Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Comment
  • Published:

ADNP in reverse gear

European Journal of Human Genetics volume 31, pages 849–850 (2023)Cite this article

Subjects

The Original Article was published on 24 February 2023

Breakthroughs in next-generation sequencing technologies, most notably whole-exome sequencing (WES), have increased genetic diagnostic yield. In individuals diagnosed with a neurodevelopmental disorder such as intellectual disability (ID) or autism, this has improved diagnosis to approximately 30% of cases [1]. However, this implies that more than two-thirds of patients remain without a molecular diagnosis. To face the challenge of increasing diagnostic yield, whole genome sequencing (WGS) is currently explored for use in routine diagnostics. In contrast to WES, where only the coding regions of the genome are investigated, in WGS, the sequence of the entire patient genome is compared to that of their parents. Despite this increase in resolution, currently, the reported diagnostic rate of WGS only marginally exceeds that of WES [2]. In their article in this issue, Georget et al. [3], performed WGS as the next step in the diagnostic odyssey in a young individual affected with developmental delay, hypotonia and dysmorphic features who was left without a diagnosis following routine clinical testing, including WES. They found an inversion in the genomic sequence of the Activity-Dependent Neuroprotective Protein (ADNP) gene that remained undetectable in the WES but was exposed following WGS. Mutations in the ADNP gene are associated with a diagnosis of Helsmoortel-Van der Aa syndrome (HVDAS; OMIM #615873) [4], in line with the clinical presentation of the patient in this study.

The intronic breakpoints are characterized by an AluSq10 sequence on one end and an AluY sequence on the other (Fig. 1). Both sequences are in inverse orientation and almost 80% identical, and the authors suggest non-allelic recombination as the underlying mechanism causative of the inversion. The ADNP gene is located in a large homozygous region. In this respect, it is of interest to mention that large stretches of homozygosity have been suggested to predisposed to somatic deletions as a consequence of an increased rate of allelic homologous recombination [6]. It can be speculated that this might underlie non-allelic homologous recombination (NAHR) in the observed region, in line with the observation of an increased mutational rate in large homozygous regions [7].

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Heterozygous loss of function of the ADNP gene due to an intragenic inversion.

References

  1. Vissers LELM, van Nimwegen KJM, Schieving JH, Kamsteeg E-J, Kleefstra T, Yntema HG, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017;19:1055–63.

    Article  PubMed  PubMed Central  Google Scholar 

  2. van der Sanden BPGH, Schobers G, Corominas Galbany J, Koolen DA, Sinnema M, van Reeuwijk J, et al. The performance of genome sequencing as a first-tier test for neurodevelopmental disorders. Eur J Hum Genet. 2023;31:81–8.

    Article  PubMed  Google Scholar 

  3. Georget M, Lejeune E, Buratti J, Servant E, le Guern E, Heron D, 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

    Article  PubMed  Google Scholar 

  4. 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 

  5. D’Incal CP, Van Rossem KE, De Man K, Konings A, Van Dijck A, Rizzuti L, et al. Chromatin remodeler Activity-Dependent Neuroprotective Protein (ADNP) contributes to syndromic autism. Clin Epigenetics. 2023;15:45.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Roehl AC, Cooper DN, Kluwe L, Helbrich A, Wimmer K, Högel J, et al. Extended runs of homozygosity at 17q11.2: an association with type-2 NF1 deletions? Hum Mutat. 2010;31:325–34.

    Article  CAS  PubMed  Google Scholar 

  7. Szpiech ZA, Xu J, Pemberton TJ, Peng W, Zöllner S, Rosenberg NA, et al. Long runs of homozygosity are enriched for deleterious variation. Am J Hum Genet. 2013;93:90–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Dale Annear for editing the manuscript.

Funding

Experimental work on the ADNP gene by the authors has been supported by grants from the ERA-NET Neuron network ADNPinMED, the E-Rare project IMPACT, the Research Foundation – Flanders (FWO) and by the Research Fund of the University of Antwerp, OEC-Methusalem grant ‘GENOMED’.

Author information

Authors and Affiliations

  1. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

    Claudio Peter D’Incal & R. Frank Kooy

  2. Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium

    Claudio Peter D’Incal

Authors
  1. Claudio Peter D’Incal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R. Frank Kooy
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

RFK and CPD conceptualized and wrote this commentary. CPD designed the illustration.

Corresponding author

Correspondence to R. Frank Kooy.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

D’Incal, C.P., Kooy, R.F. ADNP in reverse gear. Eur J Hum Genet 31, 849–850 (2023). https://doi.org/10.1038/s41431-023-01360-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41431-023-01360-6

This article is cited by

Search

Advanced search

Quick links