Recently, deletions encompassing the nuclear receptor binding SET-Domain 1 
(NSD1) gene have been described as the major cause of Japanese patients with the 
Sotos syndrome, whereas point mutations have been identified in the majority of 
European Sotos syndrome patients. In order to investigate a possible 
phenotype-genotype correlation and to further define the predictive value of 
NSD1 mutations, we performed mutational analysis of the NSD1 gene in 20 patients 
and one familial case with Sotos syndrome, five patients with Weaver syndrome, 
six patients with unclassified overgrowth/mental retardation, and six patients 
with macrocephaly/mental retardation. We were able to identify mutations within 
the NSD1 gene in 18 patients and the familial case with Sotos syndrome (90%). 
The mutations (six nonsense, eight frame shifts, three splice site, one 
missense, one in-frame deletion) are expected to result in an impairment of NSD1 
function. The best correlation between clinical assessment and molecular results 
was obtained for the Sotos facial gestalt in conjunction with overgrowth, 
macrocephaly, and developmental delay. In contrast to the high mutation 
detection rate in Sotos syndrome, none of the patients with Weaver syndrome, 
unclassified overgrowth/mental retardation and macrocephaly/mental retardation, 
harbored NSD1 mutations. We tested for large deletions by FISH analysis but were 
not able to identify any deletion cases. The results indicate that the great 
majority of patients with Sotos syndrome are caused by mutations in NSD1. 
Deletions covering the NSD1 locus were not found in the patients analyzed here.