Why?

One question that has been niggling at me since Finlay was born is simply, why?

I think this is a common question for parents of children with chronic conditions. Why? What went wrong? Did we do something wrong? In many cases it can all be mixed up with feelings of guilt or anger or both.

For me it was more of a simple why. Finlay had a genetic abnormality. We weren’t to blame. There was nobody for us to blame. It simply was. Our genes mutate between every generation. Sometimes it makes no difference, sometimes it might be advantageous, and sometimes, like with us, it could be pretty devastating. Mother Nature plays to her own rules. She is often beautiful and awe-inspiring. Occasionally she sucks!

So I have never felt guilt or anger. Frustration, yes, oh yes!! But anger, no.

But the one question that wouldn’t go away was why? A genetic mutation, but which gene? What could lead to such devastating abnormalities?

Well, two causes of absent pancreas were known. Recessive mutations in the Pdx1 or Ptf1a genes had been shown to cause pancreatic agenesis. In these cases each parent had a bad copy of the gene and when the child inherited both bad copies, the pancreas didn’t grow. But for Pdx1 mutations there was usually a family history of diabetes which we didn’t have, and those cases were only missing the pancreas, not the gall bladder and had no problems with the heart or any other organ. For the Ptf1a cases they also had cerebellar agenesis, meaning they were missing a large part of their brain, sadly a fatal condition. Neither of these genes seemed plausible for Finlay.

So, I looked for other cases. I searched out every case I could find in the literature, downloading papers or writing to clinicians in far-flung corners of the world to ask for reprints. I found about 30 cases of pancreatic agenesis. Some dead, some alive. A few with a known cause, most without. One thing I noticed was that about a third of the cases also had cardiac defects. Could they all have the same cause?

The other thing I noticed was that many of the cases were from consanguineous parents, i.e. the parents were related, quite often cousins, as is common in a number of cultures. The relevance of this is that if a mutated copy of a gene exists within a family, there is a far higher chance of two people from that family passing on two mutated copies to their children than if the parents are unrelated.

What struck me was that none of the cases with cardiac defects appeared to have related parents. If these cases were caused by the presence of two mutated copies of the same gene it could be expected that at least some of the cases would be from related parents due to the increased chance of passing on two mutated copies. But the absence of related parents suggested that these cases were caused by a single non-inherited mutation, a mutation present only in the child with the disease, not the parents.

But still, which gene? Sadly, this is about as far as I got. I considered lots of genes and came up with some possibilities, but there are over 20,000 genes in a human cell. A real needle in a haystack.

Fortunately, our DNA, along with Finlay’s had been sent to the Peninsula Medical School in Exeter, England. This is where the experts in monogenic diabetes are. And they had a cohort of samples from children just like Finlay. And they had some amazing pieces of technology. What they did next was they took our DNA and that of another child with no pancreas and cardiac defects and his parents and they sequenced our genes, all of them! They sequenced the genetic code of every single one of the 20,000+ genes in our cells, over 30 million pieces of genetic code from each one of us. Then they filtered through them looking for differences.

Since the mapping of the human genome a decade ago we have had a consensus sequence for what the genetic code of a human is. And each one of us has a slightly different version of this code. When they looked through Finlay’s genes they found over 23,000 differences, single letter changes or small deletions or additions to the code.

As this condition is rare they were expecting the mutations involved to be new to science. So the next thing they did was take out all the differences that had already been found in other humans using huge databases of genetic variation. Then they excluded all the ones that weren’t in coding parts of the genes, i.e. that weren’t involved in the sequence of the gene products or that didn’t change the gene product (protein). Next, because they were looking for a non-inherited mutation they removed any differences that were found in either parent.

After all this they were left with one single mutation.

Once they had done the same with the other child’s DNA they were also left with one single mutation. A different mutation… but in the same gene!

It seemed that one gene was the cause of the disease in both children.

Then they went back to the rest of their pancreatic agenesis cases and sequenced just this single gene. Of the 27 children in their cohort 15 had mutations in this gene, and all but one of those cases had cardiac defects. And in all the cases for which DNA from both parents was available the mutation was not found in either parent: it was a non-inherited mutation.

This Sunday past these clever people at Exeter published their findings online in the journal Nature Genetics adding another gene, GATA6, to the list of causes of monogenic diabetes. Science has an important addition to the understanding of how the pancreas develops.

Like many scientific advances, this finding asks as many questions as it answers; what is the mechanism that causes Finlay’s problems? Why is there so much variation in the symptoms of these children: some have no gall bladder, some have liver problems, some have developmental delay, some are prone to seizures.

Perhaps one day we’ll figure these out. But for now I have my answer.