Can multiple family members have different types of HAE or are they normally the same type?

Jun 29, 2015

Dr. C: Thank you to Janet Long of the HAEA for forwarding this question. Certainly with all of the numbers attached to HAE it does get confusing. The genetics of HAE type I and II are very simple. Their inheritance pattern is autosomal dominant with near complete penetrance. What this means is that if one parent has the disease, each child of that parent will have a 50% chance of inheriting the disease.  If the parent has type I HAE, then an affected child will have type I HAE. Conversely, if the parent has type II HAE, then an affected child will have type II HAE. Furthermore, the disease does not skip generations, meaning that the children of an unaffected child are not at risk of having HAE due to C1 inhibitor deficiency.


Dr. Z: This inheritance pattern can be nicely explained by the mutations that cause HAE due to C1 inhibitor deficiency. Except for the X and Y chromosomes, everyone has two copies of every gene – one copy inherited from the mother and the other copy inherited from the father. HAE due to C1 inhibitor deficiency occurs when a patient either inherits a mutated copy of SERPING1 (the gene that codes for C1 inhibitor) from one of their parents or less often has a new (de novo) mutation in the gene. It turns out that all of the mutations in the gene coding for C1 inhibitor that cause type II HAE (with a single exception) are clustered in a single region of the gene in there active mobile loop at or near the P1-P1’ target site of the inhibitor. In contrast, type I mutations are scattered through the rest of the gene. When a parent with HAE due to C1 inhibitor deficiency passes on their mutated SERPING1 gene to their child, that child will have the same type of HAE as the parent because the location of the mutation determines the type of HAE. While it is theoretically possible that a child could get the normal SERPING1 gene from their affected parent but suffer from a de novo type II HAE mutation, the probability of this happening is so infinitesimally tiny that it is not worth considering.


Dr. C: Thank you, Bruce. For HAE with normal C1 inhibitor it is as usual a bit more complicated. There are pedigrees of families where the disease may not be expressed and yet passed on to the next generation. As we have not identified the genetic culprit(s) we can only say that the pattern is inherited with incomplete penetrance (expression). It would however be the same disease once again. Bruce, what thoughts do you have for our readers?


Dr. Z: The best data comes from HAE with normal C1 inhibitor patients who have a factor XII mutation. As you described, Sandra, this disease can skip generations meaning that a child (especially male children) can inherit the mutation and not swell but yet pass the gene on to his children who may swell. This makes the genetics of HAE with normal C1 inhibitor much more difficult to study. Complicating the picture is the fact that the large majority of HAE with normal C1 inhibitor patients do not have a mutation in their factor XII gene. I agree with you that HAE with normal C1 inhibitor is likely to be a heterogeneous syndrome with multiple causes, each of which will need to be understood on its own. I tend to be an optimist, and I believe that we’ll have a much better handle on the genetics of HAE with normal C1 inhibitor within the next few years. As an aside, this is one of the reasons that many of us have disliked the terminology of HAE type III, as we don’t think that it is a single type. Another reason that we dislike the type III terminology is that it is very clear that HAE due to C1 inhibitor deficiency is very different in its genetics and inheritance from HAE with normal C1 inhibitor. It should be quite evident that the child of a HAE with normal C1 inhibitor parent is not at risk of having HAE due to C1 inhibitor deficiency (type I or type II). Similarly, the child of a parent with HAE due to C1 inhibitor deficiency is not at risk of having HAE with normal C1 inhibitor.


Dr. C: Thank you, hopefully this will add some clarity for our readers. We look forward to your input, and will be back next ‘question of the week’.


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