Abstract
BackgroundWith 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.MethodsWe 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.ResultsAmong 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.ConclusionsWe 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.
Highlights
With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes
Cases of extreme macrocephaly in ASD have been correlated to mutations in the gene phosphatase and tensin homolog (PTEN) [17,18], making its testing the standard genetic screening for patients who present with autism and macrocephaly [19,20], mutations account for only a small subset of the cases and have not been clearly correlated with susceptibility to seizures in ASD [21]
We tested for GLIALCAM variants 81 individuals with ASD (50 autism-epilepsy phenotype (AEP) and 31 ASD “simplex”), 31 of them with concurrent macrocephaly
Summary
With a complex and extremely high clinical and genetic heterogeneity, autism spectrum disorders (ASD) are better dissected if one takes into account specific endophenotypes. 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. Autism is often associated with other neurological conditions, with easy genotype-phenotype correlations Within this complex framework, an attempt at identifying clinical endophenotypes could be of help to define diverse pathogenic subgroups pinpointing different genetic etiologies. Recent findings indicate that cranial overgrowth in ASD appears in the first year of life suggesting possible mechanisms accelerating brain growth in early development and predisposing to autism [11,12,13,14,15]. Cases of extreme macrocephaly in ASD have been correlated to mutations in the gene phosphatase and tensin homolog (PTEN) [17,18], making its testing the standard genetic screening for patients who present with autism and macrocephaly [19,20], mutations account for only a small subset of the cases and have not been clearly correlated with susceptibility to seizures in ASD [21]
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