Epigenomic and phenotypic characterization of DEGCAGS syndrome

Karimi K, Weis D, Aukrust I, Hsieh TC, Horackova M, Paulsen J, Mendoza Londono R, Dupuis L, Dickson M, Lesman H, Lau T, Murphy D, Hama Salih K, Al-Musawi BM, Al-Obaidi RG, Rydzanicz M, Biela M, Santos MS, Aldeeri A, Gazda HT, Pais L, Shril S, Døllner H, Bartakke S, Laccone F, Soltysova A, Kitzler T, Soliman NA, Relator R, Levy MA, Kerkhof J, Rzasa J, Houlden H, Pilshofer GV, Jobst-Schwan T, Hildebrandt F, Sousa SB, Maroofian R, Yu TW, Krawitz P, Sadikovic B, Douzgou Houge S (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1038/s41431-024-01702-y

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.

Related research project(s)

Involved external institutions

Kepler Universitätsklinikum (KUK) Austria (AT) University of Baghdad Iraq (IQ) Wrocław Medical University / Uniwersytet Medyczny we Wrocławiu Poland (PL) Centro Hospitalar e Universitário de Coimbra (CHUC) Portugal (PT) Harvard University United States (USA) (US) St. Olavs University Hospital / St. Olavs Hospital Universitetssykehuset i Trondheim Norway (NO) Aditya Birla Memorial Hospital India (IN) Ordensklinikum Linz - Elisabethinen Austria (AT) Comenius University Bratislava Slovakia (SK) McGill University Canada (CA) London Health Sciences Centre Canada (CA) University College London (UCL) United Kingdom (GB) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Universitätsklinikum Bonn Germany (DE) The Hospital for Sick Children (SickKids) Canada (CA) University of Sulaimani Iraq (IQ)

How to cite

APA:

Karimi, K., Weis, D., Aukrust, I., Hsieh, T.C., Horackova, M., Paulsen, J.,... Douzgou Houge, S. (2024). Epigenomic and phenotypic characterization of DEGCAGS syndrome. European Journal of Human Genetics. https://doi.org/10.1038/s41431-024-01702-y

MLA:

Karimi, Karim, et al. "Epigenomic and phenotypic characterization of DEGCAGS syndrome." European Journal of Human Genetics (2024).

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