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Title: | Novel genetic variants of KHDC3L and other members of the subcortical maternal complex associated with Beckwith–Wiedemann syndrome or Pseudohypoparathyroidism 1B and multi-locus imprinting disturbances |
Author: | Pignata, Laura Cecere, Francesco Verma, Ankit Hay Mele, Bruno Monticelli, Maria Acurzio, Basilia Giaccari, Carlo Sparago, Angela Hernandez Mora, Jose Ramon Monteagudo Sánchez, Ana Esteller, Manel Pereda, Arrate Tenorio Castano, Jair Palumbo, Orazio Carella, Massimo Prontera, Paolo Piscopo, Carmelo Accadia, Maria Lapunzina, Pablo Cubellis, Maria Vittoria Perez de Nanclares, Guiomar Monk, David Riccio, Andrea Cerrato, Flavia |
Keywords: | ADN Metilació Genètica DNA Methylation Genetics |
Issue Date: | 28-May-2022 |
Publisher: | Springer Science and Business Media LLC |
Abstract: | Background Beckwith-Wiedemann syndrome (BWS) and Pseudohypoparathyroidism type 1B (PHP1B) are imprinting disorders (ID) caused by deregulation of the imprinted gene clusters located at 11p15.5 and 20q13.32, respectively. In both of these diseases a subset of the patients is affected by multi-locus imprinting disturbances (MLID). In several families, MLID is associated with damaging variants of maternal-effect genes encoding protein components of the subcortical maternal complex (SCMC). However, frequency, penetrance and recurrence risks of these variants are still undefined. In this study, we screened two cohorts of BWS patients and one cohort of PHP1B patients for the presence of MLID, and analysed the positive cases for the presence of maternal variants in the SCMC genes by whole exome-sequencing and in silico functional studies. Results We identified 10 new cases of MLID associated with the clinical features of either BWS or PHP1B, in which segregate 13 maternal putatively damaging missense variants of the SCMC genes. The affected genes also included KHDC3L that has not been associated with MLID to date. Moreover, we highlight the possible relevance of relatively common variants in the aetiology of MLID. Conclusion Our data further add to the list of the SCMC components and maternal variants that are involved in MLID, as well as of the associated clinical phenotypes. Also, we propose that in addition to rare variants, common variants may play a role in the aetiology of MLID and imprinting disorders by exerting an additive effect in combination with rarer putatively damaging variants. These findings provide useful information for the molecular diagnosis and recurrence risk evaluation of MLID-associated IDs in genetic counselling. |
Note: | Reproducció del document publicat a: https://doi.org/10.1186/s13148-022-01292-w |
It is part of: | Clinical Epigenetics, 2022, vol. 14, num. 1, p. 71 |
URI: | http://hdl.handle.net/2445/186718 |
Related resource: | https://doi.org/10.1186/s13148-022-01292-w |
ISSN: | 1868-7083 |
Appears in Collections: | Articles publicats en revistes (Ciències Fisiològiques) Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) |
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