Causes of EDS

Ehlers-Danlos syndrome (EDS) is a group of related genetic disorders that affect the structure and function of connective tissue, resulting in symptoms such as abnormally flexible joints and fragile skin. Mutations in at least 20 different genes are known to cause different types of EDS, though in some cases, the underlying genetic cause is unknown.

Collagen and EDS

Many EDS-causing mutations affect the production and function of collagen, a kind of structural protein that is the main component of the extracellular matrix — the net of proteins and other molecules that helps to keep cells in place and give bodily tissues their structure and shape. When collagen is not functioning correctly, the tissue becomes abnormally weak and fragile, which ultimately leads to EDS symptoms. There are several different kinds of collagen proteins, each of which has specific functions and roles in the body.

Mutations in genes that encode different kinds or parts of collagen proteins, such as COL1A1, COL1A2, COL3A1, COL5A1, COL5A2, and COL12A1, cause some types of EDS.

Other EDS-associated genes encode for proteins that either are involved in the production of collagen, or interact with mature collagen proteins in the extracellular matrix. These include ADAMTS2, FKBP14, PLOD1, TNXB, ZNF469, PRDM5, SLC39A13, B4GALT6, B4GALT7, CHST14, DSE, C1R, and C1S genes.

Mutations in different EDS types

EDS is currently divided into 13 different types, each of which has a characteristic set of clinical symptoms and is caused by mutations in different genes.

Classical EDS

Classical EDS is characterized by abnormally stretchy skin, mobile joints, and scarring. The vast majority of cases are caused by mutations in the COL5A1 or COL5A2 genes, both of which encode components of a form of collagen called type V collagen. More rarely, classical EDS may be caused by mutations in COL1A1, which codes for type I collagen.

Classical-like EDS

As its name implies, classical-like EDS is characterized by symptoms similar to those in classical EDS. However, the underlying causes of these types are different. Specifically, classical-like EDS is caused by mutations in the TNXB gene, which encodes for a protein called tenascin-X.

Tenascin-X plays an important role in organizing collagen and maintaining collagen structure. Sometimes, patients have genetic deletions that affect TNXB and also genes that are located nearby in the DNA.

Cardiac-valvular EDS

A rare form of the disease characterized by heart problems, cardiac-valvular EDS is associated with mutations in the COL1A2 gene, which encodes a component of type I collagen.

Arthrochalasia EDS

Arthrochalasia EDS is characterized by frequent hip dislocations. It’s caused by certain mutations in the COL1A1 or COL1A2 gene, both of which code for components of type 1 collagen.

Vascular EDS

Vascular EDS, generally considered the most severe form of the disease, is mostly caused by mutations in the COL3A1 gene, which codes for a protein that forms type III collagen. Some individuals with vascular EDS also carry mutations in the COL1A1 gene, which is required to form type I collagen.

Kyphoscoliotic EDS

Mutations in the genes PLOD1 or FKBP14 cause kyphoscoliotic EDS. This type of EDS is characterized by a sideways curvature and forward rounding of the spine called kyphoscoliosis.

PLOD1 encodes for an enzyme that makes a particular modification to an amino acid (the building blocks of proteins) that is needed to produce properly functioning collagen. The FKBP14 gene encodes for a protein that helps to fold newly formed proteins, including collagens precursors, into the correct three-dimensional shape needed for correct protein function.

Dermatosparaxis EDS

Dermatosparaxis EDS, a form of EDS characterized mainly by doughy and fragile skin, is caused by mutations in the ADAMTS2 gene. This gene codes for an enzyme that chemically modifies precursor collagen molecules to form mature, functional collagen proteins.

Brittle cornea syndrome

The main feature of brittle cornea syndrome (BCS) is thinning of the cornea, the outer layer that protects the eyes. There are two subtypes of this disease with different causes: BCS type 1 is caused by mutations in the ZNF469 gene, while BCS type 2 is caused by mutations in a gene called PRDM5.

Both ZNF469 and PRDM5 code for proteins that are thought to act as transcription factors — proteins that regulate how the genetic code is “read,” controlling which genes are expressed. These specific transcription factors are thought to control the expression of collagen-related genes.

Spondylodysplastic EDS

Spondylodysplastic EDS is characterized by bowing of limbs, a short stature, and unusually sparse hair, among other symptoms. Some cases are caused by mutations in the SLC39A13 gene, which encodes for a protein that is responsible for the transport of zinc ions through the cell membrane. Zinc, a mineral the body does not make on its own, is essential for the function of connective tissues.

Other cases are caused by mutations in the genes B4GALT6 or B4GALT7, both of which code for proteins that add sugar molecules to proteins — a type of chemical modification needed for the proper functioning of connective tissue.

Musculocontractural EDS

People with musculocontractural EDS are born with adducted thumbs and clubfoot. An adducted thumb is one that twists back over the palm of the hand, clenching in the fist, while a clubfoot is one that points inward and down.

Most cases of this type are caused by mutations in the CHST14 gene, which encodes for a protein that is responsible for chemical modifications needed for collagen and other proteins to work correctly.

More rarely, musculocontractural EDS may be caused by mutations in the gene DSE. This gene codes for the protein D4ST1, which helps to make a complex sugar molecule that’s needed to modify certain proteins, including some proteins in the extracellular matrix. Of note, DSE mutations have been linked with milder disease compared with CHST14 mutations.

Myopathic EDS

Myopathic EDS, which is characterized by muscle weakness and wasting, is caused by mutations in the COL12A1 gene, which encodes type XII collagen.

Periodontal EDS

The rarest form of EDS, periodontal EDS, is characterized by gum disease. This type of EDS is caused by mutations in the C1R or C1S genes. Both of these genes code for components of the complement system, a group of immune proteins in the blood. Research indicates that periodontal EDS-causing mutations lead to the production of complement proteins that interact abnormally with collagen and other components of connective tissue.

Hypermobile EDS

Hypermobile EDS is the most common form of EDS, and generally is considered the mildest form of the disease. Although hypermobile EDS is assumed to be a genetic condition, since it can be passed from parents to their biological children, the specific genetic mutation or mutations that cause the disease are unknown in the vast majority of cases. Some rare cases of hypermobile EDS have been linked with mutations in the TNXB or COL3A1 genes.

Inheritance of EDS

People with EDS can pass disease-causing mutations to their biological children; the specifics of how EDS is inherited depend on the particular gene and mutation.

For most genes, everyone inherits two copies, one from each biological parent.

Disease-causing mutations in some genes, like COL1A1, COL1A2COL3A1, C1R, and C1S, are inherited in an autosomal dominant manner, which means that one mutated copy of the gene is sufficient to cause disease. Patients with EDS caused by mutations in these genes have a 50% chance of passing the disease-causing mutation to their biological children.

Mutations in other genes — like TNXB, PLOD1, ADAMTS2, FKBP14 ZNF469 or PRDM5, SLC39A13, and CHST14 — are inherited in an autosomal recessive manner, which means that both copies of the gene must be mutated for the disease to develop. People with just one mutated copy of these genes are called “carriers,” because they will not develop EDS, but they can pass the disease-causing mutation to their children. If two carriers together have biological children, there is a 25% chance that each child will inherit both disease-causing mutations, and will therefore develop EDS. There also is a 50% chance that any child will be carriers themselves, and a 25% chance that they will not inherit any copy of the disease-causing mutation.

People with a family history of EDS can learn more by speaking with a genetic counselor before they have biological children.

In some genes, such as COL12A1, mutations can be inherited in either an autosomal recessive or autosomal dominant manner, depending on the specific mutation.

 

Last updated: Jan. 5, 2022, by Marisa Wexler MS

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