Niels Vos, Sadegheh Haghshenas, Liselot van der Laan, Perle K M Russel, Kathleen Rooney, Michael A Levy, Raissa Relator, Jennifer Kerkhof, Haley McConkey, Saskia M Maas, Lisenka E L M Vissers, Bert B A de Vries, Rolph Pfundt, Mariet W Elting, Johanna M van Hagen, Nienke E Verbeek, Marjolijn C J Jongmans, Phillis Lakeman, Lynne Rumping, Danielle G M Bosch, Antonio Vitobello, Christel Thauvin-Robinet, Laurence Faivre, Sophie Nambot, Aurore Garde, Marjolaine Willems, David Genevieve, Gaël Nicolas, Tiffany Busa, Annick Toutain, Marion Gérard, Varoona Bizaoui, Bertrand Isidor, Giuseppe Merla, Maria Accadia, Charles E Schwartz, Katrin Ounap, Mariëtte J V Hoffer, Marjan M Nezarati, Marie-José H van den Boogaard, Matthew L Tedder, Curtis Rogers, Alfredo Brusco, Giovanni B Ferrero, Marta Spodenkiewicz, Richard Sidlow, Alessandro Mussa, Slavica Trajkova, Emma McCann, Henry J Mroczkowski, Sandra Jansen, Laura Donker-Kaat, Floor A M Duijkers, Kyra E Stuurman, Marcel M A M Mannens, Mariëlle Alders, Peter Henneman, Susan M White, Bekim Sadikovic, Mieke M van Haelst
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引用次数: 0
Abstract
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.
期刊介绍：
Human Genetics is a monthly journal publishing original and timely articles on all aspects of human genetics. The Journal particularly welcomes articles in the areas of Behavioral genetics, Bioinformatics, Cancer genetics and genomics, Cytogenetics, Developmental genetics, Disease association studies, Dysmorphology, ELSI (ethical, legal and social issues), Evolutionary genetics, Gene expression, Gene structure and organization, Genetics of complex diseases and epistatic interactions, Genetic epidemiology, Genome biology, Genome structure and organization, Genotype-phenotype relationships, Human Genomics, Immunogenetics and genomics, Linkage analysis and genetic mapping, Methods in Statistical Genetics, Molecular diagnostics, Mutation detection and analysis, Neurogenetics, Physical mapping and Population Genetics. Articles reporting animal models relevant to human biology or disease are also welcome. Preference will be given to those articles which address clinically relevant questions or which provide new insights into human biology.
Unless reporting entirely novel and unusual aspects of a topic, clinical case reports, cytogenetic case reports, papers on descriptive population genetics, articles dealing with the frequency of polymorphisms or additional mutations within genes in which numerous lesions have already been described, and papers that report meta-analyses of previously published datasets will normally not be accepted.
The Journal typically will not consider for publication manuscripts that report merely the isolation, map position, structure, and tissue expression profile of a gene of unknown function unless the gene is of particular interest or is a candidate gene involved in a human trait or disorder.
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