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Mutation Screening of the PTEN Gene in Patients With Autism Spectrum Disorders and Macrocephaly


Mutation Screening of the PTEN Gene in Patients With Autism Spectrum Disorders and Macrocephaly

Joseph D Buxbaum et al. Am J Med Genet B Neuropsychiatr Genet.


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.


Fig. 1
Fig. 1
a: Exon/intron structure of the PTEN gene, with main functional domains and mutations described in patients with autism spectrum disorder reported previously [Zori et al., 1998; Goffin et al., 2001; Parisi et al., 2001; Delatycki et al., 2003; Butler et al., 2005]; the mutation identified in the present study (D326N) is indicated in bold. Non-coding sequences in exons 1 and 9 are indicated in gray. b: Alignment of the PTEN gene with homologous genes of other species shows the conservation of residue D326 in exon 8 implicated in our patient. Amino acids that are not conserved are shaded in gray. [Color figure can be viewed in the online issue, which is available at]

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