Epigenetic Variation May Be Responsible for Hereditary Disorders

Genomics researchers have suggested that some hereditary disorders are caused by epigenetic variation that modifies gene expression rather than by traditional mutation that changes the sequence of DNA bases.

Certain human traits such as neurodevelopmental disorders (NDs) and congenital anomalies (CAs) are believed to be primarily genetic in origin. However, even after whole-genome sequencing (WGS), a substantial fraction of such disorders remain unexplained.


To solve this mystery, investigators at the Icahn School of Medicine at Mount Sinai (New York, NY, USA) proposed that some cases of ND–CA were likely caused by aberrant DNA methylation leading to epigenetic variation (epivariation) that disrupted genome function.

To test this theory, the investigators compared DNA methylation profiles from 489 individuals with ND–CAs to 1534 samples from control subjects. In the May 25, 2018, online edition of the journal Nature Communications, they reported that epivariations frequently occurred in the human genome. De novo epivariations were significantly enriched in ND-CA cases, while RNAseq analysis showed that epivariations often had an impact on gene expression comparable to loss-of-function mutations.

"Our study suggests that these epigenetic mutations are a significant contributor to human disease," said senior author Dr. Andrew Sharp, associate professor of genetic and genomic sciences at the Icahn School of Medicine. "These findings can open up a whole new world in what we know about disease and genetic profiling. Investigating DNA methylation when profiling genomes for disease mutations could help us uncover causative defects in congenital and neurodevelopmental diseases that have eluded us for years."

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Icahn School of Medicine at Mount Sinai