Mutations in NSD1 are responsible for Sotos syndrome, but are not a frequent finding in other overgrowth phenotypes.
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.
Türkmen
Seval
S
Institut für Medizinische Genetik, Humboldt-Universität, Charité, Berlin, Germany.
Gillessen-Kaesbach
Gabriele
G
Meinecke
Peter
P
Albrecht
Beate
B
Neumann
Luitgard M
LM
Hesse
Volker
V
Palanduz
Sükrü
S
Balg
Stefanie
S
Majewski
Frank
F
Fuchs
Sigrun
S
Zschieschang
Petra
P
Greiwe
Monika
M
Mennicke
Kirsten
K
Kreuz
Friedmar R
FR
Dehmel
Harald J
HJ
Rodeck
Burkhard
B
Kunze
Jürgen
J
Tinschert
Sigrid
S
Mundlos
Stefan
S
Horn
Denise
D
D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D002872:Chromosome Deletion; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D006130:Growth Disorders / Q000235:genetics*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D011110:Polymorphism, Genetic; D013577:Syndrome
D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human