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Open Access Research article

Mutation analysis of the NSD1 gene in patients with autism spectrum disorders and macrocephaly

Joseph D Buxbaum123, Guiqing Cai123, Gudrun Nygren4, Pauline Chaste567, Richard Delorme567, Juliet Goldsmith123, Maria Råstam4, Jeremy M Silverman23, Eric Hollander23, Christopher Gillberg48, Marion Leboyer679 and Catalina Betancur107*

Author Affiliations

1 Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, USA.

2 Department of Psychiatry, Mount Sinai School of Medicine, New York, USA.

3 Seaver Autism Research Center, Mount Sinai School of Medicine, New York, USA.

4 Department of Child and Adolescent Psychiatry, Goteborg University, Goteborg, Sweden.

5 AP-HP, Hôpital Robert Debré, Service de Psychopathologie de l'Enfant et de l'Adolescent, Paris, France.

6 INSERM U841, Institut Mondor de Recherche Biomedicale, Psychiatric Genetics, Créteil, France.

7 Université Paris 12, Faculté de Médecine, Créteil, France.

8 Institute of Child Health, London, UK.

9 AP-HP, Groupe Hospitalier Henri Mondor – Albert Chenevier, Department of Psychiatry, Créteil, France.

10 INSERM U513, Créteil, France.

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BMC Medical Genetics 2007, 8:68  doi:10.1186/1471-2350-8-68

Published: 14 November 2007



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.


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.


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.


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.