TY - JOUR
T1 - 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
AU - Pignata, Laura
AU - Cecere, Francesco
AU - Verma, Ankit
AU - Hay Mele, Bruno
AU - Monticelli, Maria
AU - Acurzio, Basilia
AU - Giaccari, Carlo
AU - Sparago, Angela
AU - Hernandez Mora, Jose Ramon
AU - Monteagudo-Sánchez, Ana
AU - Esteller, Manel
AU - Pereda, Arrate
AU - Tenorio-Castano, Jair
AU - Palumbo, Orazio
AU - Carella, Massimo
AU - Prontera, Paolo
AU - Piscopo, Carmelo
AU - Accadia, Maria
AU - Lapunzina, Pablo
AU - Cubellis, Maria Vittoria
AU - de Nanclares, Guiomar Perez
AU - Monk, David
AU - Riccio, Andrea
AU - Cerrato, Flavia
N1 - 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).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/5/28
Y1 - 2022/5/28
N2 - 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.
AB - 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.
KW - Beckwith–Wiedemann syndrome
KW - DNA methylation
KW - Genomic imprinting
KW - Infertility
KW - Maternal-effect variants
KW - Multi-locus imprinting disturbance
KW - Pseudohypoparathyroidism
KW - Recurrent pregnancy loss
KW - Subcortical maternal complex
UR - http://www.scopus.com/inward/record.url?scp=85130798464&partnerID=8YFLogxK
U2 - 10.1186/s13148-022-01292-w
DO - 10.1186/s13148-022-01292-w
M3 - Article
C2 - 35643636
AN - SCOPUS:85130798464
VL - 14
JO - Clinical Epigenetics
JF - Clinical Epigenetics
SN - 1868-7075
IS - 1
M1 - 71
ER -