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Epigenomic and phenotypic characterization of DEGCAGS syndrome

European Journal of Human Genetics volume 32, pages 1574–1582 (2024)Cite this article

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Abstract

Developmental Delay with Gastrointestinal, Cardiovascular, Genitourinary, and Skeletal Abnormalities syndrome (DEGCAGS, MIM #619488) is caused by biallelic, loss-of-function (LoF) ZNF699 variants, and is characterized by variable neurodevelopmental disability, discordant organ anomalies among full siblings and infant mortality. ZNF699 encodes a KRAB zinc finger protein of unknown function. We aimed to investigate the genotype-phenotype spectrum of DEGCAGS and the possibility of a diagnostic DNA methylation episignature, to facilitate the diagnosis of a highly variable condition lacking pathognomonic clinical findings. We collected data on 30 affected individuals (12 new). GestaltMatcher analyzed fifty-three facial photographs from five individuals. In nine individuals, methylation profiling of blood-DNA was performed, and a classification model was constructed to differentiate DEGCAGS from controls. We expand the ZNF699-related molecular spectrum and show that biallelic, LoF, ZNF699 variants cause unique clinical findings with age-related presentation and a similar facial gestalt. We also identified a robust episignature for DEGCAGS syndrome. DEGCAGS syndrome is a clinically variable recessive syndrome even among siblings with a distinct methylation episignature which can be used as a screening, diagnostic and classification tool for ZNF699 variants. Analysis of differentially methylated regions suggested an effect on genes potentially implicated in the syndrome’s pathogenesis.

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Fig. 1: Spectrum of pathogenic variants across the ZNF699 protein domains.
Fig. 2: ZNF699-related clinical spectrum.
Fig. 3: The ZNF699 pattern of recognizable dysmorphic features.
Fig. 4: Episignature of DEGCAGS cohort.

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Data availability

Data and materials can be supplied upon request. All seven novel ZNF699 variants were deposited in ClinVar, accession numbers SCV004565351 – SCV004565357. Some of the datasets used in this study are publicly available and may be obtained from gene expression omnibus (GEO) using the following accession numbers. GEO: GSE116992, GSE66552, GSE74432, GSE97362, GSE116300, GSE95040, GSE104451, GSE125367, GSE55491, GSE108423, GSE116300, GSE 89353, GSE52588, GSE42861, GSE85210, GSE87571, GSE87648, GSE99863, and GSE35069. These include DNA methylation data from individuals with Kabuki syndrome, Sotos syndrome, CHARGE syndrome, immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, Williams-Beuren syndrome, Chr7q11.23 duplication syndrome, BAFopathies, Down syndrome, a large cohort of unresolved subjects with developmental delays and congenital abnormalities, and also several large cohorts of DNA methylation data from the general population. Remaining data are not available due to institutional or REB restrictions. EpiSign is proprietary, trademarked analytical software owned by EpiSign Inc. and parts of it are based on the methods and publicly available software that are referenced in the methods section.

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Acknowledgements

We are grateful to the participating families. This work has been generated within the Norwegian National Advisory Unit on Rare Disorders Project 2629394, ‘The post-exome clinic: improving the impact of exome sequencing for developmental disorders in Norway’ and the European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA) [EU Framework Partnership Agreement ID: 3HP-HP-FPA ERN-01-2016/739516]. The GestaltMatcher database is a service operated by the Association for Genome Diagnostics (AGD), which is a registered non-for-profit organization in Germany. GMDB aims to improve the openness and accessibility of scientific findings and to enhance collaboration amongst researchers and clinicians. GMDB is a non-profit community resource and is not linked to any one publisher or journal. We thank graphic designer Rannveig Lohne for assisting in creating Fig. 1a.

Funding

This study was funded by the Norwegian National Advisory Unit on Rare Disorders (grant #43066 to SDH), the government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-188 to BS), grants from the National Institutes of Health (DK068306) and the Begg Family Foundation (both to FH) and grants by the Interdisciplinary Center for Clinical Research Erlangen (J70) and the Deutsche Forschungsgemeinschaft (281319475) (both to TJS). Sequencing and analysis of [GAZ_431/ Patient 16] were provided by the Broad Institute of MIT and Harvard Center for Mendelian Genomics (Broad CMG) and were funded by the National Human Genome Research Institute (NHGRI) grants UM1HG008900 (with additional support from the National Eye Institute, and the National Heart, Lung and Blood Institute), and R01HG009141 (to LP). All funders played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

Author information

Author notes

  1. Hanna T. Gazda

    Present address: Takeda Development Center Americas, Inc., Cambridge, MA, USA

  2. These authors contributed equally: Karim Karimi, Denisa Weis.

Authors and Affiliations

  1. Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada

    Karim Karimi, Raissa Relator, Michael A. Levy, Jennifer Kerkhof, Jessica Rzasa & Bekim Sadikovic

  2. Department of Medical Genetics, Med Campus IV, Kepler University Hospital, Johannes Kepler, University, Linz, Austria

    Denisa Weis & Marie Horackova

  3. Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway

    Ingvild Aukrust & Sofia Douzgou Houge

  4. Department of Clinical Science, University of Bergen, Bergen, Norway

    Ingvild Aukrust

  5. Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany

    Tzung-Chien Hsieh, Hellen Lesman & Peter Krawitz

  6. Department of Medical Genetics, St. Olav’s hospital, Trondheim University Hospital, Trondheim, Norway

    Julie Paulsen & Henrik Døllner

  7. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada

    Roberto Mendoza Londono, Lucie Dupuis & Megan Dickson

  8. Institute of Human Genetics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany

    Hellen Lesman

  9. Institute of Neurology, University College London, London, UK

    Tracy Lau, David Murphy, Henry Houlden & Reza Maroofian

  10. Department of Pediatrics, College of Medicine, Sulaimani University, Sulaymaniyah, 46001, Iraq

    Khalid Hama Salih

  11. College of Medicine, University of Baghdad, Baghdad, Iraq

    Bassam M. S. Al-Musawi & Ruqayah G. Y. Al-Obaidi

  12. The Teaching Laboratories, Medical city complex, Baghdad, Iraq

    Ruqayah G. Y. Al-Obaidi

  13. Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland

    Malgorzata Rydzanicz

  14. Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases, Wroclaw Medical University, Wroclaw, Poland

    Mateus Biela

  15. Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal

    Mafalda Saraiva Santos & Sergio B. Sousa

  16. Division of Genetics and Genomics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Abdulrahman Aldeeri, Hanna T. Gazda, Lynn Pais & Timothy W. Yu

  17. Harvard Medical School, Boston, MA, USA

    Abdulrahman Aldeeri, Hanna T. Gazda, Tilman Jobst-Schwan & Timothy W. Yu

  18. Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia

    Abdulrahman Aldeeri

  19. Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA

    Shirlee Shril & Friedhelm Hildebrandt

  20. Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway

    Henrik Døllner

  21. Department of Clinical Hematology, Aditya Birla Memorial Hospital, Pune, India

    Sandip Bartakke

  22. Department of Pediatrics, Hospital of the Sister of Merci, Linz, Austria

    Franco Laccone & Gabriela V. Pilshofer

  23. Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia

    Andrea Soltysova

  24. Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia

    Andrea Soltysova

  25. Department of Human Genetics, McGill University, Montreal, QC, Canada

    Thomas Kitzler

  26. Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Cairo University, Egyptian Group for Orphan Renal Diseases, Cairo, Egypt

    Neveen A. Soliman

  27. Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany

    Tilman Jobst-Schwan

  28. University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal

    Sergio B. Sousa

  29. Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA

    Timothy W. Yu

  30. Department of Pathology and Laboratory Medicine, Western University, London, Canada

    Bekim Sadikovic

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  1. Karim Karimi
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  2. Denisa Weis
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  38. Reza Maroofian
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  39. Timothy W. Yu
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  40. Peter Krawitz
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  41. Bekim Sadikovic
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  42. Sofia Douzgou Houge
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Contributions

Conceptualization: DW, BS and SDH; Data Curation: KK, MH, IA, T-ChHs, HL., AA and DW; Formal Analysis: KK, DW, IA, and T-ChHs; Funding acquisition: FH, TJS, BS and SDH; Investigation: KK, DW, IA, T-ChHs, JP, RML, LD, MD, HL, TL, KHS, B.M.S.Al-M, RGYAl-Ob, DM, MR, MB, MSS, AA, HTG, LP, ShSh, HD, SB, FL, AS, TK, TJ-Sch, NAS, RR, MAL, JK, JS, HH, GVP, FH, SBS, RM, TWY, and SDH; Methodology: KK, T-ChHs, MAL, BS and SDH; Project Administration: HL, RM, MH, DW, KK, IA and SDH; Software: KK, IA, T-ChHs, BS and PK; Supervision: DW, RML, SBS, RM, TY, PK, BS and SDH; Validation: KK, IA, T-ChHs; Visualization: KK, DW, IA, RML, LD, T-ChHs and SDH; Writing-original draft: KK, DW, T-ChHs, IA and SDH; Writing-review and editing: KK, DW, T-ChHs, AA, BS and SDH.

Corresponding authors

Correspondence to Bekim Sadikovic or Sofia Douzgou Houge.

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Competing interests

BS is a shareholder in EpiSign Inc, company involved in commercialization of EpiSignTM technology.

Ethical approval

This study was performed according to the Declaration of Helsinki and approved by the Western Norway Regional Ethics Committee (REC 604007) and the Western Ontario University Research Ethics Board (REB 106302). Written informed consent for the publication of photographs, videos and medical information was obtained from parents/legal guardians.

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Karimi, K., Weis, D., Aukrust, I. et al. Epigenomic and phenotypic characterization of DEGCAGS syndrome. Eur J Hum Genet 32, 1574–1582 (2024). https://doi.org/10.1038/s41431-024-01702-y

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  • DOI: https://doi.org/10.1038/s41431-024-01702-y

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