Nature Genetics: Untapped genomic control regions are key to discovering the causes of rare diseases

Unexplored regions of genomic control are key to discovering the causes of rare diseases

Scientists have discovered the cause of a rare disease that has largely remained unexplored
in medical genetics.
A team of researchers at the University of Exeter found genetic changes in a region that controls genomic activity, which controls the opening or closing
of genes.
In the process, they find a key that can unlock other causes of
rare diseases.

The finding, published in the journal Nature Genetics, is a very rare case in which disease is caused only by changes outside the exome, which is the region
of the genome that codes for genes.
It was also the first time that alterations have been found to affect a gene called HK1, which normally has no role in related body tissues, in this case the pancreas
.

Until now, scientists have typically sequenced
the part of the genome that describes all of the genetic code in individuals with rare diseases.
They did this to look for variations in DNA that affect a protein that plays an important role
in organs associated with disease.
A good example is neonatal diabetes, where genetic variants disrupt the function of the pancreatic protein insulin, leading to high blood sugar levels
.

The University of Exeter team has taken a more sophisticated approach
in looking for genetic causes of congenital hyperinsulinism.
In contrast to diabetes, this disease causes babies to secrete too much insulin
from the pancreas.
This means that babies can be born very large and suffer from problems
related to low blood sugar.
If this condition is not properly treated, the brain lacks vital energy, which can lead to learning difficulties and even death
.

Until now, scientists have not been able to find a genetic cause for this condition in up to half of babies born with congenital hyperinsulinism, which is one of the
reasons why treatments are scarce.
The limited availability of drugs often does not work, sometimes meaning that patients have to endure the removal
of the pancreas.
This usually does not cure the disease and in some cases can lead to diabetes
.

Now, a team led by Dr Sarah Flanagan of the University of Exeter has broken new ground – providing answers for families and opening up a new way to
study the causes of many elusive rare diseases.

Dr.
Flanagan explains: "We've been trying to figure out what really happens to these 50 percent of babies who don't have a known genetic cause
of congenital hyperinsulinism.
We've been looking for genetic defects for years, but frustratingly, it's still hard to find
.
”

Using state-of-the-art technology, the team sequenced the genomes of 17 patients with unexplained congenital hyperinsulinism, revealing a new discovery — that the genetic variation that causes the disease occurs not in proteins, but in a "regulatory switch" that is important
for turning a protein in the pancreas on and off.

The effect of genetic variation is that HK1 is turned on
in the pancreas in patients with congenital hyperinsulinism.
The gene produces insulin even when blood sugar levels are low, but it's normally turned off
in the pancreas.
But the team found that it was active, meaning it lowered blood sugar to dangerous levels
.
Studies of a unique set of pancreatic tissues confirm this hypothesis
.

Dr Flanagan said: "It is very important
to be able to provide answers to parents who are desperate to know the cause of their child's condition.
" "Now that the HK1 variants have been identified, routine genome sequencing in sick children would be the perfect way to detect them in clinical diagnosis and thus improve outcomes
.
" These findings also pave the way for improved treatment of the disease, making it practical to develop drugs that inhibit HK1 and thus insulin production
.
”

"What's even more exciting is that this approach has the potential to unravel the causes of
other genetic diseases.
" We now know that we need to look across the genome to find genetic changes
that may affect regulatory switches.
We need to pay special attention to those proteins that are turned off in organ tissues associated with disease and study how and why they are turned off
.
This approach could rapidly advance genetics, providing answers and better treatments
.
”