Skip to main content

Thank you for visiting 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.

Quantitative facial phenotyping for Koolen-de Vries and 22q11.2 deletion syndrome


The Koolen-de Vries syndrome (KdVS) is a multisystem syndrome with variable facial features caused by a 17q21.31 microdeletion or KANSL1 truncating variant. As the facial gestalt of KdVS has resemblance with the gestalt of the 22q11.2 deletion syndrome (22q11.2DS), we assessed whether our previously described hybrid quantitative facial phenotyping algorithm could distinguish between these two syndromes, and whether there is a facial difference between the molecular KdVS subtypes. We applied our algorithm to 2D photographs of 97 patients with KdVS (78 microdeletions, 19 truncating variants (likely) causing KdVS) and 48 patients with 22q11.2DS as well as age, gender and ethnicity matched controls with intellectual disability (n = 145). The facial gestalts of KdVS and 22q11.2DS were both recognisable through significant clustering by the hybrid model, yet different from one another (p = 7.5 × 10−10 and p = 0.0052, respectively). Furthermore, the facial gestalts of KdVS caused by a 17q21.31 microdeletion and KANSL1 truncating variant (likely) causing KdVS were indistinguishable (p = 0.981 and p = 0.130). Further application to three patients with a variant of unknown significance in KANSL1 showed that these faces do not match KdVS. Our data highlight quantitative facial phenotyping not only as a powerful tool to distinguish syndromes with overlapping facial dysmorphisms but also to establish pathogenicity of variants of unknown clinical significance.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: The ages of our patients.
Fig. 2: Above: two patients with an atypical variant in the KANSL1 gene and the location of their variants in the gene.


  1. 1.

    Koolen DA, Vissers LE, Pfundt R, de Leeuw N, Knight SJ, Regan R, et al. A new chromosome 17q21.31 microdeletion syndrome associated with a common inversion polymorphism. Nat Genet. 2006;38:999–1001.

    CAS  Article  Google Scholar 

  2. 2.

    Sharp AJ, Hansen S, Selzer RR, Cheng Z, Regan R, Hurst JA, et al. Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome. Nat Genet. 2006;38:1038–42.

    CAS  Article  Google Scholar 

  3. 3.

    Shaw-Smith C, Pittman AM, Willatt L, Martin H, Rickman L, Gribble S, et al. Microdeletion encompassing MAPT at chromosome 17q21.3 is associated with developmental delay and learning disability. Nat Genet. 2006;38:1032–7.

    CAS  Article  Google Scholar 

  4. 4.

    Koolen DA, de Vries BBA. KANSL1-related intellectual disability syndrome. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, et al. editors. GeneReviews((R)). Seattle (WA): University of Washington, Seattle University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.; 2013.

  5. 5.

    Koolen DA, Kramer JM, Neveling K, Nillesen WM, Moore-Barton HL, Elmslie FV, et al. Mutations in the chromatin modifier gene KANSL1 cause the 17q21.31 microdeletion syndrome. Nat Genet. 2012;44:639–41.

    CAS  Article  Google Scholar 

  6. 6.

    Zollino M, Orteschi D, Murdolo M, Lattante S, Battaglia D, Stefanini C, et al. Mutations in KANSL1 cause the 17q21.31 microdeletion syndrome phenotype. Nat Genet. 2012;44:636–8.

    CAS  Article  Google Scholar 

  7. 7.

    Koolen DA, Pfundt R, Linda K, Beunders G, Veenstra-Knol HE, Conta JH, et al. The Koolen-de Vries syndrome: a phenotypic comparison of patients with a 17q21.31 microdeletion versus a KANSL1 sequence variant. Eur J Hum Genet. 2016;24:652–9.

    CAS  Article  Google Scholar 

  8. 8.

    McDonald-McGinn DM, Sullivan KE. Chromosome 22q11.2 deletion syndrome (DiGeorge syndrome/velocardiofacial syndrome). Medicine. 2011;90:1–18.

    Article  Google Scholar 

  9. 9.

    Campbell IM, Sheppard SE, Crowley TB, McGinn DE, Bailey A, McGinn MJ, et al. What is new with 22q? An update from the 22q and You Center at the Children’s Hospital of Philadelphia. Am J Med Genet A. 2018;176:2058–69.

    CAS  Article  Google Scholar 

  10. 10.

    McDonald-McGinn DM, Sullivan KE, Marino B, Philip N, Swillen A, Vorstman JA, et al. 22q11.2 deletion syndrome. Nat Rev Dis Prim. 2015;1:15071.

    Article  Google Scholar 

  11. 11.

    Dudding-Byth T, Baxter A, Holliday EG, Hackett A, O’Donnell S, White SM, et al. Computer face-matching technology using two-dimensional photographs accurately matches the facial gestalt of unrelated individuals with the same syndromic form of intellectual disability. BMC Biotechnol. 2017;17:90.

    Article  Google Scholar 

  12. 12.

    Gurovich Y, Hanani Y, Bar O, Nadav G, Fleischer N, Gelbman D, et al. Identifying facial phenotypes of genetic disorders using deep learning. Nat Med. 2019;25:60–4.

    CAS  Article  Google Scholar 

  13. 13.

    Nellaker C, Alkuraya FS, Baynam G, Bernier RA, Bernier FPJ, Boulanger V, et al. Enabling global clinical collaborations on identifiable patient data: the Minerva initiative. Front Genet. 2019;10:611.

    Article  Google Scholar 

  14. 14.

    van der Donk R, Jansen S, Schuurs-Hoeijmakers JHM, Koolen DA, Goltstein L, Hoischen A, et al. Next-generation phenotyping using computer vision algorithms in rare genomic neurodevelopmental disorders. Genet Med. 2019;21:1719–25.

    Article  Google Scholar 

  15. 15.

    Ferry Q, Steinberg J, Webber C, FitzPatrick DR, Ponting CP, Zisserman A, et al. Diagnostically relevant facial gestalt information from ordinary photos. Elife. 2014;3:e02020.

    Article  Google Scholar 

  16. 16.

    Amos B, Ludwiczuk B, Satyanarayanan M. Openface: a general-purpose face recognition library with mobile applications. S. Technical Report, CMU-CS-16-118, CMU School of Computer Science, Pittsburgh, PA, 2016.

  17. 17.

    Dubourg C, Sanlaville D, Doco-Fenzy M, Le Caignec C, Missirian C, Jaillard S, et al. Clinical and molecular characterization of 17q21.31 microdeletion syndrome in 14 French patients with mental retardation. Eur J Med Genet. 2011;54:144–51.

    Article  Google Scholar 

  18. 18.

    Koolen DA, Sharp AJ, Hurst JA, Firth HV, Knight SJ, Goldenberg A, et al. Clinical and molecular delineation of the 17q21.31 microdeletion syndrome. J Med Genet. 2008;45:710–20.

    CAS  Article  Google Scholar 

  19. 19.

    Hoyer J, Dreweke A, Becker C, Gohring I, Thiel CT, Peippo MM, et al. Molecular karyotyping in patients with mental retardation using 100K single-nucleotide polymorphism arrays. J Med Genet. 2007;44:629–36.

    CAS  Article  Google Scholar 

Download references


We are grateful to the patients and their parents for their participation, to the Dutch Organisation for Health Research and Development: ZON-MW grants 912-12-109 (to BBAdV and LELMV) and 916-16-015 (to JYHK), Donders Junior researcher grant 2019 (BBAdV and LELMV), Aspasia grant 015.014.066 (to LELMV). Inclusion of Radboudumc data was in part supported by the Solve-RD project that has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 779257. The patient images used for analysis in this study cannot be made openly available due to patient privacy concerns. Please contact the authors with specific queries regarding data access.

Author information



Corresponding author

Correspondence to Bert B. A. de Vries.

Ethics declarations

Conflict of interest

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.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Dingemans, A.J.M., Stremmelaar, D.E., van der Donk, R. et al. Quantitative facial phenotyping for Koolen-de Vries and 22q11.2 deletion syndrome. Eur J Hum Genet (2021).

Download citation


Quick links