Investigation of multilocus imprinting disturbance (MLID) in 101 Beckwith-Wiedemann spectrum patients

Beckwith-Wiedemann spectrum (BWSp) is an overgrowth disorder caused by both genetic and epigenetic defects within the 11p15.5 chromosomal region. The most common cause of BWSp is DNA methylation anomalies in two imprinting control regions (ICR1, the telomeric centre that includes H19/IGF2:IG-DMR and ICR2, the centromeric centre that includes KCNQ1OT1:TSS-DMR) located within the 11p15.5 locus. Previous studies demonstrated that a subset of BWSp patients had methylation defects extending beyond 11p15.5 to other chromosomal loci, an entity known as multilocus imprinting disturbances (MLID). In this study, the multilocus methylation status of 101 BWSp patients was analysed by both various methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA-E034) and methylation microarrays. MS-MLPA-ME034 detected MLID in 16 (15.8%) of the patients, which increased to 59 (58.4%) using methylation microarrays. ICR2 hypomethylation was observed in all MLID cases, and 28 imprinted differentially methylated regions (DMRs) were additionally detected. Recurrent loci associated with the genes such as GNAS, MEST, and DIRAS3, previously reported in MLID patients, were also observed as hypomethylated in our cohort. Seven out of the 48 (14.6%) MLID-BWSp patients with complete data on type of conception were born following assisted reproductive technologies (ART), indicating an appreciable proportion of MLID among ART-conceived pregnancies. This study underscores the value of genome-wide methylation analyses in revealing molecular complexity, improving diagnostic accuracy, and informing prenatal care in BWSp with MLID. Future research should further explore the long-term clinical implications of MLID and the underlying molecular mechanisms.

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Journal
Clinical Epigenetics
Published
2026-04-26
DOI
https://doi.org/10.1186/s13148-026-02077-1
Primary Topic
Genetic Syndromes and Imprinting
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article
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article

Investigation of multilocus imprinting disturbance (MLID) in 101 Beckwith-Wiedemann spectrum patients

Ana Patiño‐García, Blanca Gener, Boris Groisman, Juan A. Jimenez‐Estrada et al.
Clinical Epigenetics
Genetic Syndromes and Imprinting
article

Investigation of multilocus imprinting disturbance (MLID) in 101 Beckwith-Wiedemann spectrum patients

Ana Patiño‐García, Blanca Gener, Boris Groisman, Juan A. Jimenez‐Estrada, Alicia Delicado, Vanesa Lotersztein, E. Gomez, Eugenia Antolin, Javier López Pisón, Ignacio Díez López, Carmen González Armengod, Dolores Elorza, Isabel Lorda Sánchez, Bradford Coffee, Jaime Sánchez del Pozo, Elisabeth Steichen, Inés Bueno, Javier Arcas, Ana Vega, Alicia de Ureta Huertos, Antonio González Meneses, Alberto L. Rosa, Almudena Alonso, Enriqueta Román, Blasco Gonzalez, Ignacio Pascual Pascual, Pedro Arias, Alfredo Santana, Antonio González‐Meneses, Andrea Villavicencio, Alejandro Parra, Claudia Arberas, Ernesto Goldschmidt, Alfredo García Alix, Carlos Rodríguez‐Antolín, Fermina López Grondona, C. Contessotto, Cristina Silván, Carlos Alcalde Martín, Graciela Mercado, Carmen Benito, Hamilton Cassinelli, Pablo Barbero, Aleixandre Blanquer, Daniel Armenta, Gloria Gacio, Analía Bredani, Cristina Olivas, Esteban Marfil, Arteche Ocasar, Carmen Martín Seisdedos, Antonio Baldellon, Giovannucci Uzielli, Ignacio Vázquez Rio, Javier Fernández, Jesús Barreiro, A Hernández, Jaume Campistol, Amparo Sanchís, Spanish OverGrowth Registry Initiative, Esther Geán, Elisa Zambrano, Fco. Javier Martínez Sarries, Carmen Aragón Fernández, Enrique Caro Cruz, Ignacio Arroyo, Ignacio Onsurbe Ramírez, Carmen Roche, Andrea Solari, Claudia Toledo Pacheco, A. Nieto, Natalia Gallego-Zazo, Eduardo Castilla, Ana Moreno, Mario Cazalla, Fernando De Almeida Santos, Fernández Córdoba, Denise Cavalcanti, Lucía Miranda-Alcaraz, Fernando Vargas, Ignacio Pascual Castroviejo, Antonio Martinez Carrascal, Amaya Rodríguez, J. Miguel García Vegada, Manuel Rodríguez-Canó, Feliciano Ramos, Javier García Planells, Angelina Acosta, Claudia Perandones, F. Javier Gascón Jiménez, Ieda Orioli, Mónica Mora-Gómez, Elena Zamora, Anna María Cueto González, Isabel Espejo Portero, A. Plasencia, Francisco Martínez, Aranzazu Diaz de Bustamante, Encarna Guillén Navarro
article en

Abstract

Beckwith-Wiedemann spectrum (BWSp) is an overgrowth disorder caused by both genetic and epigenetic defects within the 11p15.5 chromosomal region. The most common cause of BWSp is DNA methylation anomalies in two imprinting control regions (ICR1, the telomeric centre that includes H19/IGF2:IG-DMR and ICR2, the centromeric centre that includes KCNQ1OT1:TSS-DMR) located within the 11p15.5 locus. Previous studies demonstrated that a subset of BWSp patients had methylation defects extending beyond 11p15.5 to other chromosomal loci, an entity known as multilocus imprinting disturbances (MLID). In this study, the multilocus methylation status of 101 BWSp patients was analysed by both various methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA-E034) and methylation microarrays. MS-MLPA-ME034 detected MLID in 16 (15.8%) of the patients, which increased to 59 (58.4%) using methylation microarrays. ICR2 hypomethylation was observed in all MLID cases, and 28 imprinted differentially methylated regions (DMRs) were additionally detected. Recurrent loci associated with the genes such as GNAS, MEST, and DIRAS3, previously reported in MLID patients, were also observed as hypomethylated in our cohort. Seven out of the 48 (14.6%) MLID-BWSp patients with complete data on type of conception were born following assisted reproductive technologies (ART), indicating an appreciable proportion of MLID among ART-conceived pregnancies. This study underscores the value of genome-wide methylation analyses in revealing molecular complexity, improving diagnostic accuracy, and informing prenatal care in BWSp with MLID. Future research should further explore the long-term clinical implications of MLID and the underlying molecular mechanisms.

Clinical Epigenetics
Hospital Universitario Insular de Gran Canaria (ES), Hospital Universitario La Paz (ES), Centro de Genética Clínica (PT), Hospital La Paz Institute for Health Research (ES), Centro de Investigación Biomédica en Red (ES), Hospital Clínico Universitario Lozano Blesa (ES), Centro de Implantología Cirugía Oral y Maxilofacial (ES), Hospital Universitario Virgen del Rocío (ES), Universidad Autónoma de Madrid (ES), Universidad de Extremadura (ES)
Instituto de Salud Carlos III
Openalex Percentile: Top 13%
Genetic Syndromes and Imprinting
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