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

Abstract

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.

• Authors: Maria Marchese, Valerio Conti, Giulia Valvo, Francesca Moro, Filippo Muratori, Raffaella Tancredi, Filippo M Santorelli, Renzo Guerrini, Federico Sicca
• Journal: BMC medical genetics (BMC Med Genet) Vol. 15 Pg. 26 (Feb 27 2014) ISSN: 1471-2350 [Electronic] England
• PMID: 24580998 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cell Cycle Proteins
• HEPACAM protein, human
• Proteins
• PTEN Phosphohydrolase
• PTEN protein, human

Topics

• Abnormalities, Multiple (genetics)
• Adolescent
• Amino Acid Sequence
• Autistic Disorder (genetics)
• Base Sequence
• Cell Cycle Proteins
• Child
• Child, Preschool
• DNA Mutational Analysis
• Epilepsy (genetics)
• Female
• Frameshift Mutation
• Genetic Association Studies
• Genetic Predisposition to Disease
• Genetic Testing
• Humans
• Male
• Megalencephaly (genetics)
• Molecular Sequence Data
• PTEN Phosphohydrolase (genetics)
• Proteins (genetics)
• Young Adult