Genetics and Inheritance of EDS and HSD

Genetics

DNA is the genetic material that we inherit from our parents. Genes are sections of DNA that provide instructions for making proteins. Proteins carry out most of the processes that allow our bodies to function.

Differences in our genes are normal. Genetic variation is what makes each of us unique – it is what separates a blue eye from a brown eye or curly hair from straight. These differences are the result of genetic variants.

Genetic variants are different versions of the same gene. Genes carry the instructions for making proteins, so different genetic variants can result in different proteins. These proteins give us our traits, or characteristics. One genetic variant of a gene may produce blue eyes, while another variant of the same gene may produce brown eyes.

Most genetic variants are harmless and do not negatively affect how the body functions. These are called benign variants. Some genetic variants are harmful because they contain errors in the instructions for making proteins. This can lead to faulty proteins that prevent the body from functioning properly, which can lead to illness. Harmful genetic variants are called pathogenic variants.

Genetic Testing 101 – Dr. Clair Francomano

The Ehlers-Danlos syndromes (EDS) are a group of genetic connective tissue disorders. Each type of EDS is caused by pathogenic variants of genes that provide the instructions for making connective tissue proteins. hEDS is the most common type of EDS, but the genetic cause(s) of hEDS are unknown. The other types of EDS are associated with specific pathogenic variants. Genetic testing is available for every type of EDS except for hEDS.

Type of EDS 

(In order of estimated prevalence)

Approximate PrevalenceAssociated Gene(s)Affected Protein(s)Inheritance Pattern

Distinguishing Features

1 in 3,100 – 5000UnknownUnknownAutosomal Dominant
  • Generalized joint hypermobility
  • Join instability
  • Chronic Pain
1 in 20,000 – 40,000COL5A1Type V collagenAutosomal Dominant
  • Skin fragility with extensive atrophic scarring
  • Very stretchy skin with velvety or doughy texture
COL5A2Type V collagen
COL1A1Type I collagen
1 in 100,000 – 200,000COL3A1Type III collagenAutosomal Dominant
  • Arterial fragility with aneurysm/dissection/rupture
  • Organ fragility and rupture
  • Extensive bruising
  • Pneumothorax
COL1A1Type I collagen
Less than 1 in 1,000,000C1RC1rAutosomal Dominant
  • Severe, early-onset gum disease with tooth loss
  • Pretibial plaques (discoloration of shins)
C1SC1s
Less than 1 in 1,000,000PLOD1LH1Autosomal Recessive
  • Congenital/early-onset kyphoscoliosis
  • Congenital hypotonia
FKBP14FKBP22
Less than 1 in 1,000,000B4GALT7β4GalT7Autosomal Recessive
  • Short stature
  • Muscle weakness
  • Limb bowing
  • Craniofacial features
B3GALT6β3GalT6
SLC39A13ZIP13
Less than 1 in 1,000,000ZNF469ZNF469Autosomal Recessive
  • Severe problems with the cornea of the eye
  • Hearing loss
PRDM5PRDM5
Less than 1 in 1,000,000COL1A1Type I collagenAutosomal Dominant
  • Severe joint hypermobility
  • Congenital bilateral hip dislocation
COL1A2Type 1 collagen
Less than 1 in 1,000,000CHST14D4ST1Autosomal Recessive
  • Congenital multiple contractures
  • Craniofacial features
DSEDSE
Less than 1 in 1,000,000TNXBTenascin XBAutosomal Recessive
  • Stretchy, velvety skin without atrophic scarring
  • Foot deformities
  • Leg swelling
Less than 1 in 1,000,000ADAMTS2ADAMTS-2Autosomal Recessive
  • Extreme skin fragility
  • Craniofacial features
  • Loose, excessive skin
  • Severe bruising
  • Short limbs
Less than 1 in 1,000,000COL12A1Type XII collagenAutosomal Dominant or Recessive
  • Congenital hypotonia
  • Proximal joint contractures
Less than 1 in 1,000,000COL1A2Type I collagenAutosomal Recessive
  • Severe heart valve insufficiency
  • Hypermobile EDS (hEDS) »

    Approximate Prevalence
    1 in 3,100 – 5000
    Associated Gene(s) and Affected Protein(s)
    Unknown (Unknown)
    Inheritance Pattern
    Autosomal Dominant
    Distinguishing Features
    Generalized joint hypermobility
    Joint instability
    Chronic pain
  • Classical EDS (cEDS) »

    Approximate Prevalence
    1 in 20,000 – 40,000
    Associated Gene(s) and Affected Protein(s)
    COL5A1 (Type V collagen)
    COL5A2 (Type V collagen)
    COL1A1 (Type I collagen)
    Inheritance Pattern
    Autosomal Dominant
    Distinguishing Features
    Skin fragility with extensive atrophic scarring
    Very stretchy skin with velvety or doughy texture
  • Vascular EDS (vEDS) »

    Approximate Prevalence
    1 in 100,000 – 200,000
    Associated Gene(s) and Affected Protein(s)
    COL3A1 (Type III collagen)
    COL1A1(Type I collagen)
    Inheritance Pattern
    Autosomal Dominant
    Distinguishing Features
    Arterial fragility with aneurysm/dissection/rupture
    Organ fragility and rupture
    Pneumothorax
  • Periodontal EDS (pEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    C1R (C1r)
    C1S (C1s)
    Inheritance Pattern
    Autosomal Dominant
    Distinguishing Features
    Severe, early-onset gum disease with tooth loss
    Pretibial plaques (discoloration of shins)
  • Kyphoscoliotic EDS (kEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    PLOD1 (LH1)
    FKBP14 (FKBP22)
    Inheritance Pattern
    Autosomal Recessive
    Distinguishing Features
    Congenital/early-onset kyphoscoliosis
    Congenital hypotonia
  • Spondylodysplastic EDS (spEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    B4GALT7 (β4GalT7)
    B3GALT6 (β3GalT6)
    SLC39A13 (ZIP13)
    Inheritance Pattern
    Autosomal Recessive
    Distinguishing Features
    Short stature
    Muscle weakness
    Limb bowing
    Craniofacial features
  • Brittle cornea syndrome (BCS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    ZNF469 (ZNF469)
    PRDM5 (PRDM5)
    Inheritance Pattern
    Autosomal Recessive
    Distinguishing Features
    Severe problems with the cornea of the eye
    Hearing loss
  • Arthrochalasia EDS (aEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    COL1A1 (Type I collagen)
    COL1A2 (Type I collagen)
    Inheritance Pattern
    Autosomal Dominant
    Distinguishing Features
    Severe joint hypermobility
    Congenital bilateral hip dislocation
  • Musculocontractural EDS (mcEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    CHST14 (D4ST1)
    DSE (DSE)
    Inheritance Pattern
    Autosomal Recessive
    Distinguishing Features
    Congenital multiple contractures
    Craniofacial features
  • Classical-like EDS (clEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    TNXB (Tenascin XB)
    Inheritance Pattern
    Autosomal Recessive
    Distinguishing Features
    Stretchy, velvety skin without atrophic scarring
    Foot deformities
    Leg swelling
  • Dermatosparaxis EDS (dEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    ADAMTS2 (ADAMTS-2)
    Interitance Pattern
    Autosomal Recessive
    Distinguishing Features
    Extreme skin fragility
    Craniofacial features
    Loose, excessive skin
    Severe bruising
    Short limbs
  • Myopathic EDS (mEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    COL12A1 (Type XII collagen)
    Inheritance Pattern
    Autosomal Dominant or Recessive
    Distinguishing Features
    Congenital hypotonia
    Proximal joint contractures
  • Cardiac-valvular EDS (cvEDS) »

    Approximate Prevalence
    Less than 1 in 1,000,000
    Associated Gene(s) and Affected Protein(s)
    COL12A2 (Type I collagen)
    Inheritance Pattern
    Autosomal Recessive
    Distinguishing Features
    Severe heart valve insufficiency

The Ehlers-Danlos syndromes are a group of heritable connective tissue disorders. Each type is caused by pathogenic genetic variants that prevent connective tissue from functioning properly. Twelve types of EDS have known genetic causes, and some types are associated with multiple different genes. The genetic cause(s) of hEDS have not been identified.

The genetic causes of hEDS have not been identified, but hEDS appears to follow a dominant inheritance pattern. There are several research studies around the world currently working to identify the genetic cause(s) of hEDS, including the Hypermobile Ehlers-Danlos Genetic Evaluation (HEDGE) Study. Researchers are also studying other factors that can contribute to the development of hEDS.

It is suspected that there are multiple genetic variants that cause hEDS. Several genetic variants have been associated with hEDS, but these variants represent a very small number of cases of hEDS, with some only being reported in one family. Genetic testing is not available for hEDS because the genetic cause of most cases is unknown. Instead, the diagnosis of hEDS is given to those who meet the clinical diagnostic criteria for hEDS.

The cause(s) of HSD have not been identified. Currently, we do not know if HSD is a genetic disorder. We do know that joint hypermobility tends to run in families, but not everyone with joint hypermobility has a type of HSD. More research is needed to better understand the cause(s) of HSD.

Genetic testing is used to identify differences in DNA. The results can be used to confirm or rule out specific genetic disorders. If a doctor suspects a person has a certain genetic disorder, they will test the gene(s) associated with that condition. The test can tell them if the person has the genetic variant(s) associated with that condition.

When genetic testing is ordered, a genetic sample (usually blood or saliva) is collected and sent to a lab. The lab will perform tests and report back information about a person’s genetic variants and whether they are known to be associated with any disease.

Genetic testing is available for every type of EDS except for hEDS. If a person meets the clinical diagnostic criteria for a type of EDS other than hEDS, genetic testing should be done to confirm the diagnosis. Because the genetic cause(s) of hEDS have not yet been identified, there is no genetic test for hEDS. hEDS is diagnosed when a person meets the clinical diagnostic criteria.

Because hEDS is the most common type, accounting for more than 90% of all cases of EDS, most people with EDS will not need genetic testing for diagnosis. It is not necessary for a person with hEDS or HSD to have genetic testing unless there is reason to suspect that they may have a genetic disorder for which testing is available.

Next-generation sequencing (NGS) is the most common approach for diagnosing most types of EDS. NGS can be used to identify what genetic variants a person has of specific gene(s) of interest. Targeted sequencing can be used to look at a single gene or a group of genes, known as a gene panel. Some labs offer an “Ehlers-Danlos syndrome panel” or “connective tissue disorder panel” that includes many of the genes known to cause types of EDS and other heritable connective tissue disorders. Doctors can also request testing of specific genes based on the signs and symptoms a person has.

Whole genome sequencing (WGS) can be used to look at all of a person’s DNA. Whole exome sequencing (WES) can be used to look at all the DNA expressed in the body. These tests are typically used for research, such as identifying new pathogenic genetic variants. Single gene tests and gene panels provide a much more targeted approach when looking for specific genetic variants in genes of interest.

If no pathogenic variants are identified through sequencing, a copy number variant (CNV) detection strategy can be used to identify large duplications and deletions. If genetic testing is not available, other techniques can be used to detect differences in proteins that are seen in certain types of EDS. You can read more about testing for each type of EDS here.

Direct-to-consumer genetic testing services (such as 23andMe and Ancestry.com) are not helpful for diagnosing any type of EDS or HSD. These products test a relatively small number of single nucleotide polymorphisms (SNPs). SNPs are not the same thing as pathogenic genetic variants. Direct-to-consumer genetic testing cannot take the place of clinical genetic testing and cannot be used to support a diagnosis. In order to receive an accurate diagnosis and appropriate care, all genetic testing should be ordered and interpreted by a medical professional.

Genetic variants are classified based on their potential to cause harm. The American College of Medical Genetics and Genomics classifies genetic variants into five categories:

  • Pathogenic (harmful)
  • Likely pathogenic (likely harmful)
  • Variant of uncertain significance
  • Likely benign (likely harmless)
  • Benign (harmless)

Pathogenic variants are known to be associated with disease. Benign variants are not associated with any risk of disease. Variants of uncertain (or unknown) significance (VUS) are variants that we do not fully understand yet. VUS are not known to be associated with any disease but have not been proven to be benign.

As we learn more about a VUS, it may be reclassified into a different risk category. A VUS may be reclassified as benign if research shows that the variant does not impact protein function or if the variant is found in many healthy people. Less commonly, a VUS may also be reclassified as pathogenic if it is found to impact protein function in a way that can cause disease.

Each type of Ehlers-Danlos syndrome is caused by specific pathogenic variants. Variants of uncertain significance are not known to cause any type of EDS. If a VUS is found in a gene that is associated with a type of EDS but the person does not meet the diagnostic criteria for that type, then there is no reason to suspect that they have this condition. Genetic variation is normal and expected. In the absence of corresponding symptoms, a VUS does not impact diagnosis. If a person meets the diagnostic criteria for a type of EDS and has a VUS in a gene that is associated with that condition, a doctor may recommend additional testing to better understand the VUS.

Sometimes a “provisional clinical diagnosis” is made when a person meets the clinical diagnostic criteria for a type of EDS but does not have positive genetic testing results. This may happen when genetic testing is unavailable or when genetic testing does not identify pathogenic variants. In these cases, the person’s symptoms should be clearly distinguishable from other conditions, including other types of EDS. Some symptoms are common across most types of EDS, such as joint hypermobility, pain, and fatigue. A provisional clinical diagnosis should only be made when there is no other explanation for that person’s symptoms.

The genetic cause of hEDS is unknown, so there is no genetic test for hEDS. hEDS is diagnosed when a person meets the clinical diagnostic criteria for hEDS.

It is possible for someone to be the first person in their family with a specific genetic variant. Sometimes genetic disorders are the result of de novo mutations. De novo mutations are changes to the DNA that occur spontaneously due to errors in a germ cell (egg or sperm) of one of the parents. De novo mutations may lead to a person having a genetic variant that neither of their parents had. Once a genetic variant has been introduced through a de novo mutation, a person may pass this variant on to their children.

While it is technically possible for a person to have more than one type of EDS, it is statistically extremely unlikely for this to happen. If a person has two pathogenic variants that are associated with different types of EDS, they may indeed have two types of EDS. However, only a very small number of these cases have ever been reported.

According to the current diagnostic criteria, a person cannot be diagnosed with both hEDS and another type of EDS. The diagnostic criteria require that other types of EDS be ruled out for a person to be diagnosed with hEDS. This means you cannot meet the diagnostic criteria for hEDS if you have another type of EDS. If a person has positive genetic testing results for a type of EDS, they would be diagnosed with that type of EDS, not hEDS.

It is possible to have symptoms of a type of EDS without actually having that type. Each type of EDS has a unique set of symptoms and features. Some features are found in multiple types of EDS, as well as in people without any type of EDS. The diagnostic criteria describe the combination of features that are associated with each type of EDS. If a person meets the diagnostic criteria for a type of EDS other than hEDS, they should have genetic testing to confirm or rule out the diagnosis.

Inheritance

Humans have two copies of each gene because we inherit one copy from each parent. The combination of genetic information we have in both copies of a gene is called our genotype. Our genotype determines our traits, or phenotype. Sometimes we inherit the same version of a gene from both parents. This is called a homozygous genotype. When we inherit different genetic variants from each parent, this is known as a heterozygous genotype.

Sometimes, just one copy of a genetic variant is enough to produce a certain trait. For other traits, two copies of the genetic variant must be present to produce the trait. This results in different inheritance patterns for different traits. All types of EDS are inherited in either an autosomal dominant or autosomal recessive inheritance pattern. The term autosomal means that the gene is not located on the sex (X or Y) chromosomes, so males and females have an equal chance of inheriting the genetic variant. Dominant and recessive refer to the number of copies of a variant that are required to produce a trait or condition.

Autosomal Dominant Inheritance 

Dominant inheritance means that a condition is caused by one copy of a pathogenic variant. This means if a person inherits the pathogenic variant from either of their parents, they will have the condition. If a person has a condition with a dominant inheritance pattern, each of their children will have a 50% chance of inheriting the pathogenic variant. Therefore, each child of an affected parent has a 50% chance of having the condition. If both parents are affected, each child has a 75% chance of having the condition.

hEDS, cEDS, vEDS, pEDS, and aEDS are inherited in an autosomal dominant pattern. mEDS can be inherited in an autosomal dominant or autosomal recessive pattern.

Autosomal Recessive Inheritance 

Recessive inheritance means that a condition is caused by two copies of a pathogenic variant. This means a person must inherit the pathogenic variant from both parents in order to have the condition. People with one copy of a recessive pathogenic variant are called carriers. Carriers do not have the condition themselves, but they may pass the pathogenic variant on to their children. Two healthy carriers can have a child with a recessive genetic disorder.

In order for a person to inherit a condition with a recessive inheritance pattern, both parents must have at least one copy of the pathogenic variant. The chances of inheriting a recessive genetic disorder depend on how many copies of the pathogenic genetic variant each parent has.

ig_post_genetic_inheritence_Autosomal_recessive_inheritance _scenario_1_WEB
ig_post_genetic_inheritence_Autosomal_recessive_inheritance _scenario_2_WEB
ig_post_genetic_inheritence_Autosomal_recessive_inheritance _scenario_3_WEB

kEDS, spEDS, BCS, mcEDS, clEDS, dEDS, and cvEDS are inherited in an autosomal recessive pattern. mEDS can be inherited in an autosomal dominant or autosomal recessive pattern.

Yes. It is possible for people with EDS to pass the condition on to their children. The chances of inheriting a genetic disorder depend on the inheritance pattern and how many copies of the pathogenic variant each parent has. If a condition follows a dominant inheritance pattern, each child of an affected parent has a 50% chance of inheriting the condition. If a condition follows a recessive inheritance pattern, a child must inherit the pathogenic genetic variant from both parents to inherit the condition.

Yes. If a child inherits EDS from their parent, they will have the same type of EDS as their parent. Each type of EDS is caused by different genetic variants. When people with a type of EDS have children, they may pass the genetic variant responsible for their EDS to their children. The children would inherit the same genetic variant as their parent, so they would have the same type of EDS as them. The chances of inheriting a type of EDS depend on the inheritance pattern for that type.

Not necessarily. The symptoms of EDS are diverse and vary both between and within each type. Even within the same family, two people with the same type of EDS may have very different symptoms and may be affected by each symptom to varying degrees.

Yes. It is possible for a person to have a type of EDS that neither of their parents had. There are two ways this can happen.

  1. If a condition has a recessive inheritance pattern, people with one copy of the pathogenic genetic variant are carriers of the condition. Carriers do not have the condition but can pass the pathogenic genetic variant on to their children. If both parents are carriers of a condition, their child may inherit two copies of the pathogenic variant and be affected by the condition.
  2. It is also possible to be the first person in your family with a specific genetic variant. Sometimes genetic disorders are the result of de novo mutations. De novo mutations may alter the DNA in ways that lead to a person having a genetic variant that neither of their parents had.

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