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