NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes

Abstract

Sotos syndrome is a childhood overgrowth syndrome characterized by a distinctive facial appearance, height and head circumference >97th percentile, advanced bone age, and developmental delay. Weaver syndrome is characterized by the same criteria but has its own distinctive facial gestalt. Recently, a 2.2-Mb chromosome 5q35 microdeletion, encompassing NSD1, was reported as the major cause of Sotos syndrome, with intragenic NSD1 mutations identified in a minority of cases. We evaluated 75 patients with childhood overgrowth, for intragenic mutations and large deletions of NSD1. The series was phenotypically scored into four groups, prior to the molecular analyses: the phenotype in group 1 (n=37) was typical of Sotos syndrome; the phenotype in group 2 (n=13) was Sotos-like but with some atypical features; patients in group 3 (n=7) had Weaver syndrome, and patients in group 4 (n=18) had an overgrowth condition that was neither Sotos nor Weaver syndrome. We detected three deletions and 32 mutations (13 frameshift, 8 nonsense, 2 splice-site, and 9 missense) that are likely to impair NSD1 functions. The truncating mutations were spread throughout NSD1, but there was evidence of clustering of missense mutations in highly conserved functional domains between exons 13 and 23. There was a strong correlation between presence of an NSD1 alteration and clinical phenotype, in that 28 of 37 (76%) patients in group 1 had NSD1 mutations or deletions, whereas none of the patients in group 4 had abnormalities of NSD1. Three patients with Weaver syndrome had NSD1 mutations, all between amino acids 2142 and 2184. We conclude that intragenic mutations of NSD1 are the major cause of Sotos syndrome and account for some Weaver syndrome cases but rarely occur in other childhood overgrowth phenotypes.

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

“…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.…”

“…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)].…”

Epigenetic regulation of memory: implications in human cognitive disorders

“…For example, H3K9 tri-and di-methylation are associated with repressive heterochromatin, while H3K9 mono-methylation is found at active genes (66). Many different mediators of histone methylation have been implicated in ID, including the HDMs, Jumonji/ARID domain-containing protein 1c (JARID1c) and PHD finger protein 8 (PHF8), and the HMTs, euchromatin histone methyltransferase 1 (EHMT1), nuclear receptor binding SET domain protein 1 (NSD1), mixed lineage leukemia 2 (MLL2), and MLL3, suggesting that these modifications can play a role in human cognitive function (67)(68)(69)(70)(71)(72)(73).…”

Evaluation of NSD2 and NSD3 in overgrowth syndromes

“…Samples were ascertained and phenotypically scored as previously described. 2 The analysis included 12 cases typical for Sotos syndrome, six cases with facies similar but not classic of Sotos syndrome, eight with Weaver syndrome and 44 with a nonspecific overgrowth condition that was not Sotos or Weaver syndrome. The remaining eight cases could not be categorised because facial photographs were not available at the time of the study.…”