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

Laura Pignata, Francesco Cecere, Ankit Verma, Bruno Hay Mele, Maria Monticelli, Basilia Acurzio, Carlo Giaccari, Angela Sparago, Jose Ramon Hernandez Mora, Ana Monteagudo-Sánchez, Manel Esteller, Arrate Pereda, Jair Tenorio-Castano, Orazio Palumbo, Massimo Carella, Paolo Prontera, Carmelo Piscopo, Maria Accadia, Pablo Lapunzina, Maria Vittoria CubellisGuiomar Perez de Nanclares, David Monk, Andrea Riccio, Flavia Cerrato

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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.

Original languageEnglish
Article number71
JournalClinical Epigenetics
Issue number1
Publication statusPublished - 28 May 2022


  • Beckwith–Wiedemann syndrome
  • DNA methylation
  • Genomic imprinting
  • Infertility
  • Maternal-effect variants
  • Multi-locus imprinting disturbance
  • Pseudohypoparathyroidism
  • Recurrent pregnancy loss
  • Subcortical maternal complex

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