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Novel de novo pathogenic variant in the GNAI1 gene as a cause of severe disorders of intellectual development

Journal of Human Genetics volume 67, pages 209–214 (2022)Cite this article

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Abstract

Pathogenic sequence variant in the GNAI1 gene were recently introduced as a cause of novel syndrome with a manifestation of variable developmental delay and autistic features. In our study, we report a case of monozygotic twins with severe intellectual disability and motor delay and developmental dysphasia. Both probands and their parents were examined using multi-step molecular diagnostic algorithm including whole-exome sequencing (WES), resulting in the identification of a novel, de novo pathogenic sequence variant in the GNAI1 gene, NM_002069.6:c.815 A>G, p.(Asp272Gly) in probands. Using WES we also verified the microarray findings of a familial 8q24.23q24.3 duplication and heterozygous 5q13.2 deletion, not associated with clinical symptoms in probands. Our results confirmed the role of the GNAI1 gene in the pathogenesis of syndromic neurodevelopmental disorders. They support trio- or quatro-based WES as a suitable molecular diagnostics method for the simultaneous detection of clinically relevant sequence variants and CNVs in individuals with neurodevelopmental disorders and rare diseases.

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Fig. 1: The visualization of the substitution in the GNAI1 gene NM_002069.6:c.815 A>G detected by WES.
Fig. 2: The verification of substitution in the GNAI1 gene NM_002069.6:c.815 A>G by Sanger sequencing.
Fig. 3: The visualization of the 5-bp deletion in the ATM gene NM_000051.3:c.3693_3697del detected by WES.

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Data availability

The novel GNAI1 gene variant NM_002069.5:c.815 A>G and associated phenotypes were submitted to Leiden Open Variation Database v.3.0 (Global Variome shared LOVD) under the accession number #0000763680 (https://databases.lovd.nl/shared/variants/0000763680#00008639). The general overview for the novel GNAI1 gene variant pathogenicity is available in the VarSome database via a permanent link: varso.me/XCDS. Microarray data for probands A and B are available in the database EGA under the accession number EGAD00001007742, WES data for probands A and B and their parents are available in the database EGA under the accession number EGAD00001007736. Sanger sequencing data, including the chromatograms of the probands and the parents for the GNAI1 pathogenic variant, and the MLPA outputs for 5q13.2 deletion are stored in the Figshare online digital repository (doi.org/10.6084/m9.figshare.14401019 and doi.org/10.6084/m9.figshare.14423438).

The outputs of predictor pathogenicity tools for the GNAI1 pathogenic variant are stored in the Figshare online digital repository (doi.org/10.6084/m9.figshare.14401697). The other supporting data (qPCR analysis and other pathogenicity predictors) are available from the corresponding author on the reasonable request.

Supplementary information is available at Journal of Human Genetics’s website.

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Acknowledgements

The authors are thankful to the family for its participation, and all physicians and medical staff providing the specialized medical examinations supporting and completing the diagnosis of our patients.

Funding

This work was supported by Ministry of Health of the Czech Republic, grant nr. NU20-07-00145. All rights reserved.

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Authors and Affiliations

  1. Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic

    Marketa Wayhelova, Vladimira Vallova, Petr Broz, Dominika Loubalova, Jan Smetana & Petr Kuglik

  2. Laboratory of Cytogenomics, Centre of Molecular Biology and Genetics, Department of Internal Medicine, Haematology and Oncology, University Hospital Brno, Brno, Czech Republic

    Marketa Wayhelova, Vladimira Vallova, Hana Filkova & Petr Kuglik

  3. Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University Prague and Faculty Hospital Motol, Prague, Czech Republic

    Petr Broz

  4. Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK

    Aneta Mikulasova

  5. Department of Medical Genetics and Genomics, University Hospital Brno, Brno, Czech Republic

    Marketa Wayhelova, Klara Drabova & Renata Gaillyova

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  1. Marketa Wayhelova
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Contributions

All authors contributed to the study conception and design. MW and VV analysed and interpreted the WES data regarding the probands’ phenotypes using relevant literature, databases and in silico tools. MW was a major contributor in writing the manuscript. PB processed raw WES data using advanced bioinformatics tools through in-house developed pipeline for SNV and indel calling and variant annotation. PB and AM performed CNV calling from processed WES data. DL, VV and JS performed and interpreted microarray analysis. MW and HF performed qPCR, Sanger sequencing and MLPA verification analyses. KD and RG provided specialized genetic counselling for the probands and their family and interpreted the laboratory findings in the clinical context. PK contributed towards the interpretation of data and performed general scientific supervision and general critical revision of the manuscript. All authors discussed the results, reviewed and approved the manuscript.

Corresponding authors

Correspondence to Marketa Wayhelova or Petr Kuglik.

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Competing interests

The authors declare no competing interests.

Ethical approval and consent to participate

All procedures performer involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Approval was obtained from the Research Ethics Committee of Masaryk University (reference number EKV-2019-056) and Ethics Committee of University Hospital Brno (10-120619/EK). Written informed consent was obtained from the parents of the patients before the procedure of genetic analyses. This case report does not include any personal information leading to the identification of any participants. The consent for publication was obtained in the scope of informed consent.

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Wayhelova, M., Vallova, V., Broz, P. et al. Novel de novo pathogenic variant in the GNAI1 gene as a cause of severe disorders of intellectual development. J Hum Genet 67, 209–214 (2022). https://doi.org/10.1038/s10038-021-00988-w

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