Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes

Türkmen, Seval; Gillessen‐Kaesbach, Gabriele; Meinecke, Peter; Albrecht, Beate; Neumann, Luitgard M.; Hesse, V.; Palandüz, Şükrü; Balg, Stefanie; Majewski, F.; Fuchs, Sigrun; Zschieschang, Petra; Greiwe, M; Mennicke, Kirsten; Kreuz, Friedmar R.; Dehmel, Harald J; Rodeck, Burkhard; Kunze, Jürgen; Tinschert, Sigrid; Mundlos, Stefan; Horn, Denise

doi:10.1038/sj.ejhg.5201050

Cited by 122 publications

(139 citation statements)

References 16 publications

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“…Further studies in nonJapanese patients with Sotos syndrome have shown mutations to be more predominant, occurring in 48% to 90% of patients, and the common deletion occurring in 5% to 18% of patients. 14,17,18 These studies also demonstrated the lack of NSD1 mutations or deletions in individuals with other overgrowth phenotypes. 14,17,18 NSD1 mutations were described in two patients with Beckwith-Wiedemann syndrome and in several patients with Weaver syndrome.…”

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confidence: 66%

“…10 Most cases of Sotos syndrome are sporadic, but several familial cases have been reported, indicating dominant inheritance of this condition. [11][12][13][14] Mutations in the NSD1 (nuclear receptor SET domain-containing protein) gene were first identified in Japanese individuals with Sotos syndrome. 15,16 These initial studies reported a 2.2 Mb deletion that included NSD1 in 57% of patients and mutations within the gene in 10%.…”

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confidence: 99%

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NSD1 analysis for Sotos syndrome: Insights and perspectives from the clinical laboratory

Waggoner

Raca

Welch

et al. 2005

Genetics in Medicine

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Purpose: Sotos syndrome is a genetic disorder characterized primarily by overgrowth, developmental delay, and a characteristic facial gestalt. Defects in the NSD1 gene are present in approximately 80% of patients with Sotos syndrome. The goal of this study was to determine the incidence of NSD1 abnormalities in patients referred to a clinical laboratory for testing and to identify clinical criteria that distinguish between patients with and without NSD1 abnormalities. Methods: Deletion or mutation analysis of the NSD1 gene was performed on 435 patients referred to our clinical genetics laboratory. Detailed clinical information was obtained on 86 patients with and without NSD1 abnormalities, and a clinical checklist was developed to help distinguish between these two groups of patients. Results: Abnormalities of the NSD1 gene were identified in 55 patients, including 9 deletions and 46 mutations. Thus, in the clinical laboratory setting, deletions were found in 2% and mutations in 21% of samples analyzed, because not all patients had both tests. Thirty-three previously unreported mutations in the NSD1 gene were identified. Clinical features typically associated with Sotos syndrome were not found to be significantly different between individuals with and without NSD1 abnormalities. The clinical checklist developed included poor feeding, increased body mass index, and enlarged cerebral ventricles, in addition to the typical clinical features of Sotos syndrome, and was able to distinguish between the two groups with 80% sensitivity and 70% specificity. Conclusions:The dramatic decrease in the frequency of finding NSD1 abnormalities in the clinical laboratory is likely because of the heterogeneity of the patient population. Our experience from a diagnostic laboratory can help guide clinicians in deciding for whom NSD1 genetic analysis is indicated. Genet Med 2005:7(8):524-533.

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confidence: 66%

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confidence: 99%

NSD1 analysis for Sotos syndrome: Insights and perspectives from the clinical laboratory

Waggoner

Raca

Welch

et al. 2005

Genetics in Medicine

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“…Mutations and deletions of NSD1 account for the majority of patients with SoS (Kurotaki et al 2002Douglas et al 2003;Nagai et al 2003;Rio et al 2003;Turkmen et al 2003;de Boer et al 2004;TattonBrown et al 2005). However, in a considerable group of patients with characteristic SoS features, no abnormalities of NSD1 can be detected.…”

Section: Discussionmentioning

confidence: 99%

“…Since the identification of NSD1, to our knowledge only a few SoS patients with neoplasia have been confirmed to harbor a NSD1 alteration. This included three neuroblastomas Turkmen et al 2003;Tatton-Brown and Rahman 2004), a ganglioglioma (Deardorff et al 2004), a presacral ganglioneuroma, three sacrococcygeal teratomas, a small cell lung carcinoma, T-cell lymphoma, and acute lymphocytic leukaemia (Tatton-Brown and Rahman 2004;Rahman 2005). Our analysis of the methylation status of the NSD1 promoter region could easily be applied to tumor tissues in Sotos patients with a NSD1 alteration.…”

Section: Discussionmentioning

confidence: 99%

“…Aberrations of the nuclear receptor binding SET domain containing protein 1 (NSD1) gene at 5q35 include intragenic mutations and submicroscopic whole-gene deletions (Kurotaki et al 2002Douglas et al 2003;Nagai et al 2003;Rio et al 2003;Turkmen et al 2003;de Boer et al 2004;Tatton-Brown et al 2005). In approximately 10-40% of typical SoS patients without a detected NSD1 abnormality, different aberrations of NSD1 or locus heterogeneity should be considered [see review by Visser and Matsumoto (2003)].…”

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confidence: 99%

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Analysis of the NSD1 promoter region in patients with a Sotos syndrome phenotype

et al. 2005

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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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Diagnosis of Cryptic Chromosomal Syndromes by Fluorescence In Situ Hybridization (FISH)

2010

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Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes

Cited by 122 publications

References 16 publications

NSD1 analysis for Sotos syndrome: Insights and perspectives from the clinical laboratory

NSD1 analysis for Sotos syndrome: Insights and perspectives from the clinical laboratory

Analysis of the NSD1 promoter region in patients with a Sotos syndrome phenotype

Diagnosis of Cryptic Chromosomal Syndromes by Fluorescence In Situ Hybridization (FISH)

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