Epigenetic defects in the human genome cause genetic disorders

For the first time, a new study has demonstrated that epigenetic defects in the human genome are very common and occur in an unlimited number of genes that lead to genetic disorders.

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Because the epigenetic variants we identify would not be detected by genome sequencing, yet can lead to the dysregulation and silencing of genes known to be linked with heritable diseases, our work shows that some types of disease-causing mutations will be missed by standard genetic testing that only looks at DNA sequence.”

Andrew Sharp, PhD, Associate Professor, Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai

Main findings

A team of researchers, headed by Dr. Andrew Sharp, an Associate Professor of Genetics and Genomic Sciences at Icahn School of Medicine at Mount Sinai, analyzed the DNA methylation profiles of over 23,000 individuals, leading to the first large-scale population survey of rare epigenetic defects in the human genome.

For the first time, the researchers discovered scores of epivariations, demonstrating that these variations are comparatively common events in humans. The team also showed that the epivariations are often linked to abnormal expression of genes, and several of these are estimated to influence genes that are implicated in Mendelian diseases.

The reported outcomes suggest that epivariations probably contribute to a major fraction of several different types of genetic disorders.

The research work also offers several new insights into the fundamental causes and biology of epivariations and demonstrates that while a few epivariations are induced by rare sequence variation that disturbs the regulatory elements, around one third also occurs somatically.

Therefore, a few epivariations are probably heritable events, whereas others are, perhaps, not passed on to the following generations. Additional examination of the data also detected several novel CGG repeat expansions that underlie certain epivariations.

The motivation of the research:

In the last 10 years, isolated reports of epigenetic defects that lead to genetic disorders, such as hereditary colon and breast cancers, have appeared in the literature. But these were believed to be very rare events.

The team sought to discover the prevalence of this kind of mutation in the human genome, establish their possible effect on all types of Mendelian diseases, and gain a deeper understanding of the biology and the underlying causes of epivariations.