Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Erfan Aref-Eshghi; Eric G Bend; Samantha Colaiacovo; Michelle Caudle; Rana Chakrabarti; Melanie Napier; Lauren Brick; Lauren Brady; Deanna Alexis Carere; Michael A Levy; Jennifer Kerkhof; Alan Stuart; Maha Saleh; Arthur L Beaudet; Chumei Li; Maryia Kozenko; Natalya Karp; Chitra Prasad; Victoria Mok Siu; Mark A Tarnopolsky; Peter J Ainsworth; Hanxin Lin; David I Rodenhiser; Ian D Krantz; Matthew A Deardorff; Charles E Schwartz; Bekim Sadikovic

doi:10.1016/j.ajhg.2019.03.008

Diagnostic Utility of Genome-wide DNA Methylation Testing in Genetically Unsolved Individuals with Suspected Hereditary Conditions

Am J Hum Genet. 2019 Apr 4;104(4):685-700. doi: 10.1016/j.ajhg.2019.03.008. Epub 2019 Mar 28.

Authors

Erfan Aref-Eshghi¹, Eric G Bend², Samantha Colaiacovo³, Michelle Caudle³, Rana Chakrabarti³, Melanie Napier³, Lauren Brick⁴, Lauren Brady⁴, Deanna Alexis Carere⁵, Michael A Levy¹, Jennifer Kerkhof⁵, Alan Stuart⁵, Maha Saleh³, Arthur L Beaudet⁶, Chumei Li⁴, Maryia Kozenko⁴, Natalya Karp³, Chitra Prasad³, Victoria Mok Siu³, Mark A Tarnopolsky⁴, Peter J Ainsworth¹, Hanxin Lin¹, David I Rodenhiser⁷, Ian D Krantz⁸, Matthew A Deardorff⁸, Charles E Schwartz², Bekim Sadikovic⁹

Affiliations

¹ Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada.
² Greenwood Genetic Center, Greenwood, SC 29646, USA.
³ Medical Genetics Program of Southwestern Ontario, London Health Sciences Centre, London, ON N6A 5W9, Canada.
⁴ Department of Pediatrics, McMaster University, Hamilton, ON L8S 4L8, Canada.
⁵ Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada.
⁶ Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
⁷ Department of Pediatrics, Biochemistry and Oncology, Western University, London, ON N6A 3K7, Canada.
⁸ The University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
⁹ Department of Pathology and Laboratory Medicine, Western University, London, ON N6A 3K7, Canada; Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON N6A 5W9, Canada. Electronic address: bekim.sadikovic@lhsc.on.ca.

Abstract

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.

Keywords: DNA methylation; clinical epigenomic testing; congenital anomaly; epi-signature; epi-variant; imprinting; multiclass prediction; neurodevelopmental syndrome; nucleotide expansion repeat; unresolved case; variant of unknown significance.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cohort Studies
Computer Simulation
Congenital Abnormalities / diagnosis
Congenital Abnormalities / genetics*
DNA Copy Number Variations
DNA Methylation*
Epigenomics
Gene Dosage
Genetic Diseases, Inborn / diagnosis*
Genetic Diseases, Inborn / genetics
Genetic Variation
Genome-Wide Association Study*
Genomic Imprinting
Humans
Phenotype
Sequence Analysis, DNA
Syndrome
Trinucleotide Repeat Expansion