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Biallelic intragenic duplication in ADGRB3 (BAI3) gene associated with intellectual disability, cerebellar atrophy, and behavioral disorder

European Journal of Human Geneticsvolume 27pages594602 (2019) | Download Citation

Abstract

In recent years, chromosomal microarray analysis has permitted the discovery of rearrangements underlying several neurodevelopmental disorders and still represents the first diagnostic test for unexplained neurodevelopmental disabilities. Here we report a family of consanguineous parents showing psychiatric disorders and their two sons both affected by intellectual disability, ataxia, and behavioral disorder. SNP/CGH array analysis in this family demonstrated in both siblings a biallelic duplication inherited from the heterozygous parents, disrupting the ADGRB3 gene. ADGRB3, also known as BAI3, belongs to the subfamily of adhesion G protein-coupled receptors (adhesion GPCRs) that regulate many aspects of the central nervous system, including axon guidance, myelination, and synapse formation. Single nucleotide polymorphisms and copy number variants involving ADGRB3 have recently been associated with psychiatric disorders. These findings further support this association and also suggest that biallelic variants affecting the function of the ADGRB3 gene may also cause cognitive impairments and ataxia.

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Acknowledgements

We thank the probands and their family for their participation in this study. For technical support, we acknowledge the participation of Drs. Silvestra Amata, Angela Spalletta, Maurizio Sturnio, Angelo Gloria, Franco Scillato, and Pietro Schinocca from the Laboratory of Medical Genetics, IRCCS Associazione Oasi M SS., Troina (Italy). We also thank Dr. Anthony Charles for English language editing. MF was funded by grant RF-2011-02350693 from the Italian Ministry of Health.

Author contributions

Corresponding author MF had full access to all of the data in the study and took responsibility for the integrity of the data, accuracy of data analysis, and final responsibility for the decision to submit for publication. CS, CR, and MF were responsible for study supervision. MF and CS drafted the manuscript and interpreted the data. LS and MS performed WES analysis. CS, LS and MV equally contributed to the manuscript. MV performed MLPA assay, long-range PCR and breakpoint analysis. LC carried out SNP/CGH array analysis. OG performed FISH analysis. CS was in charge of the patients and contributed relevant clinical data for phenotypic characterization. SC performed psychological and cognitive assessment of the patients. TM, CR, EB, and LC critically revised the manuscript. All authors contributed to the study concept and design. All authors were responsible for drafting the manuscript, contributed to the acquisition, analysis, and interpretation of data, and read and approved the final manuscript.

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Author notes

  1. These authors contributed equally: C Scuderi, L Saccuzzo, M Vinci

Affiliations

  1. Oasi Research Institute–IRCCS, Troina, Italy

    • Carmela Scuderi
    • , Mirella Vinci
    • , Lucia Castiglia
    • , Ornella Galesi
    • , Michele Salemi
    • , Eugenia Borgione
    • , Santina Città
    • , Corrado Romano
    •  & Marco Fichera
  2. Department of Biomedical and Biotechnological Sciences, Medical Genetics, University of Catania, Catania, Italy

    • Lucia Saccuzzo
    • , Teresa Mattina
    •  & Marco Fichera

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethics approval and consent to participate

The research design, in accordance with the tenets of the Declaration of Helsinki and their reviews, was approved by the Ethics Committee. The patients included in the study signed a written informed consent to participate in the study.

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The participants included in the study signed a written informed consent to publish their data.

Corresponding author

Correspondence to Marco Fichera.

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DOI

https://doi.org/10.1038/s41431-018-0321-1