Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Larissa Bilo; Eguzkine Ochoa; Sunwoo Lee; Daniela Dey; Ingo Kurth; Florian Kraft; Fay Rodger; France Docquier; Ana Toribio; Leonardo Bottolo; Gerhard Binder; György Fekete; Miriam Elbracht; Eamonn R. Maher; Matthias Begemann; Thomas Eggermann

doi:10.1186/s13148-023-01453-5

Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Larissa Bilo, Eguzkine Ochoa, Sunwoo Lee, Daniela Dey, Ingo Kurth, Florian Kraft, Fay Rodger, France Docquier, Ana Toribio, Leonardo Bottolo, Gerhard Binder, György Fekete, Miriam Elbracht, Eamonn R. Maher, Matthias Begemann, Thomas Eggermann

Aston Medical School

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking.

RESULTS: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues.

CONCLUSIONS: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.

Original language	English
Article number	35
Number of pages	12
Journal	Clinical epigenetics
Volume	15
Issue number	1
DOIs	https://doi.org/10.1186/s13148-023-01453-5
Publication status	Published - 1 Mar 2023

Bibliographical note

Copyright © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Keywords

DNA Methylation
Genomics
Genotype
High-Throughput Nucleotide Sequencing

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10.1186/s13148-023-01453-5

L Bilo et al_Molecular characterisation of 36 multilocus imprinting disturbance MLID patients
Copyright © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
Final published version, 1.58 MBLicence: CC BY 4.0

Cite this

Bilo, L., Ochoa, E., Lee, S., Dey, D., Kurth, I., Kraft, F., Rodger, F., Docquier, F., Toribio, A., Bottolo, L., Binder, G., Fekete, G., Elbracht, M., Maher, E. R., Begemann, M., & Eggermann, T. (2023). Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach. Clinical epigenetics, 15(1), Article 35. https://doi.org/10.1186/s13148-023-01453-5

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abstract = "BACKGROUND: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking.RESULTS: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues.CONCLUSIONS: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.",

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note = "Copyright {\textcopyright} The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. ",

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Bilo, L, Ochoa, E, Lee, S, Dey, D, Kurth, I, Kraft, F, Rodger, F, Docquier, F, Toribio, A, Bottolo, L, Binder, G, Fekete, G, Elbracht, M, Maher, ER, Begemann, M & Eggermann, T 2023, 'Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach', Clinical epigenetics, vol. 15, no. 1, 35. https://doi.org/10.1186/s13148-023-01453-5

TY - JOUR

T1 - Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

AU - Bilo, Larissa

AU - Ochoa, Eguzkine

AU - Lee, Sunwoo

AU - Dey, Daniela

AU - Kurth, Ingo

AU - Kraft, Florian

AU - Rodger, Fay

AU - Docquier, France

AU - Toribio, Ana

AU - Bottolo, Leonardo

AU - Binder, Gerhard

AU - Fekete, György

AU - Elbracht, Miriam

AU - Maher, Eamonn R.

AU - Begemann, Matthias

AU - Eggermann, Thomas

N1 - Copyright © The Author(s), 2023. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (https://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

PY - 2023/3/1

Y1 - 2023/3/1

N2 - BACKGROUND: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking.RESULTS: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues.CONCLUSIONS: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.

AB - BACKGROUND: Imprinting disorders (ImpDis) comprise diseases which are caused by aberrant regulation of monoallelically and parent-of-origin-dependent expressed genes. A characteristic molecular change in ImpDis patients is aberrant methylation signatures at disease-specific loci, without an obvious DNA change at the specific differentially methylated region (DMR). However, there is a growing number of reports on multilocus imprinting disturbances (MLIDs), i.e. aberrant methylation at different DMRs in the same patient. These MLIDs account for a significant number of patients with specific ImpDis, and several reports indicate a central role of pathogenic maternal effect variants in their aetiology by affecting the maturation of the oocyte and the early embryo. Though several studies on the prevalence and the molecular causes of MLID have been conducted, homogeneous datasets comprising both genomic and methylation data are still lacking.RESULTS: Based on a cohort of 36 MLID patients, we here present both methylation data obtained from next-generation sequencing (NGS, ImprintSeq) approaches and whole-exome sequencing (WES). The compilation of methylation data did not reveal a disease-specific MLID episignature, and a predisposition for the phenotypic modification was not obvious as well. In fact, this lack of epigenotype-phenotype correlation might be related to the mosaic distribution of imprinting defects and their functional relevance in specific tissues.CONCLUSIONS: Due to the higher sensitivity of NGS-based approaches, we suggest that ImprintSeq might be offered at reference centres in case of ImpDis patients with unusual phenotypes but MLID negative by conventional tests. By WES, additional MLID causes than the already known maternal effect variants could not be identified, neither in the patients nor in the maternal exomes. In cases with negative WES results, it is currently unclear to what extent either environmental factors or undetected genetic variants contribute to MLID.

KW - DNA Methylation

KW - Genomics

KW - Genotype

KW - High-Throughput Nucleotide Sequencing

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UR - http://www.scopus.com/inward/record.url?scp=85149427639&partnerID=8YFLogxK

U2 - 10.1186/s13148-023-01453-5

DO - 10.1186/s13148-023-01453-5

M3 - Article

C2 - 36859312

SN - 1868-7075

VL - 15

JO - Clinical epigenetics

JF - Clinical epigenetics

IS - 1

M1 - 35

ER -

Molecular characterisation of 36 multilocus imprinting disturbance (MLID) patients: a comprehensive approach

Abstract

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Keywords

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