title: Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly.
abstract: Mutations 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 >or=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.
authors.affiliation: Laboratory of Molecular Neuropsychiatry, Mount Sinai School of Medicine, New York, New York, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Pauline
authors.initials: P
authors.lastname: Chaste
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nygren
authors.forename: Juliet
authors.initials: J
authors.lastname: Goldsmith
authors.forename: Jennifer
authors.initials: J
authors.lastname: Reichert
authors.forename: Henrik
authors.initials: H
authors.lastname: Anckarsäter
authors.forename: Maria
authors.initials: M
authors.lastname: Rastam
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Smith
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Silverman
authors.forename: Eric
authors.initials: E
authors.lastname: Hollander
authors.forename: Marion
authors.initials: M
authors.lastname: Leboyer
authors.forename: Christopher
authors.initials: C
authors.lastname: Gillberg
authors.forename: Alain
authors.initials: A
authors.lastname: Verloes
authors.forename: Catalina
authors.initials: C
authors.lastname: Betancur
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D001216:Asparagine / Q000235:genetics; D001224:Aspartic Acid / Q000235:genetics; D001321:Autistic Disorder / Q000150:complications* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000150:complications* / Q000235:genetics*; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005820:Genetic Testing; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics*; D013577:Syndrome
chemical_list: D001224:Aspartic Acid; D001216:Asparagine; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human