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Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions.
American journal of human genetics
  • Erfan Aref-Eshghi, Western University
  • Eric G Bend
  • Samantha Colaiacovo, London Health Sciences Centre
  • Michelle Caudle, London Health Sciences Centre
  • Rana Chakrabarti, London Health Sciences Centre
  • Melanie Napier, London Health Sciences Centre
  • Lauren Brick
  • Lauren Brady
  • Deanna Alexis Carere, London Health Sciences Centrre
  • Michael A Levy, Western University
  • Jennifer Kerkhof, London Health Sciences Centre
  • Alan Stuart, London Health Sciences Centre
  • Maha Saleh, London Health Sciences Centre
  • Arthur L Beaudet
  • Chumei Li
  • Maryia Kozenko
  • Natalya Karp, London Health Sciences Centre
  • Chitra Prasad, London Health Sciences Centre
  • Victoria Mok Siu, London Health Sciences Centre
  • Mark A Tarnopolsky
  • Peter J Ainsworth, Western University
  • Hanxin Lin, Western University
  • David I Rodenhiser, Western University
  • Ian D Krantz
  • Matthew A Deardorff
  • Charles E Schwartz
  • Bekim Sadikovic, Western University
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Conventional genetic testing of individuals with neurodevelopmental presentations and congenital anomalies (ND/CAs), i.e., the analysis of sequence and copy number variants, leaves a substantial proportion of them unexplained. Some of these cases have been shown to result from DNA methylation defects at a single locus (epi-variants), while others can exhibit syndrome-specific DNA methylation changes across multiple loci (epi-signatures). Here, we investigate the clinical diagnostic utility of genome-wide DNA methylation analysis of peripheral blood in unresolved ND/CAs. We generate a computational model enabling concurrent detection of 14 syndromes using DNA methylation data with full accuracy. We demonstrate the ability of this model in resolving 67 individuals with uncertain clinical diagnoses, some of whom had variants of unknown clinical significance (VUS) in the related genes. We show that the provisional diagnoses can be ruled out in many of the case subjects, some of whom are shown by our model to have other diseases initially not considered. By applying this model to a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants in this cohort, we identify 15 case subjects with syndromic Mendelian disorders, 12 case subjects with imprinting and trinucleotide repeat expansion disorders, as well as 106 case subjects with rare epi-variants, a portion of which involved genes clinically or functionally linked to the subjects' phenotypes. This study demonstrates that genomic DNA methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlights the potential value of epigenomic testing in the routine clinical assessment of ND/CAs.

Citation Information
Erfan Aref-Eshghi, Eric G Bend, Samantha Colaiacovo, Michelle Caudle, et al.. "Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions." American journal of human genetics Vol. 104 Iss. 4 (2019) p. 685 - 700
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