Previously unexplored genomic control regions hold the key to identifying the causes of rare disease

Scientists have discovered the cause of a rare condition within a part of the genome.


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Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product disrupts normal cellular function. Non-coding elements largely control this silencing, and their disruption might cause human disease.

A region of the genome that has received little attention in medical genetics has become the source of a rare illness. A group at the University of Exeter has discovered genetic alterations in an area that regulates the function of the genome by turning genes on or off. As a result, they have found a key that could help identify further causes of uncommon illnesses.

This research is a very unusual instance of a disease caused by mutations beyond the exome, the area of the genome that codes for genes. A gene called HK1 that ordinarily plays no part in the relevant body tissue, in this case, the pancreas, has, for the first time, been found to be impacted by alterations.

Scientists’ search for a genetic cause of Congenital Hyperinsulinism took a more complex path. In contrast to diabetes, this condition results in babies’ pancreas secreting excessive insulin. Babies may be born very large and experience low blood sugar-related issues. If the illness is not treated properly, the brain could run out of essential nutrients, resulting in learning disabilities or even death.

The team led by Dr. Sarah Flanagan at the University of Exeter has given answers and unlocked a new way of investigating the causes of many elusive rare diseases.

Dr. Flanagan explained: “We’ve struggled to determine what’s going on in these 50 percent of babies with no known genetic cause of Congenital Hyperinsulinism. We’ve been looking for defects in genes for years, but it remained frustratingly elusive.”

Scientists used advanced technology to sequence the genomes of 17 individuals with Congenital Hyperinsulinism. They found that the genetic variants that were causing the disease did not occur within a protein but within a ‘regulatory switch,’ which is important for turning on and off a protein in the pancreas.

Patients with Congenital Hyperinsulinism had their pancreas’ HK1 turned on due to genetic variations. Normally, the pancreas turns off the gene that causes insulin to be generated even when blood sugar levels are low. However, the scientists discovered that it was active, which meant it was trying to drop blood sugar to risky levels. This idea was supported by examining a special collection of pancreatic tissue.

Dr. Flanagan said“It’s incredibly important to be able to provide answers to parents who have been desperate to know the cause of their child’s condition. Now that the HK1 variants have been discovered, routine genome sequencing in sick children would be the perfect method to detect them at clinical diagnosis, allowing for improved outcomes. These findings also pave the way for improved treatment of this condition with the development of drugs that inhibit HK1, and consequently insulin production, being a real possibility.”

“Even more exciting is the potential for this approach to unlock causes of other genetic conditions. We now know that we need to look across the whole genome to find genetic changes that may affect regulatory switches. We need to focus on the proteins turned off in the disease-relevant organ tissue and study how and why they are turned off. That approach could rapidly advance genetics and provide answers and better treatments.”

Journal Reference:

  1. Wakeling, M.N., Owens, N.D.L., Hopkinson, J.R. et al. Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism. Nat Genet (2022). DOI: 10.1038/s41588-022-01204-x


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