. A younger brother died at birth and had a low birth weight, hypospadias, and a horseshoe kidney. Repeated chromosome analyses with high resolution banding in the propositus and his parents were apparently normal. Chromosome painting eventually disclosed the cryptic translocation in the father with unbalanced karyotype in the propositus. The importance of additional FISH analysis in patients with unexplained mental retardation, physical anomalies, and apparently normal chromosomes is emphasized.
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PMID:Detection of a cryptic translocation t(13;20)(q34;p13) in an unexplained case of MCA/MR: value of FISH over high resolution banding. 1049 96

Mental retardation is a life-long disability occurring in 2-3% of all children. Genetic causes are very heterogeneous and the clinical presentation most often non-specific. Current diagnostic tools can only identify a specific aetiology in 50-70%, and more importantly, often do not exclude a genetic cause in apparently sporadic cases of mental retardation. A proven genetic aetiology has many implications for the extended family. Fragile X syndrome is the most prevalent cause of inherited mental retardation and occurs in 2-6% of both females and males. Chromosomes and fragile X syndrome should be routinely investigated in patients with mental retardation of unknown aetiology. Molecular cytogenetics (FISH) provide specific diagnosis of several rare and clinically recognizable syndromes. Provision of extended clinical information is critical at referral, so that the most relevant investigations may be selected. Biochemical and molecular investigations can be performed for an increasing number of distinct but all very rare conditions associated with mental retardation. Efficient methods for simultaneous investigation of a panorama of rare biochemical and molecular abnormalities are now available and might improve the diagnostic yield considerably in the near future. We recommend a long-term diagnostic follow-up which allows us to apply modern methods and diagnose syndromes with phenotypes developing over several years.
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PMID:[Genetic causes of mental retardation--diagnostic possibilities]. 1050 54

The clinical features of the 9p-deletion syndrome include dysmorphic facial features (trigonocephaly, midface hypoplasia, upward-slanting palpebral fissures, and a long philtrum) and mental retardation. The majority of these patients appear to have similar cytogenetic breakpoints in 9p22, but some cases show phenotypic heterogeneity. To define the breakpoints of the deleted chromosomes, we studied 24 patients with a deletion of 9p, by high-resolution cytogenetics, FISH with 19 YACs, and PCR using 25 different sequence-tagged sites. Of 10 different breakpoints identified, 9 were localized within an approximately 5-Mb region, in 9p22-p23, that encompasses the interval between D9S1869 (telomeric) and D9S162 (centromeric). Eight unrelated patients had a breakpoint (group 1) in the same interval, between D9S274 (948h1) and D9S285 (767f2), suggesting a chromosome-breakage hotspot. Among 12 patients, seven different breakpoints (groups 3-9) were localized to a 2-Mb genomic region between D9S1709 and D9S162, which identified a breakpoint-cluster region. The critical region for the 9p-deletion syndrome maps to a 4-6-Mb region in 9p22-p23. The results from this study have provided insight into both the heterogeneous nature of the breakage in this deletion syndrome and the resultant phenotype-karyotype correlations.
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PMID:Chromosome breakage hotspots and delineation of the critical region for the 9p-deletion syndrome. 1052 4

Rubinstein-Taybi syndrome (RTS) is a dominant Mendelian disorder characterised by mental retardation, a typical facies, broad thumbs and short stature. Previous reports indicated that 4-25% of RTS patients have a submicroscopic 16p13.3 deletion of the CBP gene. Using FISH and cosmid probes RT100, RT191 and RT203 we studied 45 RTS patients from Germany, the Czech Republic, Austria and Turkey and found four deletions (8.9%, pooled data including other studies: 11%). All deletions were interstitial; three spanned the CBP gene (RT100-RT203) and one was smaller (RT100 only). Previous studies reported no phenotype-genotype correlation between RTS patients with or without a deletion. Our findings suggest a more severe phenotype. The mean age at presentation was 0.96 years in patients with a deletion as against 11.12 years in those without. Patients A and B with a deletion died in infancy which is rare in RTS and was not observed among the other patients. Patients A and D had accessory spleens, Patient A with hypoplastic left heart, abnormal pulmonary lobulation and renal agenesis. This is the second report of hypoplastic left heart and the first report of polysplenia with RTS. The signs suggest a developmental field defect (disturbance of laterality) either as a newly recognised pattern of RTS, or alternatively a novel contiguous gene syndrome.
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PMID:FISH studies in 45 patients with Rubinstein-Taybi syndrome: deletions associated with polysplenia, hypoplastic left heart and death in infancy. 1057 6

In the search for genetic causes of mental retardation, we have studied a five-generation family that includes 10 individuals in generations IV and V who are affected with mild-to-moderate mental retardation and mild, nonspecific dysmorphic features. The disease is inherited in a seemingly autosomal dominant fashion with reduced penetrance. The pedigree is unusual because of (1) its size and (2) the fact that individuals with the disease appear only in the last two generations, which is suggestive of anticipation. Standard clinical and laboratory screening protocols and extended cytogenetic analysis, including the use of high-resolution karyotyping and multiplex FISH (M-FISH), could not reveal the cause of the mental retardation. Therefore, a whole-genome scan was performed, by linkage analysis, with microsatellite markers. The phenotype was linked to chromosome 16p13.3, and, unexpectedly, a deletion of a part of 16pter was demonstrated in patients, similar to the deletion observed in patients with ATR-16 syndrome. Subsequent FISH analysis demonstrated that patients inherited a duplication of terminal 3q in addition to the deletion of 16p. FISH analysis of obligate carriers revealed that a balanced translocation between the terminal parts of 16p and 3q segregated in this family. This case reinforces the role of cryptic (cytogenetically invisible) subtelomeric translocations in mental retardation, which is estimated by others to be implicated in 5%-10% of cases.
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PMID:Familial mental retardation syndrome ATR-16 due to an inherited cryptic subtelomeric translocation, t(3;16)(q29;p13.3). 1063 Nov 33

Two familial and seven sporadic patients with neurofibromatosis 1-who showed dysmorphism, learning disabilities/mental retardation, and additional signs and carried deletions of the NF1 gene-were investigated by use of a two-step FISH approach to characterize the deletions. With FISH of YAC clones belonging to a 7-Mb 17q11.2 contig, we estimated the extension of all of the deletions and identified the genomic regions harboring the breakpoints. Mosaicism accounted for the mild phenotype in two patients. In subsequent FISH experiments, performed with locus-specific probes generated from the same YACs by means of a novel procedure, we identified the smallest region of overlapping (SRO), mapped the deletion breakpoints, and identified the genes that map to each deletion interval. From centromere to telomere, the approximately 0.8-Mb SRO includes sequence-tagged site 64381, the SUPT6H gene (encoding a transcription factor involved in chromatin structure), and NF1. Extending telomerically from the SRO, two additional genes-BLMH, encoding a hydrolase involved in bleomycin resistance, and ACCN1, encoding an amiloride-sensitive cation channel expressed in the CNS-were located in the deleted intervals of seven and three patients, respectively. An apparently common centromeric deletion breakpoint was shared by all of the patients, whereas a different telomeric breakpoint defined a deletion interval of 0.8-3 Mb. There was no apparent correlation between the extent of the deletion and the phenotype. This characterization of gross NF1 deletions provides the premise for addressing correctly any genotype-phenotype correlation in the subset of patients with NF1 deletions.
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PMID:NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes. 1063 Nov 40

Rubinstein-Taybi syndrome (RTS) is a malformation syndrome characterised by facial abnormalities, broad thumbs, broad big toes, and mental retardation. In a subset of RTS patients, microdeletions, translocations, and inversions involving chromosome band 16p13.3 can be detected. We have previously shown that disruption of the human CREB binding protein (CREBBP or CBP) gene, either by these gross chromosomal rearrangements or by point mutations, leads to RTS. CBP is a large nuclear protein involved in transcription regulation, chromatin remodelling, and the integration of several different signal transduction pathways. Here we report diagnostic analysis of CBP in 194 RTS patients, divided into several subsets. In one case the mother is also suspect of having RTS. Analyses of the entire CBP gene by the protein truncation test showed 4/37 truncating mutations. Two point mutations, one 11 bp deletion, and one mutation affecting the splicing of the second exon were detected by subsequent sequencing. Screening the CBP gene for larger deletions, by using different cosmid probes in FISH, showed 14/171 microdeletions. Using five cosmid probes that contain the entire gene, we found 8/89 microdeletions of which 4/8 were 5' or interstitial. This last subset of microdeletions would not have been detected using the commonly used 3' probe RT1, showing the necessity of using all five probes.
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PMID:Diagnostic analysis of the Rubinstein-Taybi syndrome: five cosmids should be used for microdeletion detection and low number of protein truncating mutations. 1069 51

Rubinstein-Taybi syndrome (RTS) is a multiple congenital anomalies and mental retardation syndrome characterized by facial abnormalities, broad thumbs, and broad big toes. We have shown previously that disruption of the human CREB-binding protein (CBP) gene, either by gross chromosomal rearrangements or by point mutations, leads to RTS. Translocations and inversions involving chromosome band 16p13.3 form the minority of CBP mutations, whereas microdeletions occur more frequently (approximately 10%). Breakpoints of six translocations and inversions in RTS patients described thus far were found clustered in a 13-kb intronic region at the 5' end of the CBP gene and could theoretically only result in proteins containing the extreme N-terminal region of CBP. In contrast, in one patient with a translocation t(2;16)(q36.3;p13.3) we show by using fiber FISH and Southern blot analysis that the chromosome 16 breakpoint lies about 100 kb downstream of this breakpoint cluster. In this patient, Western blot analysis of extracts prepared from lymphoblasts showed both a normal and an abnormal shorter protein lacking the C-terminal domain, indicating expression of both the normal and the mutant allele. The results suggest that the loss of C-terminal domains of CBP is sufficient to cause RTS. Furthermore, these data indicate the potential utility of Western blot analysis as an inexpensive and fast approach for screening RTS mutations.
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PMID:Rubinstein-Taybi syndrome caused by a De Novo reciprocal translocation t(2;16)(q36.3;p13.3). 1079 22

Cryptic rearrangements involving the telomeres are thought to account for a substantial number of patients with unexplained mental retardation and multiple congenital anomalies, although the exact incidence of these rearrangements is still unclear. With the advent of chromosome-specific telomeric probes and the use of FISH (fluorescence in situ hybridization), it is now possible to identify submicroscopic rearrangements of the distal ends of chromosomes that may otherwise go undetected using conventional cytogenetic studies. We report on a 4 1/2 year-old girl with severe mental retardation and minor anomalies who inherited the unbalanced product of a cryptic translocation involving chromosomes 2 and 17 from her father. The family history was significant for early pregnancy losses, stillbirths, and mental retardation in many other family members, suggesting segregation of a familial translocation. This translocation was detected using chromosome-specific telomere FISH probes, and not visible using conventional cytogenetic methods. Collectively, this case and those previously reported clearly demonstrate the value of a systematic search for cryptic chromosome rearrangements in patients with unexplained mental retardation with previously reported normal chromosome studies; and in particular those with a family history of mental retardation, birth defects, or early pregnancy losses.
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PMID:Detection of a cryptic translocation in a family with mental retardation using FISH and telomere region-specific probes. 1084 90


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