Open Access Highly Accessed Research article

Autism-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening

Maria Marchese1, Valerio Conti2, Giulia Valvo3, Francesca Moro1, Filippo Muratori4, Raffaella Tancredi4, Filippo M Santorelli1, Renzo Guerrini23 and Federico Sicca3*

Author Affiliations

1 Molecular Medicine Unit, IRCCS Stella Maris Foundation, Viale del Tirreno 331, Pisa, Calambrone 56128, Italy

2 Child Neurology Unit, A. Meyer Pediatric Hospital, Viale Pieraccini 24, Florence 50139, Italy

3 Clinical Neurophysiology Laboratory, IRCCS Stella Maris Foundation, Viale del Tirreno 331, Pisa, Calambrone 56128, Italy

4 Developmental Psychiatry Unit, IRCCS Stella Maris Foundation, Viale del Tirreno 331, Pisa, Calambrone 56128, Italy

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BMC Medical Genetics 2014, 15:26  doi:10.1186/1471-2350-15-26

Published: 27 February 2014



With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. Comorbidity of ASD with epilepsy (or paroxysmal EEG) has long been described and seems to have strong genetic background. Macrocephaly also represents a well-known endophenotype in subgroups of ASD individuals, which suggests pathogenic mechanisms accelerating brain growth in early development and predisposing to the disorder. We attempted to estimate the association of gene variants with neurodevelopmental disorders in patients with autism-epilepsy phenotype (AEP) and cranial overgrowth, analyzing two genes previously reported to be associated with autism and macrocephaly.


We analyzed the coding sequences and exon-intron boundaries of GLIALCAM, encoding an IgG-like cell adhesion protein, in 81 individuals with Autism Spectrum Disorders, either with or without comorbid epilepsy, paroxysmal EEG and/or macrocephaly, and the PTEN gene in the subsample with macrocephaly.


Among 81 individuals with ASD, 31 had concurrent macrocephaly. Head circumference, moreover, was over the 99.7th percentile (“extreme” macrocephaly) in 6/31 (19%) patients. Whilst we detected in GLIALCAM several single nucleotide variants without clear pathogenic effects, we found a novel PTEN heterozygous frameshift mutation in one case with “extreme” macrocephaly, autism, intellectual disability and seizures.


We did not find a clear association between GLIALCAM mutations and AEP-macrocephaly comorbidity. The identification of a novel frameshift variant of PTEN in a patient with “extreme” macrocephaly, autism, intellectual disability and seizures, confirms this gene as a major candidate in the ASD-macrocephaly endophenotype. The concurrence of epilepsy in the same patient also suggests that PTEN, and the downstream signaling pathway, might deserve to be investigated in autism-epilepsy comorbidity. Working on clinical endophenotypes might be of help to address genetic studies and establish actual causative correlations in autism-epilepsy.

Autism spectrum disorders; Autism-epilepsy phenotype; Macrocephaly; GLIALCAM; PTEN