ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance

Eguzkine Ochoa, Sunwoo Lee, Benoit Lan-Leung, Renuka P. Dias, Ken K. Ong, Jessica A. Radley, Gustavo Pérez de Nanclares, Rosa Martinez, Graeme Clark, Ezequiel Martin, Luis Castaño, Leonardo Bottolo, Eamonn R. Maher

Research output: Contribution to journalArticlepeer-review


PURPOSE: Disruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research.

METHODS: We report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations.

RESULTS: Across a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified.

CONCLUSION: ImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.

Original languageEnglish
Pages (from-to)463-474
Number of pages12
JournalGenetics in medicine : official journal of the American College of Medical Genetics
Issue number2
Early online date3 Dec 2021
Publication statusPublished - Feb 2022


  • Diagnostic assay
  • Genomic imprinting
  • Imprinting disorders
  • Methylation
  • Multilocus imprinting disturbance


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