Epigenomic and phenotypic characterization of DEGCAGS syndrome.

Autor: Karimi K; Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada., Weis D; Department of Medical Genetics, Med Campus IV, Kepler University Hospital, Johannes Kepler, University, Linz, Austria., Aukrust I; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.; Department of Clinical Science, University of Bergen, Bergen, Norway., Hsieh TC; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany., Horackova M; Department of Medical Genetics, Med Campus IV, Kepler University Hospital, Johannes Kepler, University, Linz, Austria., Paulsen J; Department of Medical Genetics, St. Olav's hospital, Trondheim University Hospital, Trondheim, Norway., Mendoza Londono R; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada., Dupuis L; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada., Dickson M; Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada., Lesman H; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.; Institute of Human Genetics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany., Lau T; Institute of Neurology, University College London, London, UK., Murphy D; Institute of Neurology, University College London, London, UK., Hama Salih K; Department of Pediatrics, College of Medicine, Sulaimani University, Sulaymaniyah, 46001, Iraq., Al-Musawi BMS; College of Medicine, University of Baghdad, Baghdad, Iraq., Al-Obaidi RGY; College of Medicine, University of Baghdad, Baghdad, Iraq.; The Teaching Laboratories, Medical city complex, Baghdad, Iraq., Rydzanicz M; Department of Medical Genetics, Medical University of Warsaw, Warsaw, Poland., Biela M; Department of Pediatrics, Endocrinology, Diabetology and Metabolic Diseases, Wroclaw Medical University, Wroclaw, Poland., Santos MS; Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal., Aldeeri A; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia., Gazda HT; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Takeda Development Center Americas, Inc., Cambridge, MA, USA., Pais L; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Shril S; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Døllner H; Department of Medical Genetics, St. Olav's hospital, Trondheim University Hospital, Trondheim, Norway.; Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway., Bartakke S; Department of Clinical Hematology, Aditya Birla Memorial Hospital, Pune, India., Laccone F; Department of Pediatrics, Hospital of the Sister of Merci, Linz, Austria., Soltysova A; Department of Molecular Biology, Faculty of Natural Sciences, Comenius University, Bratislava, Slovakia.; Institute for Clinical and Translational Research, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovakia., Kitzler T; Department of Human Genetics, McGill University, Montreal, QC, Canada., Soliman NA; Department of Pediatrics, Center of Pediatric Nephrology & Transplantation, Cairo University, Egyptian Group for Orphan Renal Diseases, Cairo, Egypt., Relator R; Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada., Levy MA; Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada., Kerkhof J; Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada., Rzasa J; Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada., Houlden H; Institute of Neurology, University College London, London, UK., Pilshofer GV; Department of Pediatrics, Hospital of the Sister of Merci, Linz, Austria., Jobst-Schwan T; Harvard Medical School, Boston, MA, USA.; Department of Nephrology and Hypertension, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany., Hildebrandt F; Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA., Sousa SB; Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.; University Clinic of Genetics, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal., Maroofian R; Institute of Neurology, University College London, London, UK., Yu TW; Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.; Harvard Medical School, Boston, MA, USA.; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA, USA., Krawitz P; Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany., Sadikovic B; Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada. bekim.sadikovic@lhsc.on.ca.; Department of Pathology and Laboratory Medicine, Western University, London, Canada. bekim.sadikovic@lhsc.on.ca., Douzgou Houge S; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway. sofia.douzgou.houge@helse-bergen.no.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2024 Dec; Vol. 32 (12), pp. 1574-1582. Date of Electronic Publication: 2024 Oct 19.
DOI: 10.1038/s41431-024-01702-y
Abstrakt: 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.
Competing Interests: 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.
(© 2024. The Author(s), under exclusive licence to European Society of Human Genetics.)
Databáze: MEDLINE
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