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Loss of function of ADNP by an intragenic inversion


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:, (ADNP):c.-89-3923_201%202793inv.


  1. Han JY, Lee IG. Genetic tests by next-generation sequencing in children with developmental delay and/or intellectual disability. Clin Exp Pediatr. 2019;63:195–202.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Binquet C, Lejeune C, Faivre L, Bouctot M, Asensio ML, Simon A, et al. Genome sequencing for genetics diagnosis of patients with intellectual disability: the DEFIDIAG study. Front Genet [Internet]. 2022;12:766964.

    Article  PubMed  Google Scholar 

  3. Mandel S, Gozes I. Activity-dependent neuroprotective protein constitutes a novel element in the SWI/SNF chromatin remodeling complex. J Biol Chem. 2007;282:34448–56.

    Article  CAS  PubMed  Google Scholar 

  4. Sun X, Yu W, Li L, Sun Y. ADNP controls gene expression through local chromatin architecture by association with BRG1 and CHD4. Front Cell Dev Biol. 2020 ;8:553.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Sun X, Peng X, Cao Y, Zhou Y, Sun Y. ADNP promotes neural differentiation by modulating Wnt/β-catenin signaling. Nat Commun. 2020;11:2984.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Helsmoortel C, Vulto-van Silfhout AT, Coe BP, Vandeweyer G, Rooms L, van den Ende J, et al. A SWI/SNF-related autism syndrome caused by de novo mutations in ADNP. Nat Genet. 2014;46:380–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Breen MS, Garg P, Tang L, Mendonca D, Levy T, Barbosa M, et al. Episignatures stratifying Helsmoortel-Van Der Aa syndrome show modest correlation with phenotype. Am J Hum Genet. 2020;107:555–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Huynh MT, Boudry-Labis E, Massard A, Thuillier C, Delobel B, Duban-Bedu B, et al. A heterozygous microdeletion of 20q13.13 encompassing ADNP gene in a child with Helsmoortel–van der Aa syndrome. Eur J Hum Genet. 2018;26:1497–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Van Dijck A, Vulto-van Silfhout AT, Cappuyns E, van der Werf IM, Mancini GM, Tzschach A, et al. Clinical presentation of a complex neurodevelopmental disorder caused by mutations in ADNP. Biol Psychiatry. 2019;85:287–97.

    Article  PubMed  Google Scholar 

  10. Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, et al. The human genome browser at UCSC. Genome Res. 2002;12:996–1006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gleason AC, Ghadge G, Chen J, Sonobe Y, Roos RP. Machine learning predicts translation initiation sites in neurologic diseases with nucleotide repeat expansions. PLoS One. 2022;17:e0256411.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Flynn JM, Hubley R, Goubert C, Rosen J, Clark AG, Feschotte C, et al. RepeatModeler2 for automated genomic discovery of transposable element families. Proc Natl Acad Sci. 2020;117:9451–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10.

    Article  CAS  PubMed  Google Scholar 

  14. Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062–7.

    Article  CAS  PubMed  Google Scholar 

  15. Wright ES. Using DECIPHER v2.0 to analyze big biological sequence data in R. R J. 2016;8:352–9.

    Article  Google Scholar 

  16. Stenson PD, Ball EV, Mort M, Phillips AD, Shiel JA, Thomas NST, et al. Human gene mutation database (HGMD®): 2003 update. Hum Mutat. 2003;21:577–81.

    Article  CAS  PubMed  Google Scholar 

  17. Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alföldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Puig M, Casillas S, Villatoro S, Cáceres M. Human inversions and their functional consequences. Brief Funct Genomics. 2015;14:369–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Calvo SE, Pagliarini DJ, Mootha VK. Upstream open reading frames cause widespread reduction of protein expression and are polymorphic among humans. Proc Natl Acad Sci USA 2009;106:7507–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Whiffin N, Karczewski KJ, Zhang X, Chothani S, Smith MJ, Evans DG, et al. Characterising the loss-of-function impact of 5’ untranslated region variants in 15,708 individuals. Nat Commun. 2020;11:2523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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


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; 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



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.

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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).

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