TY - JOUR
T1 - First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders
AU - Mackay, Deborah
AU - Bliek, Jet
AU - Kagami, Masayo
AU - Tenorio-Castano, Jair
AU - Pereda, Arrate
AU - Brioude, Frédéric
AU - Netchine, Irène
AU - Papingi, Dzhoy
AU - de Franco, Elisa
AU - Lever, Margaret
AU - Sillibourne, Julie
AU - Lombardi, Paola
AU - Gaston, Véronique
AU - Tauber, Maithé
AU - Diene, Gwenaelle
AU - Bieth, Eric
AU - Fernandez, Luis
AU - Nevado, Julian
AU - Tümer, Zeynep
AU - Riccio, Andrea
AU - Maher, Eamonn R.
AU - Beygo, Jasmin
AU - Tannorella, Pierpaola
AU - Russo, Silvia
AU - de Nanclares, Guiomar Perez
AU - Temple, I. Karen
AU - Ogata, Tsutomu
AU - Lapunzina, Pablo
AU - Eggermann, Thomas
N1 - Funding Information: Open Access funding enabled and organized by Projekt DEAL. The authors are supported by the following grants: Deutsche Forschungsgemeinschaft (to TE: EG 115/13-1). 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). Instituto de Salud Carlos III of the Ministry of Economy and Competitiveness (Spain) (to PL: grants # FIS 20/01053, IMPACT project 20/IMP00009). Italian Ministry of Health RC 08C724, 08C502 (to SR and PT). Wellcome Trust (WT098395/Z/12/Z, to EdF). IKT is supported in part by the Southampton NIHR Biomedical Research Centre, UK (2017-2022, IS-BRC-1215-20004). ERM thanks the NIHR Cambridge Biomedical Research Centre for research support. The University of Cambridge has received salary support for ERM from the NHS in the East of England through the Clinical Academic Reserve. The views expressed are those of the authors and not necessarily those of the NHS or Department of Health (ERM and IKT). EDF is a Diabetes UK RD Lawrence Fellow (19/005971). MK and TO are funded by the Japan Agency for Medical Research and Development (AMED) (20ek0109373h0003, 22ek0109587). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - 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.
AB - 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.
KW - Genetic testing
KW - Imprinting disorders
KW - Multi-locus imprinting disorder
KW - Multi-locus testing
KW - Overlapping phenotypes
KW - Unexpected molecular diagnosis
UR - http://www.scopus.com/inward/record.url?scp=85141474599&partnerID=8YFLogxK
U2 - https://doi.org/10.1186/s13148-022-01358-9
DO - https://doi.org/10.1186/s13148-022-01358-9
M3 - Article
C2 - 36345041
SN - 1868-7075
VL - 14
JO - Clinical epigenetics
JF - Clinical epigenetics
IS - 1
M1 - 143
ER -