NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of weaver syndrome but are rare in other overgrowth phenotypes
NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of weaver syndrome but are rare in other overgrowth phenotypes
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DOI：
10.1086/345647
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发表时间：
2003-01-01
影响因子：
9.8
通讯作者：
Rahman, N
中科院分区：
文献类型：
--
作者：
Douglas, J;Hanks, S;Rahman, N
Sotos综合征是一种儿童过度生长综合征，其特征在于独特的面部外观、身高和头围>第97百分位数、骨龄提前和发育迟缓。韦弗综合征的特征是相同的标准，但有自己独特的面部完形。最近，一个2.2 Mb的染色体5 q35微缺失，包括NSD 1，被报道为Sotos综合征的主要原因，在少数病例中发现了基因内NSD 1突变。我们评估了75例儿童期过度生长患者的NSD 1基因内突变和大缺失。在分子生物学分析之前，将该系列的表型分为四组：第1组（n = 37）的表型为Sotos综合征的典型，第2组（n = 13）的表型为Sotos样但具有一些非典型特征;第3组患者（n = 7）患有Weaver综合征，第4组患者（n = 18）患有既不是Sotos也不是Weaver综合征的过度生长状况。我们检测到3个缺失和32个突变（13个移码，8个无义，2个剪接位点和9个错义），这些突变可能会损害NSD 1的功能。截短突变分布在整个NSD 1，但有证据表明，在外显子13和23之间的高度保守的功能域的错义突变的集群。NSD 1改变的存在与临床表型之间有很强的相关性，第1组中37例患者中有28例（76%）有NSD 1突变或缺失，而第4组中没有患者有NSD 1异常。3例Weaver综合征患者有NSD 1突变，均在氨基酸2142和2184之间。我们的结论是，基因内突变的NSD 1是Sotos综合征的主要原因，并占一些韦弗综合征的情况下，但很少发生在其他儿童过度生长表型。
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.