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, 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, de Nanclares, Guiomar Perez, Monk, David, Riccio, Andrea and Cerrato, Flavia (2022) 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. Clinical Epigenetics, 14 (1). ISSN 1868-7075

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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.

Item Type: Article
Additional Information: Funding Information: The work was supported by the followings grants: INCIPIT H2020-MSCA-COFUND grant agreement—N. 665403 project (AR and AV), Associazione Italiana Ricerca sul Cancro IG 2020 N. 24405 (AR), “Progetti per la ricerca oncologica della Regione Campania” Grant: I-Cure (AR and FC), “Progetti competitivi intraAteneo” Programma V:ALERE (VAnviteLli pEr la RicErca) 2019 – grant MIRIAM from Università degli Studi della Campania "Luigi Vanvitelli” (AR, FC and AS), Instituto de Salud Carlos III (ISCIIII) of the Ministry of Economy and Competitiveness (Spain) (to GPdN and AP: PI20/00950), co-financed by the European Regional Development Fund, 2019 research unit grant from ESPE (to GdPN).
Uncontrolled Keywords: beckwith–wiedemann syndrome,dna methylation,genomic imprinting,infertility,maternal-effect variants,multi-locus imprinting disturbance,pseudohypoparathyroidism,recurrent pregnancy loss,subcortical maternal complex,molecular biology,genetics,developmental biology,genetics(clinical) ,/dk/atira/pure/subjectarea/asjc/1300/1312
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 07 Nov 2022 10:30
Last Modified: 23 Jul 2024 01:59
DOI: 10.1186/s13148-022-01292-w


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