DPH1 variants have been associated with an ultra-rare and severe neurodevelopmental disorder, mainly characterized by variable developmental delay, short stature, dysmorphic features, and sparse hair. We have identified four new patients (from two different families) carrying novel variants in DPH1, enriching the clinical delineation of the DPH1 syndrome. Using a diphtheria toxin ADP-ribosylation assay, we have analyzed the activity of seven identified variants and demonstrated compromised function for five of them [p.(Leu234Pro); p.(Ala411Argfs*91); p.(Leu164Pro); p.(Leu125Pro); and p.(Tyr112Cys)]. We have built a homology model of the human DPH1–DPH2 heterodimer and have performed molecular dynamics simulations to study the effect of these variants on the catalytic sites as well as on the interactions between subunits of the heterodimer. The results show correlation between loss of activity, reduced size of the opening to the catalytic site, and changes in the size of the catalytic site with clinical severity. This is the first report of functional tests of DPH1 variants associated with the DPH1 syndrome. We demonstrate that the in vitro assay for DPH1 protein activity, together with structural modeling, are useful tools for assessing the effect of the variants on DPH1 function and may be used for predicting patient outcomes and prognoses.

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The authors thank the families for their participation in our research studies. We are also grateful to M. Cozar for technical assistance, and to CNAG for exome sequencing. Funding was from Associació Síndrome Opitz C, Terrassa, Spain; Spanish Ministerio de Economía y Competitividad (SAF2016-75948-R, FECYT, crowdfunding PRECIPITA), Catalan Government (2014SGR932) and from CIBERER (U720), the Mindich Child Health and Development Institute (MCHDI) at the Icahn School of Medicine at Mount Sinai, and the Genetic Disease Foundation (New York, NY).

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Author notes

  1. These authors contributed equally: Roser Urreizti, Klaus Mayer, Gilad D. Evrony

  2. These authors contributed equally: Ulrich Brinkmann, Bryn D. Webb,Susanna Balcells


  1. Department of Genetics, Microbiology and Statistics, Faculty of Biology, University of Barcelona, IBUB, IRSJD, CIBERER, Barcelona, Spain

    • Roser Urreizti
    • , Laura Castilla-Vallmanya
    • , Daniel Grinberg
    •  & Susanna Balcells
  2. Roche Pharma Research and Early Development. Large Molecule Research, Roche Innovation Center, Munich, Nonnenwald 2, 82377, Penzberg, Germany

    • Klaus Mayer
    •  & Ulrich Brinkmann
  3. Center for Human Genetics & Genomics, New York University Langone Health, New York, NY, USA

    • Gilad D. Evrony
  4. Section of Medical Genetics, Mater dei Hospital, Msida, Malta

    • Edith Said
  5. Department of Anatomy and Cell Biology, University of Malta, Msida, Malta

    • Edith Said
  6. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Neal A. L. Cody
    • , Bruce D. Gelb
    •  & Bryn D. Webb
  7. Sema4, Stamford, CT, USA

    • Neal A. L. Cody
  8. Lead Molecular Design, S.L, Sant Cugat del Vallés, Spain

    • Guillem Plasencia
  9. Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Bruce D. Gelb
    •  & Bryn D. Webb
  10. Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    • Bruce D. Gelb
    •  & Bryn D. Webb


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Conflict of interest

RU, GDE, ES, LCV, BDG, DG, BDW, and SB declare no conflict of interest. KM and UB are employees of Roche. Roche is interested in identifying novel targets and approaches for disease diagnosis and therapy. NC is an employee of Sema4, a for-profit genetic testing laboratory. GP is employed by Lead Molecular Design, SL, a company that develops software and offers modeling services for pharmaceutical industries, but has no competing interests on the results of this article.

Corresponding author

Correspondence to Roser Urreizti.

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