Author:
Vos Niels,Haghshenas Sadegheh,van der Laan Liselot,Russel Perle K. M.,Rooney Kathleen,Levy Michael A.,Relator Raissa,Kerkhof Jennifer,McConkey Haley,Maas Saskia M.,Vissers Lisenka E. L. M.,de Vries Bert B. A.,Pfundt Rolph,Elting Mariet W.,van Hagen Johanna M.,Verbeek Nienke E.,Jongmans Marjolijn C. J.,Lakeman Phillis,Rumping Lynne,Bosch Danielle G. M.,Vitobello Antonio,Thauvin-Robinet Christel,Faivre Laurence,Nambot Sophie,Garde Aurore,Willems Marjolaine,Genevieve David,Nicolas Gaël,Busa Tiffany,Toutain Annick,Gérard Marion,Bizaoui Varoona,Isidor Bertrand,Merla Giuseppe,Accadia Maria,Schwartz Charles E.,Ounap Katrin,Hoffer Mariëtte J. V.,Nezarati Marjan M.,van den Boogaard Marie-José H.,Tedder Matthew L.,Rogers Curtis,Brusco Alfredo,Ferrero Giovanni B.,Spodenkiewicz Marta,Sidlow Richard,Mussa Alessandro,Trajkova Slavica,McCann Emma,Mroczkowski Henry J.,Jansen Sandra,Donker-Kaat Laura,Duijkers Floor A. M.,Stuurman Kyra E.,Mannens Marcel M. A. M.,Alders Mariëlle,Henneman Peter,White Susan M.,Sadikovic Bekim,van Haelst Mieke M.
Abstract
AbstractChung-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.
Publisher
Springer Science and Business Media LLC