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

DNA Methylation Genomics Genotype High-Throughput Nucleotide Sequencing
Beckwith–Wiedemann syndrome ImprintSeq MS-MLPA Maternal effect variants Multilocus imprinting disturbances Silver–Russell syndrome Whole-exome sequencing

Journal

Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977

Informations de publication

Date de publication:
01 03 2023
Historique:
received: 28 01 2023
accepted: 20 02 2023
entrez: 1 3 2023
pubmed: 2 3 2023
medline: 4 3 2023
Statut: epublish

Résumé

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. 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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1186/s13148-023-01453-5 PMID: 36859312 PMC: PMC9979536
pubmed: 36859312
doi: 10.1186/s13148-023-01453-5
pii: 10.1186/s13148-023-01453-5
pmc: PMC9979536
doi:

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

35

Informations de copyright

© 2023. The Author(s).

Références

J Med Genet. 2015 Jul;52(7):446-53
pubmed: 25951829
Horm Res Paediatr. 2013;80(6):457-65
pubmed: 24335096
Am J Med Genet A. 2022 Jun;188(6):1896-1903
pubmed: 35266280
Nat Rev Endocrinol. 2018 Apr;14(4):229-249
pubmed: 29377879
Clin Epigenetics. 2019 Mar 21;11(1):53
pubmed: 30898153
Am J Hum Genet. 2016 Sep 1;99(3):744-752
pubmed: 27545678
Hum Mol Genet. 2005 Apr 15;14 Spec No 1:R133-8
pubmed: 15809265
J Med Genet. 2003 Jan;40(1):62-4
pubmed: 12525545
Front Genet. 2019 Oct 15;10:955
pubmed: 31749829
Clin Epigenetics. 2016 Mar 01;8:23
pubmed: 26933465
Eur J Hum Genet. 2016 Feb;24(2):183-90
pubmed: 25898929
Am J Med Genet A. 2022 Jul;188(7):2209-2216
pubmed: 35365979
Genes (Basel). 2021 Aug 06;12(8):
pubmed: 34440388
Epigenetics. 2018;13(9):897-909
pubmed: 30221575
BMC Med Genet. 2016 Apr 14;17:29
pubmed: 27075368
Clin Epigenetics. 2022 May 28;14(1):71
pubmed: 35643636
Clin Epigenetics. 2021 May 26;13(1):119
pubmed: 34039421
Eur J Hum Genet. 2021 Apr;29(4):575-580
pubmed: 33221824
Int J Mol Sci. 2021 Mar 26;22(7):
pubmed: 33810554
Nucleic Acids Res. 2020 Nov 18;48(20):11394-11407
pubmed: 33053156
Genome Res. 2014 Apr;24(4):554-69
pubmed: 24402520
Clin Epigenetics. 2016 Jan 26;8:10
pubmed: 26819647
Genet Med. 2017 Apr;19(4):476-482
pubmed: 27632690
Nat Rev Endocrinol. 2017 Feb;13(2):105-124
pubmed: 27585961
Eur J Med Genet. 2022 Jun;65(6):104502
pubmed: 35427809
Clin Epigenetics. 2022 Mar 16;14(1):41
pubmed: 35296332
J Med Genet. 2018 Jul;55(7):497-504
pubmed: 29574422
Hum Mol Genet. 2002 May 15;11(11):1317-25
pubmed: 12019213
Nat Commun. 2015 Sep 01;6:8086
pubmed: 26323243
PLoS Genet. 2009 Mar;5(3):e1000423
pubmed: 19300480
Nat Rev Genet. 2019 Apr;20(4):235-248
pubmed: 30647469
Genet Med. 2019 Aug;21(8):1808-1820
pubmed: 30635621
Genet Med. 2022 Feb;24(2):463-474
pubmed: 34906518
Eur J Med Genet. 2009 Nov-Dec;52(6):415-6
pubmed: 19632365
Hum Reprod Update. 2015 Jul-Aug;21(4):555-7
pubmed: 25904658
Eur J Med Genet. 2017 Nov;60(11):618-626
pubmed: 28818477
Epigenomics. 2016 Jun;8(6):801-16
pubmed: 27323310
Eur J Hum Genet. 2009 May;17(5):611-9
pubmed: 19092779
Elife. 2022 Jan 20;11:
pubmed: 35049495
Hum Reprod. 2003 Dec;18(12):2508-11
pubmed: 14645164
Clin Epigenetics. 2022 Nov 7;14(1):143
pubmed: 36345041
Clin Epigenetics. 2020 Sep 14;12(1):139
pubmed: 32928291
Am J Med Genet A. 2005 Apr 15;134A(2):187-91
pubmed: 15723285
Reproduction. 2017 Dec;154(6):R161-R170
pubmed: 28916717
Hum Mol Genet. 2009 Dec 15;18(24):4724-33
pubmed: 19755383
Eur J Hum Genet. 2016 Oct;24(10):1377-87
pubmed: 27165005

Auteurs

Larissa Bilo (L)

Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Eguzkine Ochoa (E)

Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.

Sunwoo Lee (S)

Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.

Daniela Dey (D)

Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Ingo Kurth (I)

Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Florian Kraft (F)

Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Fay Rodger (F)

Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.
Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge, UK.

France Docquier (F)

Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.
Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge, UK.

Ana Toribio (A)

Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.
Stratified Medicine Core Laboratory NGS Hub, Department of Medical Genetics, University of Cambridge, Cambridge, UK.

Leonardo Bottolo (L)

Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.
MRC Biostatistics Unit, School of Clinical Medicine, University of Cambridge, Cambridge, UK.
The Alan Turing Institute, London, UK.

Gerhard Binder (G)

Pediatric Endocrinology, University Children's Hospital, Universiy of Tuebingen, Tuebingen, Germany.

György Fekete (G)

Department of Pediatrics, Semmelweis University, Budapest, Hungary.

Miriam Elbracht (M)

Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Eamonn R Maher (ER)

Department of Medical Genetics, University of Cambridge, Cambridge, CB2 0QQ, UK.

Matthias Begemann (M)

Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany.

Thomas Eggermann (T)

Medical Faculty, Institute for Human Genetics and Genome Medicine, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany. teggermann@ukaachen.de.

Articles similaires

Comprehensive comparative analysis and development of molecular markers for Lasianthus species based on complete chloroplast genome sequences.

Yue Zhang, Meifang Song, Deying Tang et al.
1.00
Genome, Chloroplast Phylogeny Genetic Markers Base Composition High-Throughput Nucleotide Sequencing

Planting density effect on poplar growth traits and soil nutrient availability, and response of microbial community, assembly and function.

Rongye Qiao, Zhen Song, Yinglong Chen et al.
1.00
Populus Soil Microbiology Soil Microbiota Fungi

Fasciola hepatica and Fasciola hybrid form co-existence in yak from Tibet of China: application of rDNA internal transcribed spacer.

Wenqiang Tang, Yule Zhou, Leyi Li et al.
1.00
Animals Cattle Tibet Fasciola Fascioliasis

Comparative genomic analysis and characterization of novel high-quality draft genomes from the coal metagenome.

Arunmozhi Bharathi Achudhan, Lilly M Saleena
1.00
Coal Metagenome Phylogeny Bacteria Genome, Bacterial

Classifications MeSH

questionsmedicales.fr › Phénomènes génétiques › Méthylation de l'ADN › Molecular characterisation of 36 multilocus...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Molecular characterisation of 36 multilocus...
questionsmedicales.fr › Phénomènes génétiques › Génotype › Molecular characterisation of 36 multilocus...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Séquençage nucléotidique à haut débit › Molecular characterisation of 36 multilocus...