Why some family members onset and others not ?

A couple of questions in the Rare Diseases Day video  are about something that aHUS folk often talk about whenever they meet up. Why some in a family have aHUS and others do not?

Familial HUS began to be recognised when it appeared that in some families HUS was not a sporadic incident; but there was  more than one family member who had HUS; however the incidents were separated by years and not at the same time, which could be explained by HUS from ecoli poisoning.

It was suspected that genetic causes, that were passed down through generations ,were at play in familial HUS, or aHUS as it became known. It has become clear that it is predisposing genetic variants, that have been found within components of the Complement System, have predisposed some people to aHUS ; even though for some people specific  genetic variants have not been found yet. As aHUS is very rare , such  specific variants will be even rarer.

It is also not fully known why ,in families which are known to carry a predisposing genetic variant , some in the family onset with aHUS and others do not. In fact of all aHUS patients , research has found only 1 in 5 of them are from a family where there  has even been a history of aHUS. ( click here for data in Table 2)

The extent to which aHUS penetrates a family varies between each predisposing genetic variant, for some it can even be 100% ; whether across single generations ,or , even down through previous generations; but mostly it is incomplete.

Historically, aHUS probably would not be a recorded cause of death in countries where records are kept. But, where there are such records and a family history is known, it is possible to track back over a century or more to establish the symptoms of kidney failure which may feature in certificated reasons for death. In modern  times  HUS or renal failure would be clear indicators ,or  even odemia , a symptom of kidney failure leading to lung failure. Even very old fashioned terms like “ dropsy of the chest” may be indicative of kidney failure.

Such a search can show that aHUS can skip several generations over a century or more before it appears again.

 

The reason for that can be explained by a study of  penetrance of aHUS in three  families in Devon with a complement factor H variant . Twenty years ago this variant was the first ever genetic cause of aHUS to be identified in 1997.( click here for more information) .

The  Devon families were studied again nearly 20 years later; this time the  penetrance of the disease in the family was looked at; and also to find out if there were additional genetic factors which might explain it.

The families were approached, and,  where individuals agreed to participate each undertook genetic tests, which went beyond what those with aHUS even today would routinely experience in their diagnosis

The results of those tests were reported for those surviving family members who had  on set- there were nine ;and those predisposed but who  had not on set – there were eighteen.

In most respects all  the family members were very  much the same, but, in two  common genetic areas, there were noticeable differences.

The genetics of the study are complicated , but in the research paper , which published the results ( click here) it was reported that two small bits of Complement Factor H looked different between each group. In one bit all but one of those who had not onset had a similar version of it;  but those who had onset mostly did not. In the other bit, none of those who had onset had the version which most of those who  had not onset had .

The researchers concluded that those who onset had mutated bits of Complement Facor H  which put them at more risk of , or less protected from , having aHUS.

The featured image above  visually expresses what this means; that even if people have  identical aHUS predisposing mutations ( red circle) ; and face the same triggering events ( green circle ),  other small differences ( orange circle) may determine the actual outcome, and what is more who is  likely  to  onset with aHUS ( in the centre) .

Because these “other genetic factors”  are much more common in the general population ( doctors call them “polymorphisms”or “haplotypes ” )  it means that a non aHUS carrying parent can reverse  the less risky / protective  bits of  Complement in the aHUS carrying parent in their offspring.

The offspring may:

  • Not inherit the aHUS  predisposing variant – they will not get aHUS;
  • Inherit the predisposing variant, but also the protective/ less risk polymorphism- they will be very unlikely to have aHUS but might;
  • Inherit the predisposing variant and also the unprotective/greater risk “polymorphism”   from the other parent.- they will be at much more risk of having aHUS and  will probably be likely to do so, if a trigger is strong enough.

The study of the Devon Family can only be of  clinical significance to an aHUS family with that specific genetic variant ( called C3643C>G; p.Arg 1215 Gly in doctors’ speak)   : but the principles behind the study are just as applicable .

Celine’s family is  different and would need its  own explanation.

But Celine and Elena , aHUS can skip generations; and the small difference in brothers and sisters can mean they have a different experience of aHUS.

Will it be possible for aHUS families to have such detailed genetic profiling and personal counselling based on it is another question for research?