Document Detail

NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes.
MedLine Citation:
PMID:  12464997     Owner:  NLM     Status:  MEDLINE    
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.
Jenny Douglas; Sandra Hanks; I Karen Temple; Sally Davies; Alexandra Murray; Meena Upadhyaya; Susan Tomkins; Helen E Hughes; Trevor R P Cole; Nazneen Rahman
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2002-12-02
Journal Detail:
Title:  American journal of human genetics     Volume:  72     ISSN:  0002-9297     ISO Abbreviation:  Am. J. Hum. Genet.     Publication Date:  2003 Jan 
Date Detail:
Created Date:  2002-12-18     Completed Date:  2003-02-21     Revised Date:  2009-11-18    
Medline Journal Info:
Nlm Unique ID:  0370475     Medline TA:  Am J Hum Genet     Country:  United States    
Other Details:
Languages:  eng     Pagination:  132-43     Citation Subset:  IM    
Section of Cancer Genetics, Institute of Cancer Research, Sutton, Surrey, United Kingdom.
Data Bank Information
Bank Name/Acc. No.:
GENBANK/AF083389;  AF332469;  AF395588;  AF419220; OMIM/117550;  130650;  153470;  162200;  182290;  194050;  277590;  312870;  602535;  605309
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MeSH Terms
Abnormalities, Multiple / genetics*
Amino Acid Sequence
Carrier Proteins / chemistry,  genetics*
Chromosome Deletion
Chromosomes, Human, Pair 5 / genetics
Craniofacial Abnormalities / genetics*
DNA Mutational Analysis
Developmental Disabilities / genetics
Exons / genetics
Growth Disorders / genetics*
Intracellular Signaling Peptides and Proteins*
Introns / genetics
Molecular Sequence Data
Mutation / genetics*
Nuclear Proteins / chemistry,  genetics*
Polymorphism, Genetic / genetics
Protein Structure, Tertiary
Sequence Deletion / genetics
Reg. No./Substance:
0/Carrier Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/NSD1 protein, human; 0/Nuclear Proteins

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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