First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders.
Genetic testing
Imprinting disorders
Multi-locus imprinting disorder
Multi-locus testing
Overlapping phenotypes
Unexpected molecular diagnosis
Journal
Clinical epigenetics
ISSN: 1868-7083
Titre abrégé: Clin Epigenetics
Pays: Germany
ID NLM: 101516977
Informations de publication
Date de publication:
07 11 2022
07 11 2022
Historique:
received:
20
05
2022
accepted:
17
10
2022
entrez:
8
11
2022
pubmed:
9
11
2022
medline:
10
11
2022
Statut:
epublish
Résumé
Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses. We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories. Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.
Sections du résumé
BACKGROUND
Imprinting disorders, which affect growth, development, metabolism and neoplasia risk, are caused by genetic or epigenetic changes to genes that are expressed from only one parental allele. Disease may result from changes in coding sequences, copy number changes, uniparental disomy or imprinting defects. Some imprinting disorders are clinically heterogeneous, some are associated with more than one imprinted locus, and some patients have alterations affecting multiple loci. Most imprinting disorders are diagnosed by stepwise analysis of gene dosage and methylation of single loci, but some laboratories assay a panel of loci associated with different imprinting disorders. We looked into the experience of several laboratories using single-locus and/or multi-locus diagnostic testing to explore how different testing strategies affect diagnostic outcomes and whether multi-locus testing has the potential to increase the diagnostic efficiency or reveal unforeseen diagnoses.
RESULTS
We collected data from 11 laboratories in seven countries, involving 16,364 individuals and eight imprinting disorders. Among the 4721 individuals tested for the growth restriction disorder Silver-Russell syndrome, 731 had changes on chromosomes 7 and 11 classically associated with the disorder, but 115 had unexpected diagnoses that involved atypical molecular changes, imprinted loci on chromosomes other than 7 or 11 or multi-locus imprinting disorder. In a similar way, the molecular changes detected in Beckwith-Wiedemann syndrome and other imprinting disorders depended on the testing strategies employed by the different laboratories.
CONCLUSIONS
Based on our findings, we discuss how multi-locus testing might optimise diagnosis for patients with classical and less familiar clinical imprinting disorders. Additionally, our compiled data reflect the daily life experiences of diagnostic laboratories, with a lower diagnostic yield than in clinically well-characterised cohorts, and illustrate the need for systematising clinical and molecular data.
Identifiants
pubmed: 36345041
doi: 10.1186/s13148-022-01358-9
pii: 10.1186/s13148-022-01358-9
pmc: PMC9641836
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
143Subventions
Organisme : Wellcome Trust
ID : WT098395/Z/12/Z
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Informations de copyright
© 2022. The Author(s).
Références
Genes (Basel). 2021 Apr 17;12(4):
pubmed: 33920525
Am J Med Genet A. 2013 Jan;161A(1):13-20
pubmed: 23239666
Diabetologia. 2013 Apr;56(4):758-62
pubmed: 23385738
J Clin Ultrasound. 2020 May;48(4):240-243
pubmed: 31994200
Pediatr Blood Cancer. 2019 Jun;66(6):e27715
pubmed: 30882989
J Med Genet. 2018 Aug;55(8):567-570
pubmed: 29455159
Eur J Hum Genet. 2015 Feb;23(2):
pubmed: 24896151
Hum Reprod Update. 2020 Feb 28;26(2):197-213
pubmed: 32068234
Eur J Hum Genet. 2015 Nov;23(11):1488-98
pubmed: 25689926
Am J Med Genet A. 2013 Aug;161A(8):1929-39
pubmed: 23804593
Eur J Hum Genet. 2015 Feb;23(2):180-8
pubmed: 24801763
Am J Med Genet A. 2017 Jul;173(7):1735-1738
pubmed: 28475229
J Med Genet. 2021 Jun;58(6):427-432
pubmed: 32576657
Eur J Hum Genet. 2021 Apr;29(4):575-580
pubmed: 33221824
Eur J Hum Genet. 2019 Sep;27(9):1326-1340
pubmed: 31235867
Genet Res (Camb). 2019 Mar 4;101:e3
pubmed: 30829192
Clin Genet. 2017 Jul;92(1):45-51
pubmed: 28032339
Nat Rev Endocrinol. 2017 Feb;13(2):105-124
pubmed: 27585961
Clin Epigenetics. 2021 Apr 7;13(1):73
pubmed: 33827678
Endocr Connect. 2022 Oct 10;11(11):
pubmed: 36064195
Horm Res Paediatr. 2020;93(3):182-196
pubmed: 32756064
J Med Genet. 2018 Jul;55(7):497-504
pubmed: 29574422
Am J Med Genet A. 2018 Jan;176(1):175-180
pubmed: 29159982
Nat Rev Endocrinol. 2018 Apr;14(4):229-249
pubmed: 29377879
J Clin Endocrinol Metab. 2018 Jul 1;103(7):2436-2446
pubmed: 29659920
Mol Genet Genomic Med. 2017 Nov;5(6):668-677
pubmed: 29178649
Am J Hum Genet. 1993 Jan;52(1):8-16
pubmed: 8434609
Trends Genet. 2016 Jul;32(7):444-455
pubmed: 27235113
Genet Med. 2019 Nov;21(11):2644-2649
pubmed: 31147633
J Clin Endocrinol Metab. 2016 Oct;101(10):3657-3668
pubmed: 27428667
Clin Genet. 2017 Jan;91(1):3-13
pubmed: 27363536
Nat Commun. 2015 Sep 01;6:8086
pubmed: 26323243
Nat Rev Genet. 2019 Apr;20(4):235-248
pubmed: 30647469
Epigenetics. 2018;13(2):117-121
pubmed: 27911167
Genet Med. 2022 Feb;24(2):463-474
pubmed: 34906518
J Mol Med (Berl). 2020 Oct;98(10):1447-1455
pubmed: 32839827
Nat Genet. 2008 Aug;40(8):949-51
pubmed: 18622393
Eur J Hum Genet. 2014 Sep;22(9):
pubmed: 24736734
J Hum Genet. 2016 Feb;61(2):87-94
pubmed: 26377239
J Hum Genet. 2016 Aug;61(8):765-9
pubmed: 27121328
Eur J Med Genet. 2020 Dec;63(12):104077
pubmed: 33010492
Genet Med. 2017 Dec;19(12):1356-1366
pubmed: 28640239
Genet Med. 2021 Jun;23(6):1065-1074
pubmed: 33547396
Eur J Hum Genet. 2019 Nov;27(11):1649-1658
pubmed: 31186545
Reproduction. 2017 Dec;154(6):R161-R170
pubmed: 28916717
Nat Rev Endocrinol. 2018 Aug;14(8):476-500
pubmed: 29959430