Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome.
Sotos syndrome is an overgrowth syndrome characterized by distinctive facial features, learning difficulties, and macrocephaly with frequent pre- and postnatal overgrowth with advanced bone age. Here, we report on our experience in the molecular diagnostic of Sotos syndrome on 116 patients. Using direct sequencing and a quantitative multiplex PCR of short fluorescent fragments (QMPSF)-based assay allowing accurate detection of both total and partial NSD1 deletions, we identified NSD1 abnormalities in 104 patients corresponding to 102 Sotos families (90%). NSD1 point mutations were detected in 80% of the index cases, large deletions removing the NSD1 gene entirely in 14%, and intragenic NSD1 rearrangements in 6%. Among the 69 detected distinct point mutations, 48 were novel. The QMPSF assay detected an exonic duplication and a mosaic partial deletion. QMPSF mapping of the 15 large deletions revealed the heterogeneity of the deletions, which vary in size from 1 to 4.5 Mb. Clinical features of NSD1-positive Sotos patients revealed that the phenotype in patients with nontruncating mutations was less severe that in patients with truncating mutations. This study confirms the heterogeneity of NSD1 alterations in Sotos syndrome and therefore the need to complete sequencing analysis by screening for partial deletions and duplications to ensure an accurate molecular diagnosis of this syndrome.
Saugier-Veber
Pascale
P
Department of Genetics, Rouen University Hospital, University of Rouen, Rouen, France.
Bonnet
Céline
C
Afenjar
Alexandra
A
Drouin-Garraud
Valérie
V
Coubes
Christine
C
Fehrenbach
Séverine
S
Holder-Espinasse
Muriel
M
Roume
Joëlle
J
Malan
Valérie
V
Portnoi
Marie-France
MF
Jeanne
Nicolas
N
Baumann
Clarisse
C
Héron
Delphine
D
David
Albert
A
Gérard
Marion
M
Bonneau
Dominique
D
Lacombe
Didier
D
Cormier-Daire
Valérie
V
Billette de Villemeur
Thierry
T
Frébourg
Thierry
T
Bürglen
Lydie
L
D000015:Abnormalities, Multiple / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D005260:Female; D018740:Genetic Heterogeneity; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D013577:Syndrome
D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human