In the model of the aHUS patient the concept of strong or weak aHUS disease causing genetic mutations is deployed not just having a predisposing mutation per se. This is new way to think about all mutations that have been found.
There is no accurate count of all those mutations but approximate numbers of reported aHUS-associated genetic variants (unique mutations/variants) in each major complement component, based on compilations in published articles puts the figures as follows
Unique variants (from a major literature aggregation of ~1,650 aHUS patients)
| Gene/Component | Approximate unique variants reported | Notes on patient frequency |
|---|---|---|
| CFH (Factor H) | ~180–220 | Most common; ~20–30% of aHUS patients |
| MCP/CD46 | ~70–80 | ~10–15% of patients |
| CFI (Factor I) | ~55–90 | ~5–10% (sometimes up to 15%) of patients |
| C3 | ~60 | ~5–10% (gain-of-function) of patients |
| CFB (Factor B) | ~20–30 | Rare; ~1–4% of patients |
| THBD (Thrombomodulin) | ~12–15 | Historically listed at ~3–5%; more recent large cohorts question its significant contribution and often treat isolated THBD variants similarly to mutation-negative cases |
This lists the number of different mutations found in each component. CFH has around 45% of all aHUS disease causing variants but only 20 to 30 % of all aHUS patients have these mutations but around 50% of all aHUS patients with a mutation.
It is interesting to see how long ago the first mutations in each complement component was found and by whom.
| Complement Component | Lead Researcher(s) / First Author | Publication Year | Key Paper Details |
|---|---|---|---|
| Factor H | Paul Warwicker (with T.H.J. Goodship group) | 1998 | Kidney International – linkage to 1q32 and first CFH mutations |
| Membrane cofactor protein (MCP) | Anna Richards | 2003 | PNAS – mutations predisposing to familial aHUS |
| Factor I | David Kavanagh | 2005 | Journal of the American Society of Nephrology – mutations predisposing to aHUS |
| Factor B | Elena Goicoechea de Jorge | 2007 | PNAS – gain-of-function mutations associated with aHUS |
| C3 | Véronique Frémeaux-Bacchi | 2008 | Blood – mutations predisposing to aHUS (gain- and loss-of-function) |
| Thrombomodulin | Mieke Delvaeye (with Marina Noris / Edward Conway group) | 2009 |
*Thrombomodulin is not a component of complement but is the last to be identified.
All discovered in Europe and three at what was to become the UKs aHUS Centre of Excellence.
For 17 years since no first mutation in any other component has been found to cause aHUS. Only more mutations/variants in the known disease predisposing components.
The number of mutation/variants in each primarily reflect unique variants catalogued from published aHUS cases (not the percentage of patients carrying a variant in that gene). Numbers continue to grow slowly with new reports; there is classification as pathogenic, likely pathogenic, or VUS strong to weaker , which evolves with new functional studies of variants found.
So with no more complement components implicated and and according to published literature there between 400 and 500 mutations/ found in the years since each was spotted for the first time, these can be spread over the top line in order of strength – from strongest to weakest – theoretically that is at present.
But there are around 30,000 prevalent patients today.
Some 40% of them have no known mutation and others have anti factor H antibodies, so that leaves 18,000 patients who have a known mutation, So it is possible that “on average” 36 patients share the same mutation. So not entirely genetically unique at least as far as aHUS is concenrened.
Everybody is different but where it important for aHUS some are the same.
Of course some may be member of the same family whether closely or distantly related with a common historic ancestor.
The latter is known as the Founder Effect i,e. a mutation that originated once in a common ancestor can spread in a population and appear in people who are not closely related by recent family history awareness. (see article number 600 for an example in one family)
Some times such families may be continents apart because of large historic population movement.
USA patients’ families may have had aHUS carrying ancestors coming from Europe and neither now know of the other. It is possible say that ancestors from a small area in Ireland may be have gone separate ways to the USA and England and current descendants would not of each yet aHUS is in each of the families today.
Also for some mutation the same can happen by chance. Some sites in complement genes are mutational “hotspots.” The same DNA change can arise independently in unrelated individuals. Even in rare variants it can happen by chance.
Overall from evidence of 1600 or so aHUS patients included in published articles which list specific genetic mutations around 450 different variants were found. An average of three to four patients share the same mutation. If multiplied 10 times for an estimated 16000 patients then that would be between 30 and 40 patients sharing a mutation.
There is no single definitive, up-to-date count of “strong” vs “weak” disease-causing variants for every complement component , because classification is ongoing, depends on functional data, population frequency, and the American College of Genetics and Genomics (ACMG) criteria, and many reported variants remain variants of uncertain significance (VUS). t studied)
One rigorous 2021 functional study expressed and tested a limited number , 105, of aHUS-associated Factor H variants, 79 were previously of undetermined disease causing and of these only about a third 29 were reclassified as disease causing the remainder were classified as benign or not causing.
When it comes to CFH is which part of its structure that the strength of the mutation is determined. More information about that can be seen in article number 531. This is what has been found for all components.
| Gene | Approximate unique variants reported | Strong / clear pathogenic (functional or enrichment support) | Weaker / VUS or likely benign |
|---|---|---|---|
| CFH | ~180–220 | Minority (~30–40% of tested) | Majority after functional review |
| MCP/CD46 | ~70–80 | Higher proportion of clear loss-of-function (expression or cofactor defects) | Still substantial VUS |
| CFI | ~55–90 | Many clear (secretion or activity defects); still many VUS | Significant number remain uncertain |
| C3 | ~60 | Most reported are gain-of-function and functionally supported when tested | Some VUS |
| CFB | ~20–30 | Majority of published ones are gain-of-function and considered strong when functionally confirmed | Fewer overall, but some uncertain |
| THBD | ~12–15 | Very few (if any) now regarded as strong; recent large cohorts find little enrichment | Most considered weak or non-contributory |
So strong disease causing variants are those with a clear impact of the workings of complement from testing them in practice or seen as staistically significant but not yet functionally tested.
But weak or uncertain mutations form a large part of all mutations found to date.
Having a strong or weak mutation will have an impact on tailoring future treatment if any is needed at all.
So in the model shown at the beginning of this article the minority of patients will be appearing to the right of the top line and the majority to the left.
Anyone with genetic test results should be able to know where their mutation(s) stands in the model and how in broad terms their tailored treatment might go.
Many of the weaker mutations may support discontinuation and most of the strong mutations may support life long therapy. And that basic tailoring of treatment may be shared with others who have the identical mutation.
Of course these patients may never know each other, nor will their doctors but when a test result comes back quite often the result is confirmed because it has been found elsewhere. But all parties are shielded by anonymity so cannot know what happened to some else.
Anyway everyone is counselled fully on their genetic results and their doctors know exactly what needs to be done. Don;t they?
However there is more to be explored than just the genetic predisposition when it comes to
Article No. 829
