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Loss of function of ADNP by an intragenic inversion

European Journal of Human Genetics (2023)Cite this article

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Abstract

ADNP is a well-known gene implicated in intellectual disability and its molecular spectrum consists mainly in loss of function variant in the ADNP last and largest exon. Here, we report the first description of a patient with intellectual disability identified with an intragenic inversion in ADNP. RNAseq experiment showed a splice skipping of the inversed exons. Moreover, in-silico analysis of initiating ATGs in the mutated transcript using contextual Kozak score suggested that several initiating ATGs were likely used to translate poisonous out-of-frame ORFs and would lead to the suppression of any in-frame rescuing translation, thereby causing haploinsufficiency. As constitutive Alu sequences with high homology were identified at both breakpoints in reversed orientation in the reference genome, we hypothesized that Alu-mediated non-allelic-homologous recombination was responsible for this rearrangement. Therefore, as this inversion is not detectable by exome sequencing, this mechanism could be a potential underdiagnosed recurrent mutation in ADNP-related disorders.

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Fig. 1: ADNP loss of function by an intragenic inversion.
Fig. 2: ADNP blood expression in Transcripts Per Million (TPM) for the patient and 38 controls.

Data availability

The datasets generated during the current study are available from the corresponding author on reasonable request. This structural variant, NM_001282531.3(ADNP):c.-89-3923_201 + 2793inv, was submitted to the ClinVar database (SCV002820080). Variation ID: 1879783 Accession number: VCV001879783.1 URL:https://www.ncbi.nlm.nih.gov/clinvar/variation/1879783/?oq=SCV002820080&m=NM_001282531.3, (ADNP):c.-89-3923_201%202793inv.

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Acknowledgements

We thank the family for participating in this study and the DEFIDIAG Study Group.

Funding

This work was supported by The French Ministry of Health in the framework of the French initiative for genomic medicine (Plan France Médecine Génomique 2025; PFMG 2025; https://www.aviesan.fr/mediatheque/fichiers/version-anglaise/actualites-en/genomic-medicine-france-2025-web). This work was supported by government funding from the Agence Nationale de la Recherche under the “Investissements d’avenir” program (ANR-10-IAHU-01). Sponsorship: Institut national de la santé et de la recherche médicale (Inserm) is the sponsor of the DEFIDIAG study.

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Authors and Affiliations

  1. Department of Medical Genetics, AP-HP.Sorbonne Université, Pitié-Salpêtrière University Hospital, Paris, France

    Mathieu Georget, Elodie Lejeune, Julien Buratti, Euphrasie Servant, Eric le Guern, Delphine Heron, Boris Keren & Jean-Madeleine de Sainte Agathe

  2. Centre de Référence Déficiences Intellectuelles de Causes Rares, Pitié-Salpêtrière University Hospital, Paris, France

    Delphine Heron

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  1. Mathieu Georget
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  8. Jean-Madeleine de Sainte Agathe
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Contributions

JMSA supervised the study and contributed to designed experiments, analyzing data, interpreting result, and writing the manuscript. MG contributed to performed technical experiments, analyzing data, interpreting result, and writing the manuscript. EL performed technical experiments. ES and JB conceived and realized bioinformatic analyses. DH performed clinical examination. BK and ELG contributed to interpreting results and writing the manuscript.

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Correspondence to Mathieu Georget.

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The authors declare no competing interests.

Ethical approval

Written informed consent for genetic analysis was obtained from the parents for clinical testing, research use and publication. The protocol was approved by the Ethics Committee Sud Méditerranée I and the French data privacy commission (CNIL, authorization 919361).

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Georget, M., Lejeune, E., Buratti, J. et al. Loss of function of ADNP by an intragenic inversion. Eur J Hum Genet (2023). https://doi.org/10.1038/s41431-023-01323-x

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