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Epigenomic and phenotypic characterization of DEGCAGS syndrome.

European journal of human genetics : EJHG

Authors: Karim Karimi, Denisa Weis, Ingvild Aukrust, Tzung-Chien Hsieh, Marie Horackova, Julie Paulsen, Roberto Mendoza Londono, Lucie Dupuis, Megan Dickson, Hellen Lesman, Tracy Lau, David Murphy, Khalid Hama Salih, Bassam M S Al-Musawi, Ruqayah G Y Al-Obaidi, Malgorzata Rydzanicz, Mateus Biela, Mafalda Saraiva Santos, Abdulrahman Aldeeri, Hanna T Gazda, Lynn Pais, Shirlee Shril, Henrik Døllner, Sandip Bartakke, Franco Laccone, Andrea Soltysova, Thomas Kitzler, Neveen A Soliman, Raissa Relator, Michael A Levy, Jennifer Kerkhof, Jessica Rzasa, Henry Houlden, Gabriela V Pilshofer, Tilman Jobst-Schwan, Friedhelm Hildebrandt, Sergio B Sousa, Reza Maroofian, Timothy W Yu, Peter Krawitz, Bekim Sadikovic, Sofia Douzgou Houge

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.

© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.

PMID: 39424669

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