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ADNP in reverse gear

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

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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.

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

References

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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’.

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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

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  1. Claudio Peter D’Incal
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  2. R. Frank Kooy
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RFK and CPD conceptualized and wrote this commentary. CPD designed the illustration.

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Correspondence to R. Frank Kooy.

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The authors declare no competing interests.

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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

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