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Macrocephaly as a Clinical Indicator of Genetic Subtypes in Autism

Authors

  • Steven Klein,

    1. Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Pantea Sharifi-Hannauer,

    1. Division of Pediatric Neurology, David Geffen School of Medicine at UCLA, Los Angeles, California
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  • Julian A. Martinez-Agosto

    Corresponding author
    1. Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine at UCLA, Los Angeles, California
    • Department of Human Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California
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Address for correspondence and reprints: Julian A. Martinez-Agosto, 695 Charles E. Young Drive South, Gonda Research Center Room 4554B, Los Angeles, CA 90095. E-mail: julianmartinez@mednet.ucla.edu

Abstract

An association between autism and macrocephaly has been previously described. A subset of cases with extreme macrocephaly (>3 standard deviation [SD], 99.7th percentile) have been correlated to mutations in the gene phosphatase and tensin homolog (PTEN). However, the phenotypic and genetic characterization of the remaining cases remains unclear. We report the phenotypic classification and genetic testing evaluation of a cohort of 33 patients with autism and macrocephaly. Within our cohort, we confirm the association of PTEN mutations and extreme macrocephaly (>3 SD, 99.7th percentile) and identify mutations in 22% of cases, including three novel PTEN mutations. In addition, we define three phenotypic subgroups: (a) those cases associated with somatic overgrowth, (b) those with disproportionate macrocephaly, and (c) those with relative macrocephaly. We have devised a novel way to segregate patients into these subgroups that will aide in the stratification of autism macrocephaly cases. Within these subgroups, we further expand the genetic etiologies for autism cases with macrocephaly by describing two novel suspected pathogenic copy number variants located at 6q23.2 and 10q24.32. These findings demonstrate the phenotypic heterogeneity of autism cases associated with macrocephaly and their genetic etiologies. The clinical yield from PTEN mutation analysis is 22% and 9% from chromosomal microarray (CMA) testing within this cohort. The identification of three distinct phenotypic subgroups within macrocephaly autism patients may allow for the identification of their respective distinct genetic etiologies that to date have remained elusive. Autism Res 2013, ●●: ●●–●●. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

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