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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
NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes
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.
0002-9297
132-143
Douglas, Jenny
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Hanks, Sandra
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Temple, I. Karen
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Davies, Sally
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Murray, Alexandra
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Upadhyaya, Meena
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Tomkins, Susan
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Hughes, Helen E.
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Cole, Trevor R.P.
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Rahman, Nazneen
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Douglas, Jenny
0af40e1f-3a73-4d8c-9e14-3c78f1eb37f7
Hanks, Sandra
69252af9-4d09-4c6c-987e-5965a21a58c7
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Davies, Sally
8ad6c139-9e5d-4530-abfc-0e940f318ca0
Murray, Alexandra
6db653ae-afc9-4856-a97a-2e40aa405b53
Upadhyaya, Meena
63533b81-2307-4ea0-8980-6b3abd5b055b
Tomkins, Susan
ee6f8f5a-1b40-43d9-a623-f821ef737a05
Hughes, Helen E.
70f25414-05ba-4215-acf5-6a8c60efc33e
Cole, Trevor R.P.
121174fc-3f81-46a1-b87a-6da9bf3ddb62
Rahman, Nazneen
d5eded76-0af9-4d72-8fea-84986bf49c51

Douglas, Jenny, Hanks, Sandra, Temple, I. Karen, Davies, Sally, Murray, Alexandra, Upadhyaya, Meena, Tomkins, Susan, Hughes, Helen E., Cole, Trevor R.P. and Rahman, Nazneen (2003) NSD1 mutations are the major cause of Sotos syndrome and occur in some cases of Weaver syndrome but are rare in other overgrowth phenotypes. The American Journal of Human Genetics, 72 (1), 132-143. (doi:10.1086/345647).

Record type: Article

Abstract

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.

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Published date: January 2003

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Local EPrints ID: 24686
URI: https://eprints.soton.ac.uk/id/eprint/24686
ISSN: 0002-9297
PURE UUID: bc722e82-ea1a-46ef-87fa-26991375b3d9

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Date deposited: 03 Apr 2006
Last modified: 17 Jul 2017 16:12

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Contributors

Author: Jenny Douglas
Author: Sandra Hanks
Author: I. Karen Temple
Author: Sally Davies
Author: Alexandra Murray
Author: Meena Upadhyaya
Author: Susan Tomkins
Author: Helen E. Hughes
Author: Trevor R.P. Cole
Author: Nazneen Rahman

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