Genetic Variants for Rare Disease More Common Than You’d Think

Researchers at Brigham and Women’s Hospital and Boston Children’s Hospital have found that screening healthy individuals for genetic risk factors for certain rare diseases may help identify more patients affected by these conditions, and even improve our understanding of disease pathology. These are the findings of the BabySeq and MedSeq Projects, which will be explored in more detail in a presentation at the upcoming 2018 American Society for Human Genetics meeting.

The projects involved the genome or exome sequencing of 269 adults and newborns, with the researchers looking at 5,000 genes. While some hereditary diseases are the result of mutations in multiple associated genes, the research team were specifically looking to identify risk variants for diseases believed to be caused by mutations in just one gene – known as monogenic conditions.

Rare hereditary cancers, cardiac problems and metabolic disorders are all examples of monogenic diseases. While they may be uncommon in the general population, these conditions can be life-threatening and patients can benefit from early diagnosis.

Of the 110 adults who underwent genome sequencing, 14.5 percent were found to carry an unanticipated risk variant for a rare disease; just over 11 percent of the 159 newborns had unexpected genetic changes. But the real benefit to this screening was realized for four adults and four newborns who were found to show clinical features consistent with a rare genetic condition that would otherwise have gone unnoticed.

In three of these cases, interventions were made to manage the genetic condition which turned out to be effective for these patients. What’s more, the screening made it possible for another newborn who was previously clinically diagnosed with a disease to have the underlying genetic cause of their condition identified.

“These results are unexpected and exciting, suggesting that if we examine enough well-established, disease-associated genes, we will unearth monogenic risk variants in more than ten percent of purportedly healthy individuals,” said Dr. Robert Green, a principal investigator on both projects and a clinical geneticist at Brigham and Women’s Hospital. “And if on the basis of these genetic clues, we carefully examine those individuals, we find that a quarter of them have previously unrecognized features of underlying disease – something that we might never have realized had we not performed genetic sequencing.”

Since genomic sequencing isn’t normally offered to healthy individuals in the context of everyday medicine, Green and his colleagues sought to determine whether there might be benefits to more routine screening. Of course, incorporating genomic sequencing into routine clinical practice would have significant economic effects, which is another aspect of the MedSeq and BabySeq programs.