DNA methylation episignature in Gabriele-de Vries syndrome

Florian Cherik (1) , Jack Reilly (2) , Jennifer Kerkhof (3) , Michael Levy (3) , Haley Mcconkey (3) , Mouna Barat-Houari (4) , Kameryn M Butler (5) , Christine Coubes (4) , Jennifer A Lee (5) , Gwenael Le Guyader (6) , Raymond J Louie (5) , Wesley G Patterson (5) , Matthew L Tedder (5) , Mads Bak (7) , Trine Bjørg Hammer (7) , William Craigen (8) , Florence Démurger (9) , Christèle Dubourg (10, 11) , Mélanie Fradin (12) , Rachel Franciskovich (8) , Eirik Frengen (13) , Jennifer Friedman (14) , Nathalie Ruiz Palares (4) , Maria Iascone (15) , Doriana Misceo (13) , Pauline Monin (16) , Sylvie Odent (10, 12) , Christophe Philippe (17) , Flavien Rouxel (4) , Veronica Saletti (18) , Petter Strømme (13) , Perla Cassayre Thulin (19) , Bekim Sadikovic (2, 3) , David Genevieve (4)

1 CHU Clermont-Ferrand
2 UWO - University of Western Ontario
3 LHSC - London Health Sciences Center
4 CHU Montpellier
5 The Greenwood Genetic Center
6 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
7 Rigshospitalet [Copenhagen]
8 BCM - Baylor College of Medicine
9 CHBA - Centre hospitalier Bretagne Atlantique (Morbihan)
10 IGDR - Institut de Génétique et Développement de Rennes
11 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
12 Centre de référence Maladies Rares CLAD-Ouest [Rennes]
13 Oslo University Hospital [Oslo]
14 UC San Diego - University of California [San Diego]
15 Hosp P Giovanni XXIII - Hospital Papa Giovanni XXIII
16 HFME - Hôpital Femme Mère Enfant [CHU - HCL]
17 CHU Dijon - Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand
18 Fondazione IRCCS Istituto Neurologico "Carlo Besta"
19 University of Utah

PURPOSE: Gabriele-de Vries syndrome (GADEVS) is a rare genetic disorder characterized by developmental delay and/or intellectual disability, hypotonia, feeding difficulties, and distinct facial features. To refine the phenotype and to better understand the molecular basis of the syndrome, we analyzed clinical data and performed genome-wide DNA methylation analysis of a series of individuals carrying a YY1 variant. METHODS: Clinical data were collected for 13 individuals not yet reported through an international call for collaboration. DNA was collected for 11 of these individuals and 2 previously reported individuals in an attempt to delineate a specific DNA methylation signature in GADEVS. RESULTS: Phenotype in most individuals overlapped with the previously described features. We described 1 individual with atypical phenotype, heterozygous for a missense variant in a domain usually not involved in individuals with YY1 pathogenic missense variations. We also described a specific peripheral blood DNA methylation profile associated with YY1 variants. CONCLUSION: We reported a distinct DNA methylation episignature in GADEVS. We expanded the clinical profile of GADEVS to include thin/sparse hair and cryptorchidism. We also highlighted the utility of DNA methylation episignature analysis for classification of variants of unknown clinical significance.

Mots clés: DNA methylation; Epigenetics; Gabriele-de Vries syndrome; Intellectual disability; YY1

Domaines: Sciences du Vivant [q-bio]

Florian Cherik, Jack Reilly, Jennifer Kerkhof, Michael Levy, Haley Mcconkey, et al.. DNA methylation episignature in Gabriele-de Vries syndrome. Genetics in Medicine, 2022, 24 (4), pp.905-914. ⟨10.1016/j.gim.2021.12.003⟩. ⟨hal-03578473⟩