First step towards a consensus strategy for multi-locus diagnostic testing of imprinting disorders

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 - © 2022. The Author(s).

PY - 2022/11/7

Y1 - 2022/11/7

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 - Humans

KW - Genomic Imprinting

KW - DNA Methylation

KW - Silver-Russell Syndrome/diagnosis

KW - Beckwith-Wiedemann Syndrome/diagnosis

KW - Growth Disorders/genetics

KW - Diagnostic Techniques and Procedures

U2 - 10.1186/s13148-022-01358-9

DO - 10.1186/s13148-022-01358-9

M3 - SCORING: Journal article

C2 - 36345041

VL - 14

JO - CLIN EPIGENETICS

JF - CLIN EPIGENETICS

SN - 1868-7075

IS - 1

M1 - 143

ER -