Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance

Clinical Epigenetics

Maria Vittoria Cubellis¹  Maria Monticelli¹  Angela Sparago²  Flavia Cerrato²  Rosita Del Prete²  Laura Pignata²  Ankit Verma³  Andrea Riccio³  Romano Tenconi⁴  Vincenzo Antona⁵  Luciano Calzari⁶  Silvia Russo⁶  Daniela Melis⁷ 

[1] Department of Biology, Università degli Studi di Napoli “Federico II”, Napoli, Italy;Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania “Luigi Vanvitelli”, Caserta, Italy;Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università degli Studi della Campania “Luigi Vanvitelli”, Caserta, Italy;Institute of Genetics and Biophysics (IGB) “Adriano Buzzati-Traverso”, Consiglio Nazionale delle Ricerche (CNR), Naples, Italy;Department of Pediatrics, Clinical Genetics, Università di Padova, Padova, Italy;Department of Sciences for Health Promotion and Mother and Child Care “G. D’Alessandro”, University of Palermo, Palermo, Italy;Medical Cytogenetics and Molecular Genetics Laboratory, Centro di Ricerche e Tecnologie Biomediche IRCCS, Istituto Auxologico Italiano, Milan, Italy;Medical, Surgical, and Dental Department, Università degli Studi di Salerno, Salerno, Italy;

关键词: Multi-locus imprinting disturbance;    PADI6;    Beckwith-Wiedemann syndrome;    Genomic imprinting;    DNA methylation;    Maternal-effect variants;    Subcortical maternal complex;    Infertility;   

DOI  :  10.1186/s13148-020-00925-2

来源: Springer

【 摘 要 】

BackgroundPADI6 is a component of the subcortical maternal complex, a group of proteins that is abundantly expressed in the oocyte cytoplasm, but is required for the correct development of early embryo. Maternal-effect variants of the subcortical maternal complex proteins are associated with heterogeneous diseases, including female infertility, hydatidiform mole, and imprinting disorders with multi-locus imprinting disturbance. While the involvement of PADI6 in infertility is well demonstrated, its role in imprinting disorders is less well established.ResultsWe have identified by whole-exome sequencing analysis four cases of Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance whose mothers are carriers of PADI6 variants. In silico analysis indicates that these variants result in loss of function, and segregation analysis suggests they act as either recessive or dominant-negative maternal-effect mutations. Genome-wide methylation analysis revealed heterogeneous and extensively altered methylation profiles of imprinted loci in the patients, including two affected sisters, but not in their healthy siblings.ConclusionOur results firmly establish the role of PADI6 in imprinting disorders. We report loss-of-function maternal-effect variants of PADI6 that are associated with heterogeneous multi-locus imprinting disturbances in the progeny. The rare finding of two siblings affected by Beckwith-Wiedemann syndrome suggests that in some cases, familial recurrence risk of these variants may be high. However, the heterogeneous phenotypes of the other pedigrees suggest that altered oocyte PADI6 function results in stochastic maintenance of methylation imprinting with unpredictable consequences on early embryo health.

【 授权许可】

CC BY