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Impact Case Study

Genetic study uncovers Ehlers-Danlos syndrome mutation

Scientists find links between a rare connective tissue disorder and mutations in a wound-healing gene called AEBP1.

17 April 2019

An international team of researchers has uncovered a genetic basis of a rare form of Ehlers-Danlos syndrome (EDS), improving diagnosis and classification of this potentially life-threatening disorder.  

Named after Edvard Ehlers and Henri-Alexandre Danlos, the dermatologists who first described the condition more than a century ago, EDS is a connective tissue disorder characterised by overly flexible joints, stretchy skin and fragile tissue, which can cause bruising, scarring and chronic pain. 

Today, EDS and its variants affect around one in 5,000 people of all ethnic backgrounds. There is no specific cure, but physical therapy can help manage discomfort and stress. There are broadly 13 types of EDS, and the severity and type of symptoms vary between people.  

Mutations at birth in several genes coding for collagen proteins, such as COL1A1, COL1A2 and COL3A1, have so far been associated with EDS, but other genes are also thought to be involved. A growing body of research points to the AEBP1 gene as a likely candidate, as this gene encodes the aortic carboxypeptidase-like protein (ACLP) that plays a key role in collagen assembly, connective tissue formation and tissue repair.  

The current study examined the AEBP1 gene in four people from three unrelated families who showed symptoms of EDS but had yet to be diagnosed. Previous tests had not revealed any abnormalities in their standard collagen-related genes. 

Analyses of skin samples showed all four had sub-normal collagen levels. Then, using a technique called exome sequencing, which involves gathering relevant DNA from the patients and parents in each family, the researchers were able to confirm variants in the AEBP1 gene.  

The study revealed the first patient inherited two different defective alleles of the AEBP1 gene, one from the mother and one from the father. The second patient inherited two identical defective alleles from both parents, who, along with an unaffected male sibling, are all carriers of the mutation. The third and fourth patients, who are siblings, had a AEBP1mutation that disrupts normal function of ACLP. Tests confirmed that the same defective allele was inherited from both parents, who are double first cousins sharing both sets of grandparents. 

Overall, the study confirms that mutations in both alleles of the AEBP1 gene are the cause of this so-called autosomal recessive subtype of EDS.  

The team, including the KACST-affiliated Fowzan Aluraya, whose work contributes to the Saudi Human Genome Project, King Abdulaziz City for Science and Technology (KACST), published their findings in The American Journal of Human Genetics.  

Accurate diagnosis of EDS and other complex disorders continues to be a subject of intense study. Given that all four patients in the present study also have foot deformities that have been associated with other forms of EDS, future research could examine the role of AEBP1 in bone development. 


  1. Blackburn, P. R., Xu, Z., Tumelty, K. E., Zhao, R. W., Monis, W. J. et al. Bi-allelic alterations in AEBP1 lead to defective collagen assembly and connective tissue structure resulting in a variant of Ehlers-Danlos syndrome. The American Journal of Human Genetics 102, 696–705 (2018).| article