title: Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly.
abstract: BACKGROUND
  Sotos syndrome is an overgrowth syndrome characterized by macrocephaly, advanced bone age, characteristic facial features, and learning disabilities, caused by mutations or deletions of the NSD1 gene, located at 5q35. Sotos syndrome has been described in a number of patients with autism spectrum disorders, suggesting that NSD1 could be involved in other cases of autism and macrocephaly.
  
  
  METHODS
  We screened the NSD1 gene for mutations and deletions in 88 patients with autism spectrum disorders and macrocephaly (head circumference 2 standard deviations or more above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions. Dosage analysis of NSD1 was carried out using multiplex ligation-dependent probe amplification.
  
  
  RESULTS
  We identified three missense variants (R604L, S822C and E1499G) in one patient each, but none is within a functional domain. In addition, segregation analysis showed that all variants were inherited from healthy parents and in two cases were also present in unaffected siblings, indicating that they are probably nonpathogenic. No partial or whole gene deletions/duplications were observed.
  
  
  CONCLUSIONS
  Our findings suggest that Sotos syndrome is a rare cause of autism spectrum disorders and that screening for NSD1 mutations and deletions in patients with autism and macrocephaly is not warranted in the absence of other features of Sotos syndrome.
authors.affiliation: Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, USA. Joseph.Buxbaum@mssm.edu
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nygren
authors.forename: Pauline
authors.initials: P
authors.lastname: Chaste
authors.forename: Richard
authors.initials: R
authors.lastname: Delorme
authors.forename: Juliet
authors.initials: J
authors.lastname: Goldsmith
authors.forename: Maria
authors.initials: M
authors.lastname: Råstam
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.forename: Eric
authors.initials: E
authors.lastname: Hollander
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D005820:Genetic Testing; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; 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