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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.

Authors
  • Pignata, Laura1
  • Cecere, Francesco1, 2
  • Verma, Ankit2
  • Hay Mele, Bruno3
  • Monticelli, Maria3
  • Acurzio, Basilia2
  • Giaccari, Carlo2
  • Sparago, Angela1
  • Hernandez Mora, Jose Ramon4
  • Monteagudo-Sánchez, Ana4
  • Esteller, Manel5, 6, 7, 8
  • Pereda, Arrate9
  • Tenorio-Castano, Jair10, 11, 12
  • Palumbo, Orazio13
  • Carella, Massimo13
  • Prontera, Paolo14
  • Piscopo, Carmelo15
  • Accadia, Maria16
  • Lapunzina, Pablo10, 11, 12
  • Cubellis, Maria Vittoria3
  • And 4 more
  • 1 Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università Degli Studi Della Campania "Luigi Vanvitelli", Caserta, Italy. , (Italy)
  • 2 Institute of Genetics and Biophysics (IGB), "Adriano Buzzati-Traverso", Consiglio Nazionale Delle Ricerche (CNR), Naples, Italy. , (Italy)
  • 3 Department of Biology, Università Degli Studi Di Napoli "Federico II", Naples, Italy. , (Italy)
  • 4 Cancer Epigenetic and Biology Program (PEBC), Imprinting and Cancer Group, Institut d'Investigació Biomedica de Bellvitge (IDIBELL), Avinguda Granvia, L'Hospitalet de Llobregat, Barcelona, Spain. , (Spain)
  • 5 Josep Carreras Leukeamia Research Institute, Can Ruti, Cami de les Escoles, Badalona, Barcelona, Spain. , (Spain)
  • 6 Centro de Investigacion Biomedica en Red Cancer (CIBERONC), Madrid, Spain. , (Spain)
  • 7 Institucio Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. , (Spain)
  • 8 Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain. , (Spain)
  • 9 Molecular (Epi)Genetics Laboratory, Rare Diseases Research Group, Bioaraba Health Research Institute, Araba University Hospital-Txagorritxu, C/Jose Atxotegi s/n, 01009, Vitoria-Gasteiz, Spain. , (Spain)
  • 10 CIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain. , (Spain)
  • 11 Institute of Medical and Molecular Genetics, INGEMM-Idipaz, Madrid, Spain. , (Spain)
  • 12 ITHACA, European Reference Network, Brussels, Belgium. , (Belgium)
  • 13 Division of Medical Genetics, Fondazione IRCCS "Casa Sollievo Della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy. , (Italy)
  • 14 Medical Genetics Unit, University and Hospital of Perugia, Perugia, Italy. , (Italy)
  • 15 Medical and Laboratory Genetics Unit, "Antonio Cardarelli" Hospital, 80131, Naples, Italy. , (Italy)
  • 16 Medical Genetics Service, Hospital "Cardinale G. Panico", 73039, Tricase, Lecce, Italy. , (Italy)
  • 17 School of Biological Sciences, University of East Anglia, Norwich, NR4 7TG, UK.
  • 18 Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università Degli Studi Della Campania "Luigi Vanvitelli", Caserta, Italy. [email protected] , (Italy)
  • 19 Institute of Genetics and Biophysics (IGB), "Adriano Buzzati-Traverso", Consiglio Nazionale Delle Ricerche (CNR), Naples, Italy. [email protected] , (Italy)
  • 20 Department of Environmental Biological and Pharmaceutical Sciences and Technologies (DiSTABiF), Università Degli Studi Della Campania "Luigi Vanvitelli", Caserta, Italy. [email protected] , (Italy)
Type
Published Article
Journal
Clinical Epigenetics
Publisher
Springer-Verlag
Publication Date
May 28, 2022
Volume
14
Issue
1
Pages
71–71
Identifiers
DOI: 10.1186/s13148-022-01292-w
PMID: 35643636
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. © 2022. The Author(s).

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