Earlier this year in the series of articles following the Rare Disease Day video one featured a question by Elisabeth from Denmark ” Why my son and not me?”
The article can be seen HERE.
Recently Global Action has received an article from the eminent aHUS researcher Prof. Santiago Rodriqez de Cordoba from Spain.
it is about the risk of a complement variant ( the preferred term now to “mutation”) carrying member of an aHUS patient’s family onseting with aHUS.
The full article can be read at this link HERE.
What Santiago and his team did was to look at family records in the Spanish aHUS Registry. The Registry had 640 entries of which there was data for 96 families with pathogenic variants which predispose people to aHUS. Plus another 7 families with a “likely” pathogenic variants but it is not certain they can cause the disease..
Data was available for 372 individuals in those 103 family pedigrees.
In addition to whether those individuals had a rare aHUS pathogenic complement variants, they were also genetically tested for two “at more risk” polymorphisms i.e. genetic variants in complement which are common in the general population. The polymorphisms tested for were CFH- H3, which is strongly associated with the risk of aHUS and MCPggaac an important risk factor.
Overall those who had onset with aHUS were more likely to have at risk polymorphisms ( around 50% ) than those who were only pathogenic variant carriers.The 372 family members were then categorised into whether they had none, or one, or two pathogenic variants and whether they had CFH-H3, or MCPggaac, risk variants or both.
Of the 286 family members related to 80 index aHUS patients ( I.e. the original family member who had aHUS) who had only one disease predisposing variant, 134 members also had the variant. So slightly more than half did not inherit the variant, Of those 134 who did only 10 had also onset with aHUS. Only one in sixteen of them by age 35 and 1 in 10 by age 48.
None of the members with no pathogenic variant had onset with aHUS, even though 80% of them had the “at risk” polymorphisms. These family members will not onset with aHUS.
Also of the non onsetting single pathogenic variant carriers, 30 % had no “at risk” polymorphism. They are unlikely to experience aHUS.
So 70% of those with a pathogenic variant are potentially at risk of aHUS. But as stated above only 10 ( with variants in C3 (2) , CFH (3) , CFB (3) and MCP (2) have actually onset. Of the 10, 4 had only the MCPggaac risk factor and 6 had both polymorphisms.
It is different matter for the 23 families with two pathogenic variants. Firstly, even with just having two pathogenic variants they have more risk of developing aHUS than those with one genetic variant. Three times the risk! Around 1 in 5 will have onset by age 35, increasing to 1 in 3 by reaching 44 years old. But when the “at risk” haplotypes are added, 1 in 2 onset by 35 , and all have onset by age 44.
Having aHUS is far from certain even if a person has a single pathogenic variant. Having ” at risk” polymorphisms, or not, influences their chances of onsetting, but not significantly.
But when carrying two pathogenic the chance of having aHUS increases, the odds shorten much further by having one “at risk” polymorphism and to certainty to onset in time if the carrier has the two at risk polymorphisms.
The table below summarises the risk of a family member also having aHUS according to pathogenic variants and polymorphisms they have.
|None||No risk||No risk||No risk||No risk|
|One||Highly unlikely||Low Risk||Low risk||Slightly higher risk|
|Two||Much higher risk||Very high risk||Very high risk||Certainty|
When it comes to someone’s aHUS genetic factors it is what it is. It was determined at conception. ”The moving finger writes and having writ moves on” ( Omar Khyyam), The disease also requires some environmental trigger too. Those genetically susceptible may face many of those hits during their life time and still not onset. But it will only be very few people, within what is a very rare disease anyway, who have a set of genetic circumstances where they face a certainty that they will onset at some time in their lives.
According to this important study for most carriers in aHUS families the outlook is not as threatening as it would seem. .
Whether people would welcome knowing not knowing their risks is a conundrum for all with genetic diseases, particularly so for one as complex and variable as aHUS. Many susceptible will have no idea of their genetic status, maybe not told even.
Genetic counselling for anyone found to have an aHUS predisposing variant presents challenges, because of the factors influencing penetrance. The polymorphism effect is one factor. Having two or more complement rare mutations can increase risk of aHUS but still not always, but with a 100% likelihood it will with ”at risk” polymorphisms. But if no mutations are found in some patients there is nothing to base genetic counselling on.
One final thought.
Although it was not within the scope of the research which inspired this article, if someone who is unlikely to onset even with a pathogenic variant but also with no “at risk” polymorphisms, has a partner with no pathogenic variant but with one or more of the two “at risk” polymorphisms, then there is a chance that any children they have who inherit the pathogenic variant may also inherit the “at risk” polymorphism and may likely onset at some point but more likely not.
aHUS could well skip a generation, even generation after generation after generation maybe and revert back somewhere down line.
So “why them not me” may be on the minds of that someone.
Article No. 542