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Targeted Gene Resequencing (Astrochip) to Explore the Tripartite Synapse in Autism–Epilepsy Phenotype with Macrocephaly

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Abstract

The frequent co-occurrence of autism spectrum disorders (ASD) and epilepsy, or paroxysmal EEG abnormalities, defines a condition termed autism–epilepsy phenotype (AEP). This condition results, in some cases , from dysfunctions of glial inwardly rectifying potassium channels (Kir), which are mainly expressed in astrocytes where they mediate neuron–glia communication. Macrocephaly is also often comorbid with autism–epilepsy (autism–epilepsy phenotype with macrocephaly, MAEP), and it is tempting to hypothesize that shared pathogenic mechanisms might explain concurrence of these conditions. In the present study, we assessed whether protein pathways involved, along with Kir channels, in astrocyte–neuron interaction at the tripartite synapse play a role in the etiopathogenesis of MAEP. Using a targeted resequencing methodology, we investigated the coding regions of 35 genes in 61 patients and correlated genetic results with clinical features. Variants were subdivided into 12 classes and clustered into four groups. We detected rare or previously unknown predicted deleterious missense changes in GJA1, SLC12A2, SNTA1, EFNA3, CNTNAP2, EPHA4, and STXBP1 in seven patients and two high-frequency variants in DLG1 in six individuals. We also found that a group of variants (predicted deleterious and non-coding), segregating with the comorbid MAEP/AEP subgroups, belong to proteins specifically involved in glutamate transport and metabolism (namely, SLC17A6, GRM8, and GLUL), as well as in potassium conductance (KCNN3). This “endophenotype-oriented” study, performed using a targeted strategy, helped to further delineate part of the complex genetic background of ASD, particularly in the presence of coexisting macrocephaly and/or epilepsy/paroxysmal EEG, and suggests that use of stringent clinical clustering might be an approach worth adopting in order to unravel the complex genomic data in neurodevelopmental disorders.

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Acknowledgments

The financial support of Telethon Italy (http://www.telethon.it/en; Grant No. GGP11188) and Fondazione Cassa di Risparmio di Lucca (Grant 567-2014) is gratefully acknowledged. We also thank Dr. Valerio Conti for technical help in molecular studies and Dr. Catherine J. Wrenn for expert proof reading.

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  1. Molecular Medicine, IRCCS Stella Maris Foundation, Viale del Tirreno 331, via dei Giacinti 2, 56128, Calambrone, Pisa, Italy

    Maria Marchese, Francesca Moro & Filippo M. Santorelli

  2. Clinical Neurophysiology Laboratory, IRCCS Stella Maris Foundation, Viale del Tirreno 331, via dei Giacinti 2, 56128, Calambrone, Pisa, Italy

    Giulia Valvo & Federico Sicca

Authors
  1. Maria Marchese
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  2. Giulia Valvo
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  3. Francesca Moro
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  4. Federico Sicca
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  5. Filippo M. Santorelli
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Corresponding authors

Correspondence to Federico Sicca or Filippo M. Santorelli.

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The authors declare that they have no conflict of interest.

Ethical Standard

This study had been approved by the IRCCS Stella Maris Ethical Committee. All procedures involving human participants were in accordance with the ethical standards of the institutional and national research committee and with 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Marchese, M., Valvo, G., Moro, F. et al. Targeted Gene Resequencing (Astrochip) to Explore the Tripartite Synapse in Autism–Epilepsy Phenotype with Macrocephaly. Neuromol Med 18, 69–80 (2016). https://doi.org/10.1007/s12017-015-8378-2

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  • DOI: https://doi.org/10.1007/s12017-015-8378-2

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