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

These GEITP pages have often discussed epigenetic effects — which, as you recall, includes DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling. In contrast to genetic effects (in which alterations in DNA sequence contribute to the phenotype), epigenetic effects represent non-DNA-sequence events that can be heritable, as well as caused by environmental factors. There are now available assays to screen genome-wide for DNA-methylation and RNA-interference (miRNAs) associations of any trait, whereas histone modifications and chromatin remodeling still require more studies before any commercial assays can be developed. The attached article focuses on the screening and diagnosis of NeuroDevelopmental syndromes with or without Congenital Anomalies (ND/CA).

Some ND/CA have shown associations with copy number variants (CNVs; segments of the genome [which often include a gene or genes] are repeated, and the number of repeats varies between individual genomes in the human population), or with some rare DNA sequence variant. However, in a large proportion of cases, the underlying genetic etiology is not identified and/or there is no clinical diagnosis. In fact, a large proportion of genetic changes identified through genetic testing in a potentially relevant gene often are not clinically interpretable; these have been termed “Variants of Unknown clinical Significance” (VUS). Authors [see attached article] therefore have chosen DNA-methylation, in an attempt to explain the etiology for some of these ND/CA patients.

DNA-methylation (genetic variants that involve a change in DNA methylation patterns of a limited number of CpGs at a specific locus) is the most commonly studied epigenetic phenomena, and genome-wide screening assays are now commercially available. DNA-methylation has long been known to be involved in causation of a certain group of syndromes — such as imprinting conditions (e,g, Prader-Willi, Angelman,Silver-Russell, and Beckwith-Weidemann syndromes; Albright hereditary osteodystrophy, and uniparental disomy) and trinucleotide repeat expansion disorders (e.g. Huntington Disease, Spinobulbar Muscular Atrophy, at least six of the Spinocerebellar Ataxia types, Dentatorubro-Pallidoluysian Atrophy, Fragile X Syndrome, Fragile XE Mental Retardation, and Friedreich Ataxia).

Authors [in attached article] investigated genome-wide DNA-methylation analysis of peripheral blood in a cohort of 965 ND/CA-affected subjects without a previous diagnostic assumption and a separate assessment of rare epi-variants (DNA-methylation differences) in this cohort. They identified 15 subjects with syndromic Mendelian disorders, 12 subjects with imprinting and trinucleotide repeat expansion disorders; most importantly, they identified 106 subjects with rare epi-variants — a portion of which involved genes clinically or functionally linked to the subjects’ phenotypes. These data show that genomic DNA-methylation analysis can facilitate the molecular diagnosis of unresolved clinical cases and highlight the potential value of epigenomic testing in the routine clinical assessment of ND/CA patients. It is possible that epigenomic testing of this type, in a study of drug response or environmental toxicant toxicity, can also be successfully performed. 🙂


Am J Hum Genet 4 Apr 2o19; 104: 685-700

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