A frequent discussion on aHUS social media platforms is about “probabilities” and “percentages”.
The probabilities of someone inheriting an aHUS predisposing variant ( mutation) from their parents and the percentage of penetrance of the disease within a family.
Two different scenarios.
The ensuing discussion usually cites figures for genetic inheritance as 50/50 or 50% , and some, through their own family’s generation experience, concluded that that was their family’ ‘s genetic penetrance too.
Others cited other percentages and probabilities from what they have read or what genetic counsellors have told them.
Getting back to the basics the chances of inheriting a genetic mutation from a carrying parent is 50%. 50% of DNA comes from each parent. If both parents carry the same mutation (and this has happened) it would be 100%.
In a family where there are several siblings, say four , with one mutation carrying parent, the probability remains 50% chance each of the siblings.
However the mathematical probability of 2 , 3. or even 4 siblings inheriting becomes 25% , 12.5% and 6.2% respectively.
It is the toss of a coin for each and the probabilities for all halve at each toss of the coin.
To determine genetic penetrance rate in a family there is a need to define the family from an index patient and outward to how many generations have there been subsequently. And broaden it for siblings and cousins.
Imagine a family with an index patient who is a great grand parent, who had three children and all subsequent parents had three children too.
That family would have 40 members. The index patient has a predisposing mutation/variant. Others are determined by a toss of coin. “Heads!” then family member predisposed , “tails” then not.
If tails is tossed then all subsequent relations to that person are called “tails” too- they cannot be predisposed to aHUS.
If heads is tossed then all subsequent descendants face an individual coin toss. These are the results of coin tosses by the author for the imaginary family.
| Relative | Number | Heads Inherited/Index | Tails Not inherited | |
| Generation 1 | Great grand parent | 1 | 1 | – |
| Generation 2 | Grand Parent and siblings | 3 | 1 | 2 |
| Generation 3 | Parent and siblings | 9 | 3 | 6 |
| Generation 4 | Child | 27 | 5 | 22 |
| Total | All | 40 | 10 | 30 |
The coin toss resulted in 9 inheriting across and through the generations. So overall genetic penetrance percentages, including the index patient, is 10/40 or 25%.
Of course this is the penetrance of the pathogenic mutation.
What happens to those 10? They may or may not onset with the disease.
There are numerous factors still to be taken into account. Most important would be gender. Puberty and pregnancy are significant triggering factors” and other modifying genetic factors. Assuming these factors each combine to make an “unfavourable outcome” 50% of the time, then, maybe only 5 of the family would likely experience an onset (including the great grandparent).
Genetic penetrance and disease penetrance in this family would be 25% and 12.5% respectively.
Different tosses of the coin could create different outcomes. If another of the three “grand siblings” had tossed a head and not tail other penetrance outcomes could result.
The author through knowing his specific mutation which is shared with a distant aHUS family elsewhere has found a common ancestor from fourteen generations ago ( more than 500 years).
A twelve times great grandfather is an index family member, who may or may not have onset with aHUS, but whose mutation has been passed down at a 50/50 rate through subsequent generations thirteen times without it being switched by other parent ancestors’ DNA.
That is like tossing a coin 14 times and it always coming up heads.
A 16,384 to 1 or 0.000061% chance.
But it is what it is.
Where births and death years are known 11 ancestors in the pedigree had a median age of 64 years ( range 26- 83) . This was in centuries when the average life span was 40 to 50 years.
The 26 year old was a female ancestor whose year of death was the same as her child being born. Most probably a “pregnancy mediated genetic complement TMA case”.
All ancestors despite their relative longevity could have onset with aHUS but four of those ancestors did not have “aHUS type” causes of death on their official death certificates. One did, lung fluid overload which could have been due to kidney failure.
The five whose ages at death are known may or may not have onset. If more than 50% had then added to the other two above. Maybe five onset in total out of the eleven. Just under 50%.
There has also been a five generational skip of the disease in this specific line of the family, so far.
But some other parts of the family have had a different experience with roughly 50 percentage of each generation layers onsetting with the disease.
Predicting aHUS involves math(s) but clear definitions of family cohorts are needed for comparisons.
So set out the known pedigree for your family. Identify those who have onset or have been given a positive genetic result and determine an “index” for the family.
Then get a coin and “predict” the others’ inheritance and for those deemed susceptible then toss the coin again. Create your own potential genetic and disease penetrance percentages rates.
Roughly the global incidence of aHUS each year is about 0.5 per million of the population.
No more than 20% of those onset will have a familial connection with aHUS , whether known or unknown at the time. That is an incidence of no more than 0.1 per million. Roughly 800 or so new patients from families each year.
That would be a one in ten million of the global population chance! Small percentages and highly improbable.
Makes you think.
Article No. 733
