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Background  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.    Methods  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.    Results  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.    Conclusions  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-epilepsy phenotype with macrocephaly suggests PTEN, but not GLIALCAM, genetic screening