Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917816 (mental retardation)
 15,867 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sotos syndrome belongs to the family of overgrowth syndromes and is characterized by large head circumference, craniofacial anomalies, advanced bone age and mental retardation. The syndrome is due to haploinsufficiency of the NSD1 gene, consisting of 23 exons with an open reading frame of 8088bp, which makes mutation screening by direct sequencing quite a laborious and expensive task. We have developed a dHPLC screening protocol for mutation detection in NSD1 and identified 9 novel mutations among 33 patients, thus achieving a mutation detection efficiency comparable to direct sequencing. A real-time quantitative PCR approach identified two patients with NSD1 deletions. Our mutation screen is compared to other studies and all published mutations and polymorphisms are summarized.
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PMID:dHPLC screening of the NSD1 gene identifies nine novel mutations--summary of the first 100 Sotos syndrome mutations. 1572 Mar 3

Here, we report the clinical and molecular analysis of 75 patients with overgrowth and mental retardation, including 45 previously reported cases [Rio et al., 2003; Baujat et al., 2004]. Two groups are distinguished: group I corresponding to patients with recognizable overgrowth syndromes (Sotos syndrome (SS), Weaver syndrome (WS), Beckwith-Wiedemann syndrome, Simpson-Golabi-Behmel syndrome (SGBS), and del(22)(qter) syndrome) (60 cases) and group II corresponding to unclassified cases (15 patients). We investigated NSD1 and GPC3 deletions or mutations, 11p15 abnormalities, and 22qter deletions. Surprisingly, in Group I, two SS patients had 11p15 abnormalities and two patients with Beckwith-Wiedemann syndrome had NSD1 aberrations. In group II, two cases of del(22)(qter) were identified but neither NSD1, 11p15, nor GPC3 abnormalities were detected. These results emphasize the clinical and molecular overlap in overgrowth conditions.
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PMID:Clinical and molecular overlap in overgrowth syndromes. 1601 Jun 74

Tall stature is less often experienced as an important problem than short stature. However, a correct diagnosis may be of eminent importance, especially when interventions are planned, or to know the natural history. Overgrowth can be caused by endocrine disorders and skeletal dysplasias, but also by several genetic syndromes. Despite a systematic diagnostic approach, there will be patients with tall stature who do not fit a known diagnosis. In this group of patients possibilities of genetic analysis do exist, but are not common practice. The FMR1 gene should be analyzed in patients with tall stature and mental retardation, and in these patients the NSD1 gene can be considered whenever some features of Sotos syndrome do exist. In tall patients without mental retardation and some features of Sotos or Beckwith-Wiedemann syndrome it may still be useful to look for mutations in the NSD1 gene, but also for changes in the 11p15 region. The various possibilities are discussed and placed in a flowchart.
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PMID:Genetic analysis of tall stature. 1619 40

A three-generation family with autosomal dominant segregation of a novel NSD1 mutation (6605G --> A, resulting in Cys2202Tyr) is reported. Haploinsufficiency of NSD1 has been identified as the major cause of Sotos syndrome. The overgrowth condition (MIM 117550) is characterized by facial anomalies, macrocephaly, advanced bone age, and learning disabilities. Manifestations in the present family include dramatically increased height, weight, and head circumference together with a long face, large mandible, and large ears, but mental deficiency was absent.
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PMID:Familial gigantism caused by an NSD1 mutation. 1622 65

Sotos syndrome (SoS, OMIM#117550) is an overgrowth disorder characterized by excessive growth-especially in the first years of childhood-distinctive craniofacial features, and various degrees of mental retardation. Haploinsufficiency of the nuclear receptor binding SET domain containing protein 1 (NSD1) gene, due to either intragenic mutations or whole-gene microdeletions, is found in the majority of patients with SoS. However, in approximately 10-40% of patients with a typical SoS phenotype, no abnormalities are detected. In this study, hemizygous hypermethylation or genomic sequence abnormalities of the promoter region of NSD1 were hypothesized to be the underlying cause in patients with a SoS phenotype, but without confirmed NSD1 alterations. In 18 patients, including one patient with a reported hepatocellular carcinoma, the promoter region of NSD1 was analyzed. However, no hypermethylation or sequence abnormalities in the promoter region could be detected. It therefore seems unlikely that such abnormalities of NSD1 are a major culprit in patients with phenotypical SoS. Additional methods are necessary for detection of other genetic or epigenetic causes of SoS.
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PMID:Analysis of the NSD1 promoter region in patients with a Sotos syndrome phenotype. 1625 63

In contrast to the numerous well-known microdeletion syndromes, only a few microduplications have been described, and this discrepancy may be due in part to methodological bias. In order to facilitate the detection of genomic microdeletions and microduplications, we developed a new assay based on QMPSF (Quantitative Multiplex PCR of Short fluorescent Fragments) able to explore simultaneously 12 candidate loci involved in mental retardation (MR) and known to be the target of genomic rearrangements. We first screened 153 patients with MR and facial dysmorphism associated with malformations, or growth anomalies, or familial history, with cytogenetically normal chromosomes, and the absence of FRAXA mutation and subtelomeric rearrangements. In this series, we found a 5q35 deletion removing the NSD1 gene in a patient with severe epilepsy, profound MR and, retrospectively, craniofacial features of Sotos syndrome. In a second series, we screened 140 patients with MR and behaviour disturbance who did not fulfil the de Vries criteria for subtelomeric rearrangements and who had a normal karyotype and no detectable FRAXA mutation. We detected a 22q11 deletion in a patient with moderate MR, obesity, and facial dysmorphism and a 4 Mb 17p11 duplication in a patient with moderate MR, behaviour disturbance, strabismus, and aspecific facial features. This new QMPSF assay can be gradually upgraded to include additional loci involved in newly recognised microduplication/microdeletion syndromes, and should facilitate wide screenings of patients with idiopathic MR and provide better estimates of the microduplication frequency in the MR population.
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PMID:Simple detection of genomic microdeletions and microduplications using QMPSF in patients with idiopathic mental retardation. 1677 31

Trisomy of 15q26-qter is frequently associated with tall stature and mental retardation. Here we describe a patient with such trisomy, without a partial monosomy of another chromosome. The tall stature in this patient is most probably caused by duplication of the IGF1R gene. A duplication of the IGF1R gene is not a frequent finding in patients with tall stature. In 38 patients with features of Sotos syndrome without NSD1 alterations, a duplication was found only once. This patient was already known to have an unbalanced 2;15 translocation. Looking for a duplication of the 15qter region is still worth consideration in patients with tall stature and features of Sotos syndrome without an NSD1 alteration, especially when there is craniosynostosis or marked speech delay.
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PMID:Tall stature and duplication of the insulin-like growth factor I receptor gene. 1705 9

MLPA analysis for a panel of syndromes with mental retardation (MRS-MLPA) was used for investigation of 258 mentally retarded and dysmorphic patients with normal conventional karyotypes (P064 probe set, MRC-Holland, for detection of (micro)deletions associated with 1p36-deletion, Sotos, Williams-Beuren, Prader-Willi, Angelman, Miller-Dieker, Smith-Magenis, and 22q11-deletion syndromes). Patients were initially referred for HR-CGH analysis and MRS-MLPA was performed retrospectively. MRS-MLPA analysis revealed imbalances in 15/258 patients (5.8%). Ten deletions were identified, including deletions of 1p36, 5q35 (Sotos syndrome), 7q11 (Williams-Beuren syndrome), 17p11 (Smith-Magenis syndrome), 15q11 (Angelman syndrome) and 22q11. Duplications were detected in 5q35, 7q11, 17p13, 17p11 and 22q11. We reviewed another 170 patients referred specifically for MRS-MLPA analysis. Eighty of these patients were referred with a clinical suspicion of a specific syndrome, which was confirmed in 17 patients (21.3%). The remaining 90 patients were referred because of mental retardation and dysmorphism but without suspicion of a specific syndrome. Seven imbalances, including four duplications, were detected in these 90 patients (7.8%). Clinical data regarding three patients investigated by MRS-MLPA are presented. The imbalances carried by these patients include a small interstitial 1p36 deletion, a small duplication of 5q35 (encompassing the NSD1 gene, which is deleted/mutated in Sotos syndrome) and a duplication of 7q11 (reciprocal of the Williams-Beuren syndrome deletion), respectively. MRS-MLPA allows testing for a number of micro-deletions/-duplications in a single experiment, thereby filling a gap between array techniques and single locus techniques. MRS-MLPA combined with Subtelomeric MLPA represents an attractive first test in a clinical algorithm for mental retardation.
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PMID:MLPA analysis for a panel of syndromes with mental retardation reveals imbalances in 5.8% of patients with mental retardation and dysmorphic features, including duplications of the Sotos syndrome and Williams-Beuren syndrome regions. 1709 Mar 94

We report array-CGH screening of 95 syndromic patients with normal G-banded karyotypes and at least one of the following features: mental retardation, heart defects, deafness, obesity, craniofacial dysmorphisms or urogenital tract malformations. Chromosome imbalances not previously detected in normal controls were found in 30 patients (31%) and at least 16 of them (17%) seem to be causally related to the abnormal phenotypes. Eight of the causative imbalances had not been described previously and pointed to new chromosome regions and candidate genes for specific phenotypes, including a connective tissue disease locus on 2p16.3, another for obesity on 7q22.1-->q22.3, and a candidate gene for the 3q29 deletion syndrome manifestations. The other causative alterations had already been associated with well-defined phenotypes including Sotos syndrome, and the 1p36 and 22q11.21 microdeletion syndromes. However, the clinical features of these latter patients were either not typical or specific enough to allow diagnosis before detection of chromosome imbalances. For instance, three patients with overlapping deletions in 22q11.21 were ascertained through entirely different clinical features, i.e., heart defect, utero-vaginal aplasia, and mental retardation associated with psychotic disease. Our results demonstrate that ascertainment through whole-genome screening of syndromic patients by array-CGH leads not only to the description of new syndromes, but also to the recognition of a broader spectrum of features for already described syndromes. Furthermore, on the technical side, we have significantly reduced the amount of reagents used and costs involved in the array-CGH protocol, without evident reduction in efficiency, bringing the method more within reach of centers with limited budgets.
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PMID:Whole-genome array-CGH screening in undiagnosed syndromic patients: old syndromes revisited and new alterations. 1712 8

Sotos syndrome is an overgrowth syndrome leading to peculiar facial characteristics, large hands and feet, and mental retardation. The maxillofacial characteristics are metopic protrusion, a high and narrow palate and a tapered mandible. In this study, we evaluated changes in maxillofacial growth in 2 patients with cerebral gigantism during the peripubertal period. Patient 1 was a boy aged 8 years at the first examination. The face showed midface retraction and a tapered mandible. Maxillary median diastema with an OJ of 2.5 mm and OB of 1.0 mm was observed, and the molar region showed mandibular mesial occlusion. Radiography revealed a lack of 15, 25, 37, 47, 14, 24, 34 and 44. Cephalometrics demonstrated maxillary and mandibular retrusion with an SNA of 68 degrees and an SNB of 70 degrees , and the patient had leptoprosopia with a mandibular plane of 38.0 degrees . This plane was 45 degrees at the time of re-examination when the patient was 14 years old, showing an increase in the lower facial height and decreases in facial axis and depth. Patient 2 was a boy aged 14 years at the first examination. The face showed mandibular retrusion and tapering. The occlusion was angle class II div. 1, OJ 14 mm, and OB -1 mm. Cephalometrics demonstrated maxillary and mandibular retrusion with an SNA of 74.5 degrees and an SNB of 69.5 degrees , and the patient had leptoprosopia with a mandibular plane of 37.0 degrees . At the time of re-examination, when the patient was 16 years old, the mandibular plane was 42.5 degrees , showing an increase in lower facial height and decreases in facial axis and depth. In this syndrome, excessive facial height without mandibular forward overgrowth is observed. Since the facial height tended to increase by growth during the peripubertal period, maxillofacial vertical growth is considered important in the treatment of this syndrome.
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PMID:Dentofacial growth in patients with Sotos syndrome. 1797 48


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