What’s new in rare disease research

Catch up with the latest in rare disorder research

Latest in Ehlers–Danlos syndrome diagnoses

Are earlier diagnoses and treatment improvements possible?

Ehlers–Danlos syndrome (EDS) is a hereditary, overlapping group of connective tissue disorders, classified clinically into three main groups, classical, vascular and hypermobility-type, but also include other rarer types. Traditionally, clinical and laboratory data are used in combination with Sanger sequencing of one or two of the most likely causative genes. Sanger sequencing is a type of first generation sequencing, which is now considered slow and expensive.

Sanger Sequencing
The Sanger sequencing method – Runs approximately 30 base pair analysis (exons)

DNA sequencing looks at the structure of DNA, which reveals the genes that are carried, also called the genotype. A clinical diagnosis uses characteristics that can be seen, i.e. that are observable, which is called the phenotype. Currently the genotype–phenotype relationship is used to make a diagnosis.

Earlier this year Weerakkody et al. published their research looking at next generation sequencing (NGS) in the diagnosis of EDS. By using this high throughput style sequencing, they were able to test 177 unrelated EDS patients. Their results highlighted all 22 variants identified by the Sanger method. However they also identified an additional 7 newly identified, pathogenic or likely pathogenic variants, leading to new diagnoses for these patients. They also discovered 18 variants of uncertain significance (VUS), of which 7, if pathogenic would mean an alteration to treatment. Four unexpected pathogenic or likely pathogenic variants were not identified by the Sanger sequencing.

Next Generation Sequencing
Next generation sequencing – Runs approximately 75–400 base pair per read and millions of reads per analysis

Sanger sequencing is now considered slow and expensive, whereas NGS features high throughput, high accuracy, and relatively low cost.

NGS could lead to earlier diagnosis by changing the way diagnoses are made, inform changes required in treatment for the benefit of the patient, improve understanding of the genotype–phenotype relationship and form the basis of preventative screening in relatives.

Current New Zealand diagnostics for EDS

Diagnosis of EDS in New Zealand is mainly achieved through clinical observations, supported by laboratory data. Where NGS is deemed of benefit, samples are usually sent abroad to laboratories in either Australia, USA or UK. For some cases with phenotypes overlapping classical or vascular EDS types, NGS testing could indicate a change in treatment that would be more beneficial for the patient’s health.

It is important to remember that for the majority of patients, clinical diagnosis and prescribed treatment would not alter as a result of NGS, so it may not be worth the extra cost. Also we need to bear in mind that NGS is not a diagnostic tool for hypermobility, the most common type of EDS. Therefore clinical diagnoses is still the main recommended course of action for EDS diagnosis in New Zealand.

Researcher pipetting DNA