Scientists at the University of Exeter have discovered the cause of a rare disorder, known as congenital hyperinsulinism (CHI), within a part of the genome that has been largely unexplored in medical genetics. The team found genetic changes in a noncoding region that controls turning genes on or off, which they say represents a very rare incidence of a disease being caused by genetic changes outside the exome. It is also the first time that variants have been shown to affect a regulatory gene, HK1, that is not normally switched on in the relevant tissue, in this case, the pancreas. The findings, the scientists suggest, could help unlock causes of other rare conditions.

Led by Sarah Flanagan, PhD, at the University of Exeter, the team reported on their study in Nature Genetics, in a paper titled, “Noncoding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism,” in which they concluded, “These findings are important for future efforts to discover noncoding regulatory variants as they establish a critical role for disallowed genes in Mendelian disease.”

“Until now, scientists have, for individuals with a rare disease, typically focused on sequencing the part of the genome that describes the genetic code of all genes. They do this by looking for variants in the DNA that affects a protein known to have an important role in the disease-relevant organ. A good example is observed in neonatal diabetes, where genetic variants disrupt the function of the pancreatic protein insulin, causing high blood sugar levels.

However, the team continued, this approach may not always be sufficient. “Genetic discovery in Mendelian disease has focused on identifying highly penetrant variants affecting the function of genes expressed in clinically affected tissue(s). While this approach has proven successful, the underlying etiology of over 3,000 presumed monogenic diseases remains undefined, of which many have notable clinical and genetic heterogeneity.”

In contrast to diabetes, congenital hyperinsulinism causes babies to secrete too much insulin from their pancreas. This means babies can be born very large, and suffer from problems associated with low blood sugar. If the condition is not treated appropriately, the brain can be starved of vital fuels, which can cause learning difficulties, or even death. Until now, scientists have been unable to find the genetic cause of the condition in up to half of babies with congenital hyperinsulinism—one reason why treatments are scarce. “CHI is characterized by inappropriate insulin secretion during hypoglycemia,” the authors further explained. “It is a clinically and genetically heterogeneous disease for which, despite extensive sequencing efforts, the underlying etiology is not known in up to 50% of individuals.”

The limited medications available often fail to work, sometimes meaning the patient has to endure their pancreas being removed. This often fails to cure the disease or in some cases can cause diabetes.

The search by Flanagan’s team for a genetic cause of congenital hyperinsulinism took a more complex path and has broken new ground—providing answers for families, and unlocking a new way of investigating the causes of many elusive rare diseases. “We’ve really struggled to work out what’s going on in these 50% of babies with no known genetic cause of congenital hyperinsulinism,” Flanagan explained. “We’ve been looking for defects in genes for years, but it remained frustratingly elusive.”

Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function,” the authors noted. “This silencing is largely controlled by noncoding elements, and their disruption might cause human disease.”

For their study, the researchers carried out what they described as “gene-agnostic screening” of the noncoding regions to look for new molecular causes of congenital hyperinsulinism. Using state-of-the-art technology the team sequenced the genomes of 17 individuals with congenital hyperinsulinism of unexplained cause. Their results revealed that the genetic variants responsible for 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. “All 17 individuals with a HK1 noncoding variant had severe early-onset CHI,” the scientists reported.

The impact of the genetic variants was that the gene, HK1—which leads to insulin being produced even when blood sugar levels are low—was turned on in the pancreas’ of patients with congenital hyperinsulinism. HK1 is usually turned off in the pancreas, but in the CHI patients with the regulatory element variants, HK1 was active in the patients—meaning it was working to lower blood sugar to dangerous levels. Studying a unique collection of pancreatic tissue confirmed this hypothesis.

“HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a ‘disallowed gene’ in these specific tissues,” the team wrote. “We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism.”

Flanagan stated, “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 specifically turn our attention to the proteins that are 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.”

The authors concluded, “Discovering noncoding regulatory variants controlling HK1 and access to a broad range of publicly available epigenomic data enabled us to identify a regulatory element critical for the selective silencing of an otherwise ubiquitously expressed gene within a single cell type … The identification of noncoding HK1 variants in individuals with CHI represents a rare example of regulatory noncoding variants affecting a gene in which coding variation does not cause the same phenotype. These findings highlight a role for undiscovered regulatory variants causing disease through inappropriate expression of a normally functioning protein in a specific cell type.”

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