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.