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
Pignata, Laura (Università Degli Studi Della Campania "Luigi Vanvitelli")
Cecere, Francesco (Università Degli Studi Della Campania "Luigi Vanvitelli")
Verma, Ankit (Institute of Genetics and Biophysics (IGB))
Hay Mele, Bruno (Università Degli Studi Di Napoli "Federico II")
Monticelli, Maria (Università Degli Studi Di Napoli "Federico II")
Acurzio, Basilia (Institute of Genetics and Biophysics (IGB))
Giaccari, Carlo (Institute of Genetics and Biophysics (IGB))
Sparago, Angela (Università Degli Studi Della Campania "Luigi Vanvitelli")
Hernandez Mora, José Ramon (Institut d'Investigació Biomèdica de Bellvitge)
Monteagudo-Sánchez, Ana (Institut d'Investigació Biomèdica de Bellvitge)
Esteller, M (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras)
Pereda, Arrate (Araba University Hospital-Txagorritxu)
Tenorio-Castano, Jair (ITHACA. European Reference Network)
Palumbo, Orazio (Fondazione IRCCS "Casa Sollievo Della Sofferenza")
Carella, Massimo (Fondazione IRCCS "Casa Sollievo Della Sofferenza")
Prontera, Paolo (Medical Genetics Unit. University and Hospital of Perugia)
Piscopo, Carmelo ("Antonio Cardarelli" Hospital)
Accadia, Maria (Hospital "Cardinale G. Panico")
Lapunzina, Pablo (ITHACA. European Reference Network)
Cubellis, Maria Vittoria (Università Degli Studi Di Napoli "Federico II")
Pérez de Nanclares, Guiomar (Araba University Hospital-Txagorritxu)
Monk, David (University of East Anglia)
Riccio, Andrea (Institute of Genetics and Biophysics (IGB))
Cerrato, Flavia (Università Degli Studi Della Campania "Luigi Vanvitelli")
Universitat Autònoma de Barcelona

Date:	2022
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.
Grants:	Instituto de Salud Carlos III PI20/00950
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Multi-locus imprinting disturbance ; Beckwith-Wiedemann syndrome ; Pseudohypoparathyroidism ; Genomic imprinting ; DNA methylation ; Maternal-efect variants ; Subcortical maternal complex ; Recurrent pregnancy loss ; Infertility
Published in:	Clinical Epigenetics, Vol. 14 Núm. 1 (december 2022), p. 71, ISSN 1868-7083

DOI: 10.1186/s13148-022-01292-w
PMID: 35643636

15 p, 1.1 MB

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Research literature > UAB research groups literature > Research Centres and Groups (research output) > Health sciences and biosciences > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP) > Josep Carreras Leukaemia Research Institute
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