Mutations Missed in Congenital Disease Screening

A type of genetic aberration has been identified as the cause of certain neurodevelopmental disorders and congenital diseases, such as autism and congenital heart disease, which are undetectable by conventional genetic testing.

The discovery that genetic mutations called epivariations are involved in these diseases could lead to more advanced diagnostic tools for many congenital and neurodevelopmental disorders. Epivariations are variations in the DNA molecule that do not affect the basic composition of the DNA molecule, called the DNA sequence, but result in a change in gene function.


An international team of scientists led by those at Icahn School of Medicine (New York, NY, USA) studied the genetic profiles of 489 patients with known neurodevelopmental or congenital disorders, who had all previously undergone genetic testing that identified no DNA mutations. These disorders had long been thought to have genetic origins, so the scientists suspected that even though conventional testing had not discovered a genetic cause for them, epivariations in their DNA could be present, resulting in gene dysfunction leading to disease.

To assess for epivariations, the team conducted methylation profiling, determining the DNA methylation within each patient's genome, finding epigenetic mutations that could be the cause of disease in approximately 20% of the studied cohort. Genome-wide DNA methylation profiling was performed using Human Methylation 450k BeadChips. Furthermore, in analyzing more than 5,000 genome profiles of individuals with no known diagnosis of congenital disease or neurodevelopmental disorder, the team discovered epigenetic mutations to be relatively common, and that they could typically be identified via a blood test.

The authors concluded that their study showed that epivariations are a relatively common feature in the human genome, that some are associated with changes in the local gene expression, and raise the possibility that they may be implicated in the etiology of developmental disorders. Andrew Sharp, PhD, an Associate Professor and lead investigator of the study, said, “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.” The study was published on May 25, 2018, in the journal Nature Communications.

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