Zebras, not horses: The genetic disease that can’t be sequenced

by EmilyMayArmstrong · July 19, 2019

Image Credit: Sajjad Sherally Fazel. No changes have been made. Avaliable under CC BY-SA 3.0 (https://tinyurl.com/coaaon8)

Growing up, I was a weird bendy kid. I used to run, dance, do gymnastics, cycle, and was uncontrollably energetic and fidgety. When I was 11 years old, my ankle slipped out of place. It was bright purple, puffy, and stopped me from dancing. When I was 13, my shoulder started dislocating every time I raised my arms to put a t-shirt on. By the age of 16, my fingers, toes, and wrists were clicking and cracking. By the age of 21 I was diagnosed with a heritable genetic disease called Ehlers Danlos Syndrome, or EDS. I was told I have the most common type, hypermobile EDS, but there was no genetic marker for it. It took me 10 years to be diagnosed, and it was only after I’d begun a Bachelor’s degree in genetics that I was taken seriously. What took me so long to be diagnosed?

Most of us have heard of Occam’s razor, and may have been told: “When you see hoof prints, think horses, not zebras”. It’s an age-old parable to remind trainee doctors that the simplest cause is most often the answer. For 10 years, I was called a hypochondriac, told I had an anxiety disorder, that it was growing pains. Sometimes, the easiest explanation is not always the correct diagnosis.

The Ehlers Danlos syndromes are a cluster of dominantly inherited collagen disorders. Collagen is the strongest and most abundant protein in the body, and it comes in numerous different forms. It gives our skin its bounce, our ligaments their flex, and our blood vessels their strength. Ehlers Danlos syndromes cause different types of collagen to lose their strength. This means skin, blood vessels, ligaments, and tendons all become weak.

EDS was first discovered in the early 20th century, but has been described as early as 400 BC by Hippocrates. The modern classification was made almost simultaneously by Edvard Ehlers, and Henri-Alexandre Danlos, from Denmark and France respectively. EDS affects approximately 1 in 5,000 people. It’s classified as a rare disease, but is this just because physicians are not properly trained to identify this condition? The average EDS patient has symptoms for 15 years before an official diagnosis. Because of this, the international symbol for EDS charities and research is, of course, the zebra.

Me, on the highest possible morphine dose in Glasgow’s Royal Infirmary after dislocating my entire left leg in 2017

Understandably, this causes a host of problems for EDS sufferers: easy bruising, dislocations, partial dislocations, digestive problems, severe fatigue, abnormal scarring, chiari malformations (when the brainstem slips out of the skull’s base), nervous system dysfunction, and unusual allergies. And those are just the physical symptoms. People with EDS are 19 times more likely to have ADHD (was diagnosed in 2018) , severe anxiety (diagnosed in 2002), and autism ¹².

The struggle to diagnose Ehlers Danlos syndromes

The first hurdle is acknowledging that sometimes it might be zebras and not horses causing the symptoms. The Ehlers Danlos Foundation recommends that “If you can’t connect the issues, think connective tissues”, and this moniker has been relatively fruitful in encouraging health care professionals to assess patients with seemingly unconnectable issues³. There are 13 types of EDS, some of which only have a handful of cases reported globally.

Luckily, 12/13 types of EDS have distinct and well-characterised disease-causing genes. These range from genes required for type 5 collagen production (Classical EDS, COL5A1 and COL5A2) to genes required for muscle contraction (Muscocontractual EDS, CHST14). The cause of any of these EDS subtypes can be due to gene deletions, mutations, or an increase in expression. Unfortunately, the most common type of EDS, the hypermobile type, has absolutely no known genetic markers. And for a genetic disease, that’s incredibly odd⁴.

How do you sequence a gene?

Normally, if a specific disease is expected, a DNA swab from blood, hair, or saliva is taken from the patient. The known, or suspected, disease-causing regions are amplified so there’s enough DNA to work with. From there, the DNA can be sequenced. This involves detecting the order of adenosine, cytosine, guanine, and thymine (the four DNA bases) in the DNA. If the bases are in the wrong order, for example, if one base is swapped for another this can cause a mutation, leading to a faulty version of the gene and the protein it codes for. Sometimes, entire genes are deleted too. In the 12/13 EDS variants that are characterised, the majority are caused by recessive mutations, meaning both parents need to carry the mutation for their offspring to be affected. Hypermobile EDS only needs one parent to carry the mystery mutation for their children to be affected⁵. In my case, both of my parents have a milder form of the disease, so my sister and I have symptoms on the more severe end of the spectrum.

A needle in a haystack: finding the cause

Why hasn’t the causative gene been identified yet? There are quite a few theories floating around. Unfortunately, the main reason is possibly due to financial constraints: we’re looking for a genetic needle in a global haystack. Luckily enough, a very rich mysterious benefactor (no, seriously), has donated £1,000,000 towards the sequencing efforts. This will involve sequencing the entire genomes of 1000 EDS hypermobile type sufferers globally, cross-comparing gene mutations, and hopefully finding the cause⁶.

A prime example of hypermobility in my elbow

Or, it may be possible that the disease is not caused by a structural deficiency in collagen at all. In 2016, a group of researchers discovered a gene expansion repeat, commonly found in patients with EDS hypermobility type. An expansion repeat is where a gene is copied more than once, which often directly translates to an increase in protein production⁷. Scientists at the National Institutes of Health identified a gene expansion common in people with many of the previously described symptoms. This gene codes for alpha tryptase, a protein found in the blood that is commonly involved in allergic responses⁸. More of a gene means more protein which means higher levels of alpha tryptase in the blood, ultimately meaning heightened responses to just about anything (in my case, I’m bizarrely allergic to cinnamon and aerosol propellants — no mulled wine at Christmas for me!)

The outlook for people with EDS can be vastly different. Whilst not life-threatening, hypermobile EDS can severely compromise the quality of life for a number of people. I’m lucky to (just about) be walking around on my own two feet, using a crutch occasionally. Others are tube fed, house-bound, and have little-to-no way to escape the excruciating pains caused by multiple daily dislocations. Still, there is hope, as sequencing efforts are well underway. Hopefully in a few years time, I’ll be writing a new article about the discovery of a brand-new disease-causing mutation, and hopefully, we can move towards prenatal testing, proper palliative care, and better diagnostics.

If you are diagnosed with Ehlers Danlos Hypermobility type, consider signing up for the 1000 genomes project, here.

This article was specialist edited by Kirstin Leslie and copy-edited by Caitlin Duncan.