Joseph D. Buxbaum1,2, Guiqing Cai1,2, Tiziana Zalla3,4, Gudrun Nygren5, Juliet Goldsmith1,2, Jennifer Reichert1,2, Henrik Anckarsäter5, Maria Råstam5, Christopher J. Smith1, George Kirov1, Eric Hollander1, Marion Leboyer6,3, Christopher Gillberg5,7, Alain Verloès8, Catalina Betancur3
1Department of Psychiatry and Seaver Autism Research Center, Mount Sinai School of Medicine, New York, New York
2Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, New York
3INSERM U513, Créteil, France
4Service de Psychopathologie de l'Enfant et de l'Adolescent, AP-HP, Hôpital Robert Debré, Paris, France
5Department of Child and Adolescent Psychiatry, Goteborg University, Goteborg, Sweden
6Department of Psychiatry, AP-HP, Hôpital Henri Mondor et Hôpital Albert Chenevier, Créteil, France
7Department of Psychiatry, Saint George's Hospital Medical School, London, United Kingdom
8Department of Genetics, AP-HP, Hôpital Robert Debré, Paris, France
Tóm tắt
AbstractMutations in the PTEN gene are associated with a broad spectrum of disorders, including Cowden syndrome (CS), Bannayan–Riley–Ruvalcaba syndrome, Proteus syndrome, and Lhermitte–Duclos disease. In addition, PTEN mutations have been described in a few patients with autism spectrum disorders (ASDs) and macrocephaly. In this study, we screened the PTEN gene for mutations and deletions in 88 patients with ASDs and macrocephaly (defined as ≥2 SD above the mean). Mutation analysis was performed by direct sequencing of all exons and flanking regions, as well as the promoter region. Dosage analysis of PTEN was carried out using multiplex ligation‐dependent probe amplification (MLPA). No partial or whole gene deletions were observed. We identified a de novo missense mutation (D326N) in a highly conserved amino acid in a 5‐year‐old boy with autism, mental retardation, language delay, extreme macrocephaly (+9.6 SD) and polydactyly of both feet. Polydactyly has previously been described in two patients with Lhermitte–Duclos disease and CS and is thus likely to be a rare sign of PTEN mutations. Our findings suggest that PTEN mutations are a relatively infrequent cause of ASDs with macrocephaly. Screening of PTEN mutations is warranted in patients with autism and pronounced macrocephaly, even in the absence of other features of PTEN‐related tumor syndromes. © 2007 Wiley‐Liss, Inc.
