The detection of a strong episignature for Chung-Jansen syndrome, partially overlapping with Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Journal

Human genetics
ISSN: 1432-1203
Titre abrégé: Hum Genet
Pays: Germany
ID NLM: 7613873

Informations de publication

Date de publication:
24 May 2024
Historique:
received: 14 12 2023
accepted: 09 05 2024
medline: 24 5 2024
pubmed: 24 5 2024
entrez: 24 5 2024
Statut: aheadofprint

Résumé

Chung-Jansen syndrome is a neurodevelopmental disorder characterized by intellectual disability, behavioral problems, obesity and dysmorphic features. It is caused by pathogenic variants in the PHIP gene that encodes for the Pleckstrin homology domain-interacting protein, which is part of an epigenetic modifier protein complex. Therefore, we hypothesized that PHIP haploinsufficiency may impact genome-wide DNA methylation (DNAm). We assessed the DNAm profiles of affected individuals with pathogenic and likely pathogenic PHIP variants with Infinium Methylation EPIC arrays and report a specific and sensitive DNAm episignature biomarker for Chung-Jansen syndrome. In addition, we observed similarities between the methylation profile of Chung-Jansen syndrome and that of functionally related and clinically partially overlapping genetic disorders, White-Kernohan syndrome (caused by variants in DDB1 gene) and Börjeson-Forssman-Lehmann syndrome (caused by variants in PHF6 gene). Based on these observations we also proceeded to develop a common episignature biomarker for these disorders. These newly defined episignatures can be used as part of a multiclass episignature classifier for screening of affected individuals with rare disorders and interpretation of genetic variants of unknown clinical significance, and provide further insights into the common molecular pathophysiology of the clinically-related Chung-Jansen, Börjeson-Forssman-Lehmann and White-Kernohan syndromes.

Identifiants

DOI: 10.1007/s00439-024-02679-w PMID: 38787418
pubmed: 38787418
doi: 10.1007/s00439-024-02679-w
pii: 10.1007/s00439-024-02679-w
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : Genome Canada
ID : OGI-188

Informations de copyright

© 2024. The Author(s).

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Auteurs

Niels Vos (N)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Sadegheh Haghshenas (S)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada.

Liselot van der Laan (L)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Perle K M Russel (PKM)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Kathleen Rooney (K)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada.

Michael A Levy (MA)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada.

Raissa Relator (R)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada.

Jennifer Kerkhof (J)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada.

Haley McConkey (H)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada.
Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada.

Saskia M Maas (SM)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Lisenka E L M Vissers (LELM)

Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.

Bert B A de Vries (BBA)

Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.

Rolph Pfundt (R)

Department of Human Genetics, Research Institute for Medical Innovation, Radboud University Medical Center, 6525 GA, Nijmegen, The Netherlands.

Mariet W Elting (MW)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Johanna M van Hagen (JM)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Nienke E Verbeek (NE)

Department of Genetics, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.

Marjolijn C J Jongmans (MCJ)

Department of Genetics, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.

Phillis Lakeman (P)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Lynne Rumping (L)

Center for Medical Genetics, Antwerp University Hospital, University of Antwerp, Drie Eikenstraat 655, 2650, Edegem, Belgium.

Danielle G M Bosch (DGM)

Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Antonio Vitobello (A)

Université de Bourgogne, Inserm U1231, Equipe GAD, Dijon, France.
CHU Dijon Bourgogne, FHU-TRANSLAD, Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, 21000, Dijon, France.

Christel Thauvin-Robinet (C)

Université de Bourgogne, Inserm U1231, Equipe GAD, Dijon, France.
CHU Dijon Bourgogne, FHU-TRANSLAD, Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, 21000, Dijon, France.
CHU Dijon Bourgogne, Centre de Génétique, Centre de Référence Maladies Rares «Déficiences Intellectuelles de Causes Rares», FHU-TRANSLAD, Dijon, France.

Laurence Faivre (L)

Université de Bourgogne, Inserm U1231, Equipe GAD, Dijon, France.
CHU Dijon Bourgogne, Centre de Génétique, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs», FHU-TRANSLAD, Dijon, France.

Sophie Nambot (S)

Université de Bourgogne, Inserm U1231, Equipe GAD, Dijon, France.
CHU Dijon Bourgogne, FHU-TRANSLAD, Unité Fonctionnelle Innovation en Diagnostic Génomique Des Maladies Rares, 21000, Dijon, France.
CHU Dijon Bourgogne, Centre de Génétique, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs», FHU-TRANSLAD, Dijon, France.

Aurore Garde (A)

Université de Bourgogne, Inserm U1231, Equipe GAD, Dijon, France.
CHU Dijon Bourgogne, Centre de Génétique, Centre de Référence Maladies Rares «Déficiences Intellectuelles de Causes Rares», FHU-TRANSLAD, Dijon, France.

Marjolaine Willems (M)

INserm U1183, Department of Clinical Genetics, Montpellier University, 34090 CHU Montpellier, Montpellier, France.

David Genevieve (D)

INserm U1183, Department of Clinical Genetics, Montpellier University, 34090 CHU Montpellier, Montpellier, France.

Gaël Nicolas (G)

Inserm U1245 and CHU Rouen, Department of Genetics and Reference Center for Developmental Disorders, Univ Rouen Normandie, 76000, Rouen, France.

Tiffany Busa (T)

Department of Medical Genetics, Timone Hospital, Marseille, France.

Annick Toutain (A)

Genetics Department, University Hospital, UMR 1253, iBrain, University of Tours, Inserm, Tours, France.

Marion Gérard (M)

APHP, Department of Genetics, Robert Debré Hospital, 75019, Paris, France.

Varoona Bizaoui (V)

Clinical Genetics and Neurodevelopmental Disorders, Centre Hospitalier de L'Estran, 50170, Pontorson, France.

Bertrand Isidor (B)

Service de Génétique Médicale, CHU de Nantes, 44000, Nantes, France.

Giuseppe Merla (G)

Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, Foggia, Italy.
Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131, Naples, Italy.

Maria Accadia (M)

Servizio di Genetica Medica, Ospedale Cardinale G. Panico, Tricase, LE, Italy.

Charles E Schwartz (CE)

Department of Pediatrics and Human Development, College of Human Medicine, Michigan State University, Grand Rapids, MI, 49503, USA.

Katrin Ounap (K)

Department of Clinical Genetics, Genetic and Personalized Medicine Clinic, Tartu University Hospital, Tartu, Estonia.
Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.

Mariëtte J V Hoffer (MJV)

Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.

Marjan M Nezarati (MM)

Genetics Program, North York General Hospital, Toronto, ON, M2K 1E1, Canada.

Marie-José H van den Boogaard (MH)

Department of Genetics, University Medical Center Utrecht, 3584 CX, Utrecht, The Netherlands.

Matthew L Tedder (ML)

Greenwood Genetic Center, Greenwood, SC, 29646, USA.

Curtis Rogers (C)

Greenwood Genetic Center, Greenwood, SC, 29646, USA.

Alfredo Brusco (A)

Department of Medical Sciences, University of Torino, Via Santena 19, 10126, Turin, Italy.
Unit of Medical Genetics, Città Della Salute e Della Scienza Hospital, Turin, Italy.

Giovanni B Ferrero (GB)

Department of Clinical and Biological Science, University of Torino, Turin, Italy.

Marta Spodenkiewicz (M)

Service de Génétique, CRMR AnDDI-Rares, CHU Reims, Reims, France.

Richard Sidlow (R)

Department of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA, USA.

Alessandro Mussa (A)

Department of Public Health and Pediatric Sciences, University of Torino, Turin, Italy.
Pediatric Clinical Genetics Unit, Regina Margherita Childrens' Hospital, Turin, Italy.

Slavica Trajkova (S)

Department of Medical Sciences, University of Torino, Via Santena 19, 10126, Turin, Italy.

Emma McCann (E)

Liverpool Center for Genomic Medicine, Liverpool Women's Hospital, Liverpool, UK.

Henry J Mroczkowski (HJ)

Department of Pediatrics, Le Bonheur Children's Hospital, Memphis, TN, USA.
Division of Genetics, Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN, USA.

Sandra Jansen (S)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Laura Donker-Kaat (L)

Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Floor A M Duijkers (FAM)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Kyra E Stuurman (KE)

Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.

Marcel M A M Mannens (MMAM)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Mariëlle Alders (M)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Peter Henneman (P)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands.

Susan M White (SM)

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, 3052, Australia.
Department of Paediatrics, University of Melbourne, Melbourne, Australia.

Bekim Sadikovic (B)

Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, ON, N6A 5W9, Canada. bekim.sadikovic@lhsc.on.ca.
Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada. bekim.sadikovic@lhsc.on.ca.

Mieke M van Haelst (MM)

Amsterdam UMC, Department of Human Genetics, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. m.vanhaelst@amsterdamumc.nl.
Amsterdam Reproduction & Development Research Institute, Amsterdam, The Netherlands. m.vanhaelst@amsterdamumc.nl.
Amsterdam UMC, Department of Paediatrics, Emma Children's Hospital, University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands. m.vanhaelst@amsterdamumc.nl.
Amsterdam UMC, Emma Center for Personalized Medicine, Amsterdam, The Netherlands. m.vanhaelst@amsterdamumc.nl.

Classifications MeSH