Preprint Variants in the Kallikrein Gene Family and Hypermobile Ehlers-Danlos Syndrome, 2024, Gensemer et al

Abstract

Hypermobile Ehlers-Danlos syndrome (hEDS) is a common heritable connective tissue disorder that lacks a known genetic etiology. To identify genetic contributions to hEDS, whole exome sequencing was performed on families and a cohort of sporadic hEDS patients.

A missense variant in Kallikrein-15 (KLK15 p. Gly226Asp), segregated with disease in two families and genetic burden analyses of 197 sporadic hEDS patients revealed enrichment of variants within the Kallikrein gene family.

To validate pathogenicity, the variant identified in familial studies was used to generate knock-in mice. Consistent with our clinical cohort, Klk15G224D/+ mice displayed structural and functional connective tissue defects within multiple organ systems.

These findings support Kallikrein gene variants in the pathogenesis of hEDS and represent an important step towards earlier diagnosis and better clinical outcomes.

https://www.researchsquare.com/article/rs-4547888/v1?redirect=/article/rs-4547888

 

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I just read this posted in a Long Covid Reddit and was about to post it here. It's just a pre-print but could @Jonathan Edwards take a look at it?

 

As far as I can see this is just a report of a gene variant in two families with EDS. I would forget the hEDS. In these families it is presumably the basis of their EDS, which I guess has limited visceral involvement and so comes under type III (hyper mobile type) although the knock in mice had other organs involved.

I don't think it is of any relevance to ME/CFS. It is just another very rare gene found in two EDS families. EDS isn't really a disease. It is a rag-bag of about a hundred different rare dominant gene defects affecting connective tissues.

 

I am not hypermobile so I don't have real personal interest in this area, other than curiosity.

I would agree that if it were just the two EDS families it would have no relevance to hEDS. However, given they looked at a larger cohort it seems like there is some signal there, even if these mutations did not occur in everyone.

@Jonathan Edwards if the finding that 33% of hEDS patients have a rare variant in the KLK gene was found to be generally applicable, do you think that would justify the use of the hEDS label in people who had that variant? Is it plausible that there are other variants that create generalized hypermobility issues without being caused by a single currently identified gene? Just like the EDS label refers to a set of rare gene defects affecting connective tissues, perhaps hEDS refers to a slightly different presentation due to different or multiple gene defects.

Of course, even if that is the case, the connection to ME/CFS would still be tenuous.

 

The basic point is that EDS is defined as a monogenic dominant or sex linked recessive disorder. There has always been a group called type III, or hypermobile only. The problem with the term hEDS is that it has become a standard term simply for hypermobility, which in 99% of cases will be polygenic and not EDS at all.

The only sensible thing to do at this stage is to reclassify EDS according to individual gene defect. The original set of types (maybe 13) were never based on anything other than vague similarity. There aren't 13 defects, there are many more. Each one will have a different spectrum of problems. Much better to identify each person as having EDS with gene mutation xyzzy and to stop using EDS or hEDS for a wider spectrum of hypermobility.

 

That makes a lot of sense to me, thanks