title: Heterogeneity of NSD1 alterations in 116 patients with Sotos syndrome.
abstract: 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.
authors.affiliation: Department of Genetics, Rouen University Hospital, University of Rouen, Rouen, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Saugier-Veber
authors.forename: Céline
authors.initials: C
authors.lastname: Bonnet
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.forename: Valérie
authors.initials: V
authors.lastname: Drouin-Garraud
authors.forename: Christine
authors.initials: C
authors.lastname: Coubes
authors.forename: Séverine
authors.initials: S
authors.lastname: Fehrenbach
authors.forename: Muriel
authors.initials: M
authors.lastname: Holder-Espinasse
authors.forename: Joëlle
authors.initials: J
authors.lastname: Roume
authors.forename: Valérie
authors.initials: V
authors.lastname: Malan
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Portnoi
authors.forename: Nicolas
authors.initials: N
authors.lastname: Jeanne
authors.forename: Clarisse
authors.initials: C
authors.lastname: Baumann
authors.forename: Delphine
authors.initials: D
authors.lastname: Héron
authors.forename: Albert
authors.initials: A
authors.lastname: David
authors.forename: Marion
authors.initials: M
authors.lastname: Gérard
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonneau
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Valérie
authors.initials: V
authors.lastname: Cormier-Daire
authors.forename: Thierry
authors.initials: T
authors.lastname: Billette de Villemeur
authors.forename: Thierry
authors.initials: T
authors.lastname: Frébourg
authors.forename: Lydie
authors.initials: L
authors.lastname: Bürglen
mesh_terms: 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
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C113272:NSD1 protein, human