Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders
The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith...
| Main Authors: | , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Taylor & Francis Group
2018-09-01
|
| Series: | Epigenetics |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/15592294.2018.1514230 |
| _version_ | 1797678890024435712 |
|---|---|
| author | L. Fontana M. F. Bedeschi S. Maitz A. Cereda C. Faré S. Motta A. Seresini P. D’Ursi A. Orro V. Pecile M. Calvello A. Selicorni F. Lalatta D. Milani S. M. Sirchia M. Miozzo S. Tabano |
| author_facet | L. Fontana M. F. Bedeschi S. Maitz A. Cereda C. Faré S. Motta A. Seresini P. D’Ursi A. Orro V. Pecile M. Calvello A. Selicorni F. Lalatta D. Milani S. M. Sirchia M. Miozzo S. Tabano |
| author_sort | L. Fontana |
| collection | DOAJ |
| description | The identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID. |
| first_indexed | 2024-03-11T23:06:30Z |
| format | Article |
| id | doaj.art-636a1de7037f49c083e24d8c49ec7ca6 |
| institution | Directory Open Access Journal |
| issn | 1559-2294 1559-2308 |
| language | English |
| last_indexed | 2024-03-11T23:06:30Z |
| publishDate | 2018-09-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Epigenetics |
| spelling | doaj.art-636a1de7037f49c083e24d8c49ec7ca62023-09-21T13:09:21ZengTaylor & Francis GroupEpigenetics1559-22941559-23082018-09-0113989790910.1080/15592294.2018.15142301514230Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disordersL. Fontana0M. F. Bedeschi1S. Maitz2A. Cereda3C. Faré4S. Motta5A. Seresini6P. D’Ursi7A. Orro8V. Pecile9M. Calvello10A. Selicorni11F. Lalatta12D. Milani13S. M. Sirchia14M. Miozzo15S. Tabano16Università degli Studi di MilanoFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoMBBM Foundation, San Gerardo MonzaPapa Giovanni XXIII HospitalFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoFondazione IRCCS Ca’ Granda - Ospedale Maggiore PoliclinicoInstitute for Biomedical TechnologiesInstitute for Biomedical TechnologiesInstitute for maternal and child health IRCCS Burlo GarofoloFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoASST LarianaFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoFondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoUniversità degli Studi di MilanoUniversità degli Studi di MilanoUniversità degli Studi di MilanoThe identification of multilocus imprinting disturbances (MLID) appears fundamental to uncover molecular pathways underlying imprinting disorders (IDs) and to complete clinical diagnosis of patients. However, MLID genetic associated mechanisms remain largely unknown. To characterize MLID in Beckwith-Wiedemann (BWS) and Silver-Russell (SRS) syndromes, we profiled by MassARRAY the methylation of 12 imprinted differentially methylated regions (iDMRs) in 21 BWS and 7 SRS patients with chromosome 11p15.5 epimutations. MLID was identified in 50% of BWS and 29% of SRS patients as a maternal hypomethylation syndrome. By next-generation sequencing, we searched for putative MLID-causative mutations in genes involved in methylation establishment/maintenance and found two novel missense mutations possibly causative of MLID: one in NLRP2, affecting ADP binding and protein activity, and one in ZFP42, likely leading to loss of DNA binding specificity. Both variants were paternally inherited. In silico protein modelling allowed to define the functional effect of these mutations. We found that MLID is very frequent in BWS/SRS. In addition, since MLID-BWS patients in our cohort show a peculiar pattern of BWS-associated clinical signs, MLID test could be important for a comprehensive clinical assessment. Finally, we highlighted the possible involvement of ZFP42 variants in MLID development and confirmed NLRP2 as causative locus in BWS-MLID.http://dx.doi.org/10.1080/15592294.2018.1514230beckwith-wiedemann syndromesilver-russell syndromemultilocus imprinting disturbancestargeted next-generation sequencingepigenotype-phenotype correlations |
| spellingShingle | L. Fontana M. F. Bedeschi S. Maitz A. Cereda C. Faré S. Motta A. Seresini P. D’Ursi A. Orro V. Pecile M. Calvello A. Selicorni F. Lalatta D. Milani S. M. Sirchia M. Miozzo S. Tabano Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders Epigenetics beckwith-wiedemann syndrome silver-russell syndrome multilocus imprinting disturbances targeted next-generation sequencing epigenotype-phenotype correlations |
| title | Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders |
| title_full | Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders |
| title_fullStr | Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders |
| title_full_unstemmed | Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders |
| title_short | Characterization of multi-locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15.5 related imprinting disorders |
| title_sort | characterization of multi locus imprinting disturbances and underlying genetic defects in patients with chromosome 11p15 5 related imprinting disorders |
| topic | beckwith-wiedemann syndrome silver-russell syndrome multilocus imprinting disturbances targeted next-generation sequencing epigenotype-phenotype correlations |
| url | http://dx.doi.org/10.1080/15592294.2018.1514230 |
| work_keys_str_mv | AT lfontana characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT mfbedeschi characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT smaitz characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT acereda characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT cfare characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT smotta characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT aseresini characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT pdursi characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT aorro characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT vpecile characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT mcalvello characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT aselicorni characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT flalatta characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT dmilani characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT smsirchia characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT mmiozzo characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders AT stabano characterizationofmultilocusimprintingdisturbancesandunderlyinggeneticdefectsinpatientswithchromosome11p155relatedimprintingdisorders |