Clinical characteristics.

Vascular Ehlers-Danlos syndrome (vEDS) is characterized by arterial, intestinal, and/or uterine fragility; thin, translucent skin; easy bruising; characteristic facial appearance (thin vermilion of the lips, micrognathia, narrow nose, prominent eyes); and an aged appearance to the extremities, particularly the hands. Vascular dissection or rupture, gastrointestinal perforation, or organ rupture are the presenting signs in most adults with vEDS. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection but also may occur spontaneously. The majority (60%) of individuals with vEDS who are diagnosed before age 18 years are identified because of a positive family history. Neonates may present with clubfoot, hip dislocation, limb deficiency, and/or amniotic bands. Approximately half of children tested for vEDS in the absence of a positive family history present with a major complication at an average age of 11 years. Four minor diagnostic features – distal joint hypermobility, easy bruising, thin skin, and clubfeet – are most often present in those children ascertained without a major complication.

Diagnosis/testing.

The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic variant in COL3A1.

Management.

Treatment of manifestations: Creation of an organized care team is one of the first tasks to complete upon the initial diagnosis. The team should include a primary care physician, vascular surgeon, general surgeon, cardiologist, pulmonologist, and geneticist. Affected individuals should carry documentation of their genetic diagnosis, such as a MedicAlert^® bracelet or necklace, an emergency contact letter, or vEDS "passport." Affected individuals are instructed to seek immediate medical attention for sudden, unexplained pain, coordinated through the primary care physician when possible. Treatment may include medical or surgical management for arterial complications, bowel rupture, or uterine rupture during pregnancy.

Surveillance: May include periodic arterial screening by ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast. Blood pressure monitoring on a regular basis is recommended to allow for early treatment if hypertension develops.

Agents/circumstances to avoid: Trauma (collision sports, heavy lifting, and weight training with extreme lifting); arteriography should be discouraged and used only to identify life-threatening sources of bleeding prior to surgical intervention because of the risk of vascular injury; routine colonoscopy in the absence of concerning symptoms or a strong family history of colon cancer; elective surgery unless the benefit is expected to be substantial.

Evaluation of relatives at risk: It is appropriate to evaluate first-degree relatives in order to identify as early as possible those who could benefit from surveillance, awareness of treatment for potential complications, and appropriate restriction of high-risk physical activities; evaluation usually starts with clinical assessment and, even in the absence of clinical signs, progresses to molecular genetic testing for the known familial pathogenic variant.

Pregnancy management: Affected women have a 5% mortality risk with each pregnancy. The issue of management and recommendations is complicated by the recognition that many of the women who became pregnant, and their providers, learn of the diagnosis at the time of delivery and the onset of complications. In pregnant women with a known diagnosis, maternal risks should be discussed, and these women should be followed in a high-risk obstetric program. Management decisions about nature and timing of delivery can be stratified by the nature of the genetic alteration.

Genetic counseling.

Vascular EDS is an autosomal dominant disorder. About 50% of individuals diagnosed with vEDS have an affected parent; about 50% of affected individuals have the disorder as the result of a COL3A1 pathogenic variant that occurred as a de novo event in the individual or as a de novo event in an apparently unaffected, mosaic parent. Each child of an individual with vEDS has a 50% chance of inheriting the pathogenic variant and developing complications of the disorder. Once the COL3A1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for vEDS are possible.

Suggestive Findings

Vascular EDS should be considered in individuals with any one (and especially with two) of the following major clinical findings or several minor diagnostic criteria, particularly in those younger than age 40 years.

Major clinical findings

• Arterial aneurysms, dissection, or rupture
• Intestinal rupture, most often in the sigmoid colon
• Uterine rupture during pregnancy
• Family history of vEDS

Other clinical findings

• Pneumothorax/hemopneumothorax
• Easy bruising (spontaneous or with minimal trauma)
• Thin, translucent skin (especially noticeable on the chest/abdomen)
• Carotid-cavernous sinus fistula
• Talipes equinovarus (clubfoot)
• Facial appearance that includes thin vermilion of the lips, micrognathia, narrow nose, protuberant eyes
• Acrogeria (an aged appearance to the extremities, particularly the hands)
• Hypermobility of small joints
• Tendon/muscle rupture
• Early-onset varicose veins
• Chronic joint subluxations/dislocations
• Congenital dislocation of the hips

Establishing the Diagnosis

The diagnosis of vEDS is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in COL3A1 by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of a heterozygous COL3A1 variant of uncertain significance does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

The most comprehensive descriptions of clinical features and natural history derive from two types of studies of individuals with vascular Ehlers-Danlos syndrome (vEDS): a cross-sectional and retrospective view obtained at the time of diagnostic testing [Pepin et al 2014] and a nearly 15-year-long cohort study from one group in France [Frank et al 2015, Frank et al 2019]. A retrospective review of the health history of more than 1,200 individuals with vEDS delineated the natural history of the disorder [Pepin et al 2014]. The majority of individuals were ascertained on the basis of a major complication (70%) at an average age of 30 years.

Genotype-Phenotype Correlations

More than 600 unique COL3A1 pathogenic variants have been aggregated into the Ehlers Danlos Syndrome Variant Database with an additional 250 in ClinVar. Approximately 5% of COL3A1 variants result in haploinsufficiency. Individuals with a COL3A1 null variant have a 15-year delay in onset of complications, improved life expectancy (close to that of the US population), and significantly fewer obstetric and bowel complications than are seen with other types of COL3A1 pathogenic variants [Leistritz et al 2011, Pepin et al 2014, Frank et al 2015].

Among the 1,200 individuals with vEDS described by Pepin et al [2014], survival depended in part on the nature of the pathogenic variant. Survival was longest for those with a null variant and shortest for those with a splice donor site variant that resulted in exon skipping, or a substitution for a triple helical glycine residue (in the repeating Gly-Xaa-Yaa triplets) by a large residue (valine, aspartic acid, glutamic acid, or arginine). The location of the variant within the triple helix did not have a discernable effect on survival. Similar survival patterns were described in the French cohort of 126 individuals with COL3A1 pathogenic variants [Frank et al 2015]. These differences in populations are difficult to use to counsel individuals because of significant intra- and interfamilial variability in age of complication and survival for the same pathogenic variant.

Penetrance

In families identified on the basis of clinical complications, penetrance of the vEDS phenotype appears to be close to 100% in adults with a missense or exon-skipping alteration; the age at which the pathogenic variant becomes penetrant may vary. COL3A1 null variants have significantly later penetrance in part because of the rarity of minor clinical features in the majority of individuals with vEDS identified with a pathogenic null alteration [Leistritz et al 2011]. In rare individuals with heterozygous null variants no clinical signs are present in the eighth and ninth decades.

Nomenclature

The following terms for vEDS have been used:

• "Status dysvascularis" was introduced by Georg Sack in 1936; the term was never used extensively.
• "Familial acrogeria," introduced by Heinrich Gottron in 1940, probably included some individuals with vEDS.
• "Sack-Barabas syndrome" or the "Sack-Barabas type of Ehlers-Danlos syndrome" was used after Barabas [1967] introduced the disorder to the English-language literature.
• "Ehlers Danlos syndrome type IV" was introduced by Beighton in his 1979 review of classification following its inclusion as the fourth entry in his 1969 review.
• "Vascular Ehlers Danlos syndrome" was adopted with the 1998 revision of the EDS classification and in the 2017 extension and revision.

Prevalence

There are no good estimates of the prevalence of vEDS in any population. More than 2,000 affected individuals in the United States have been identified on the basis of biochemical and genetic testing and analysis of family pedigrees [PH Byers, personal observation], leading to a minimum prevalence estimate of 1:150,000. The decreased frequency of certain classes of pathogenic variants suggests that the overall prevalence of individuals with pathogenic variants in COL3A1 (see Molecular Genetics) could approach that of individuals with pathogenic variants in COL1A1, which is estimated at close to 1:20,000 (measured incidence of osteogenesis imperfecta of about 1:10,000 births/pregnancies, of which more than 90% have pathogenic variants in the type I collagen genes, of which about 60% are in COL1A1). Studies of medical records and insurance records that used the co-occurrence of two or more of the major complications as a surrogate for vEDS produced an estimated prevalence of about 1:10,000. Studies of a cohort of all admissions to Mt Sinai Hospital in New York by whole exome sequencing resulted in an upper bound frequency of slightly less than 1:20,000 [Lui et al 2023]. All these estimates have limitations, but the general conclusion is that vEDS is more common than previously recognized and needs to be considered in several clinical settings.

Because many families with vEDS are identified only after a severe complication or death, it is likely that individuals/families with pathogenic variants in COL3A1 and a mild phenotype do not come to medical attention and thus go undetected. In addition, because of the perceived rarity of the disorder, it is seldom considered, and nonvascular complications may not raise diagnostic suspicion of vEDS.

Evaluations Following Initial Diagnosis

There has been a gradual transition in the approach to both surveillance and intervention prior to arterial events in individuals with vascular Ehlers-Danlos syndrome (vEDS). This shift appears to reflect increased recognition of the diagnosis of vEDS both at the time of an event and before, the creation of centers of excellence and experience for vEDS both in the United States and in other countries, and differences in surgical techniques and approaches with a move away from open intervention and increased use of endovascular approaches. Nonetheless, there is still no consensus regarding the appropriate extent of evaluation at the time of initial diagnosis. To establish the extent of disease and needs in an individual diagnosed with vEDS, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) provide a baseline with which to evaluate progression.

• Because of the risk for asymptomatic aneurysm/dissection, initial visualization of the arterial tree is commonly undertaken [Chu et al 2014, Frank et al 2015]; the approach employed varies by geographic region and by institution (see Surveillance). Approach to a vascular evaluation depends on the age of the individual, family history of events, and the circumstances in which the diagnosis is made.
• Because no specific gastrointestinal (GI) findings are known to precede or predict bowel rupture, invasive GI evaluation is of no benefit.
• Consultation with a clinical geneticist and/or genetic counselor is recommended.
• Following diagnosis, the most crucial aspect of management is the creation of an organized care team (see Treatment of Manifestations).
• Review of lifestyle with the affected individual and emphasis of the importance of minimizing collision activities and sports is recommended.

Treatment of Manifestations

The most crucial aspect of management is the creation of an organized care team that includes a primary care physician, vascular surgeon, and general surgeon, as well as cardiologist and pulmonologist depending on initial evaluation. A geneticist is often valuable for integration of care. This team is responsible for the organization of ordinary and extraordinary care. In addition, individuals with vEDS should carry documentation of their genetic diagnosis, such as a MedicAlert^®, emergency letter, or vEDS "passport." The care team needs to develop contingency plans for immediate care.

Affected individuals should be instructed to seek immediate medical attention for sudden, unexplained pain.

Surgical intervention may be lifesaving in the face of bowel rupture, arterial rupture, or organ rupture (e.g., the uterus in pregnancy).

• When surgery is required for treatment, it is appropriate to target the approach and minimize surgical exploration because of the risk of inadvertent damage to other tissues [Oderich et al 2005]. In addition, an approach of "judicious underhydration" may help to prevent the recognized cycle of complications, which is thought to arise, in part, from overhydration used to maintain blood pressure.
• In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of vEDS and its associated tissue fragility [Shalhub et al 2014].

There are no guidelines to direct recommendations for elective repair in individuals with aneurysm(s) and vEDS.

• A decision about the timing and approach of an elective vascular procedure or the use of endovascular approaches is typically based on an individualized risk-versus-benefit assessment.
• Reports of successful endovascular approaches are growing. A retrospective review of open versus endovascular repair of splenic artery aneurysm and dissection strongly favors the endovascular approach, with fewer complications and deaths [Shalhub et al 2023], but approaches to other arterial involvement await analysis.

Prompt surgical intervention of bowel rupture is usually essential to limit the extent of infection and facilitate early restoration of bowel continuity.

• Death from bowel rupture is uncommon because intervention is generally effective.
• Bowel continuity can be restored successfully in most instances, usually three to six months after the initial surgery.
• The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend partial or total colectomy at the time of the initial event to reduce the risk of recurrent bowel rupture [Frank et al 2015].
• Some physicians and affected individuals consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [Fuchs & Fishman 2004]. A minority of individuals with vEDS have bowel rupture, and this approach as a prophylactic measure adds unnecessary surgical risk.

Surveillance

The use of surveillance of the arterial vasculature assumes that effective interventions will decrease the risk of arterial dissection or rupture and prolong life. At a time when an open surgical approach was the only option, the benefit of surveillance could not be established. As endovascular approaches to management of aneurysms and dissection become more available, earlier intervention is considered and surveillance may have greater benefit. There are, however, no published data assessing the efficacy of screening strategies in identifying the regions in the arterial vasculature at highest risk; conversely, there are examples in which regions of concern in the arterial vasculature failed to progress and arterial rupture occurred at other, more distant sites. Thus, the benefit of controlled studies cannot be overemphasized.

If undertaken, noninvasive imaging such as ultrasound examination, magnetic resonance angiogram, or computed tomography angiogram with and without venous contrast is preferred to identify aneurysms, dissections, and vascular ruptures [Chu et al 2014]. Because arterial tear/dissection may result at the site of entry of the catheter and at sites of high-pressure injection, conventional arteriograms are not recommended. When surveillance is undertaken, repeat measure depends on the pathology identified, but in the presence of a normal vascular tree, screening at 18- to 24-month intervals appears to be the common practice.

Blood pressure monitoring on a regular basis is recommended to allow for early treatment if hypertension develops, thus reducing the risk for vascular stress and injury.

Agents/Circumstances to Avoid

Trauma. Because of inherent tissue fragility, it is prudent for individuals with vEDS to avoid collision sports (e.g., football), heavy lifting, and weight training with extreme lifting. Note: No evidence suggests that moderate recreational exercise is detrimental.

Arteriography. Conventional arterial angiography (with contrast injection) should be discouraged because it has been associated with added de novo complications [Zilocchi et al 2007]. Arterial tear/dissection may result at the site of entry of the catheter; furthermore, injection pressure may lead to arterial aneurysms. Arteriography is currently best used as part of a planned interventional procedure, such as coil embolization or stenting of bleeding arteries.

Routine colonoscopy. There are several reports of colonoscopy-associated bowel perforation in individuals with vEDS. Virtual colonoscopy, which also involves insufflation, may have similar complications. Routine colonoscopy for cancer screening is discouraged in the absence of concerning symptoms or a strong family history of colorectal cancer. Individuals with vEDS who have a family history of colon cancer are encouraged to use genetic testing for colon cancer risk assessment (provided the genetic etiology of colon cancer has been established in an affected family member) and screening of stool DNA to detect luminal malignancies. Use of capsular cameras may provide sufficient data in at-risk individuals.

Elective surgery. Because tissue fragility results in a higher risk of surgical complications, elective surgery for individuals with vEDS is generally discouraged unless the benefit is expected to be substantial. In general, avoidance of surgery in favor of more conservative management is advised, although data about elective surgery are just beginning to emerge and this approach needs to be reevaluated.

Evaluation of Relatives at Risk

It is appropriate to evaluate first-degree relatives of an affected individual in order to identify as early as possible those who could benefit from surveillance, awareness of treatment for potential complications, and appropriate restriction of high-risk physical activities. Evaluation usually starts with clinical assessment and, even in the absence of clinical signs, progresses to molecular genetic testing for the known familial pathogenic variant.

• Molecular genetic testing if the pathogenic variant in the family is known;
• In the unusual circumstance in which clinical evaluation strongly suggests the diagnosis but it has not been confirmed by genetic analysis, the first step would be to review the genetic testing in the proband and determine if it is complete or should be extended to a more detailed evaluation or to analysis of other genes. If a genetic diagnosis remains elusive, then evaluation for complications seen in the proband can drive the assessment.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality. The most extensive study, which included evaluation of more than 500 pregnancies in 253 women [Murray et al 2014], found a mortality rate of about 5% per pregnancy. This is lower than previously identified and may be because a significant number of the women included knew about the diagnosis before pregnancy or delivery. About half the women in the study had no complications. For others, prematurity and uterine, cervical, and vaginal tears led to morbidity. The issue of management and recommendations is complicated by the recognition that many of the women who became pregnant, and their providers, learned of the diagnosis at the time of delivery and the onset of complications or after a later problem pregnancy.

Increasingly, the practice is to plan delivery by cesarean section at 36-38 weeks' gestation to avoid the extensive tissue injury that can accompany vaginal delivery. This procedure can be associated with an increased risk of hemorrhage and inadvertent damage to nearby abdominal organs.

Thought should be given to stratifying intervention by consideration of the underlying COL3A1 pathogenic variant. For example, pregnancy complications are rare among women with heterozygous null variants, and a number of women with substitutions of triple helical glycine by alanine (the next smallest amino acid) have had multiple uncomplicated pregnancies. Surgical intervention may increase complications in this group.

When the diagnosis is known in the mother, the maternal risks should be discussed and all options considered, preferably in the pre-pregnancy decision-making period. The decision to proceed with pregnancy should involve enlarging the care team to include a high-risk obstetric service. Plans for early delivery should include the presence of the vascular surgeon and potentially the general surgeon.

It is essential to educate the pregnant woman and her family regarding possible complications and the need for close monitoring.

Therapies Under Investigation

A clinical trial in France to determine if addition of an angiotensin receptor blocker to celiprolol decreases arterial complications and extends life expectancy is currently under way (NCT02597361).

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Vascular Ehlers-Danlos syndrome (vEDS) is an autosomal dominant disorder; about half of affected individuals have an affected parent and about half of affected individuals have the disorder as the result of a de novo pathogenic variant.

Note: Biallelic COL3A1 pathogenic variants have been reported in individuals with polymicrogyria and other features in addition to characteristic manifestations of vEDS (see Genetically Related Disorders).

Risk to Family Members

Parents of a proband

• About 50% of individuals diagnosed with vEDS have an affected parent.
• An individual with vEDS may have the disorder as the result of a COL3A1 pathogenic variant that occurred as a de novo event in the individual or as a de novo event in an apparently unaffected, mosaic parent. The proportion of affected individuals with a de novo pathogenic variant is about 50%.
• If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing (if the proband has a known COL3A1 pathogenic variant) and physical exam are recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and assess their need for surveillance.
• Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, reduced penetrance, early death of a parent before the onset of symptoms, late onset of the disease in an affected parent, or parental mosaicism [Legrand et al 2019]. Therefore, de novo occurrence of a COL3A1 pathogenic variant cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the COL3A1 pathogenic variant.
• If the proband has a known COL3A1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
  • The proband has a de novo pathogenic variant.
  • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. In families in which the proband has an apparently de novo pathogenic variant, parental mosaicism is seen in 1% or more of families, depending on the study [Legrand et al 2019]. To date, parents mosaic for a COL3A1 pathogenic variant are not known to be symptomatic or to have had complications compatible with the diagnosis of vEDS, though further investigation is needed [Legrand et al 2019]. Two families in which there appears to be isolated gonadal mosaicism have been identified [Byers et al 2003, Palmeri et al 2003].

Sibs of a proband. The risk to the sibs depends on the clinical/genetic status of the proband's parents:

• If a parent of the proband is affected and/or is known to have the COL3A1 pathogenic variant identified in the proband, the risk to each sib is 50%.
• If the proband has a known COL3A1 pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to the sibs is about 1% because of the possibility of parental gonadal mosaicism [Byers et al 2003, Palmeri et al 2003, Legrand et al 2019].
• If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband are still presumed to be at increased risk for vEDS because of the possibility of reduced penetrance in a heterozygous parent or parental gonadal mosaicism.

Offspring of a proband

• Each child of an individual with vEDS has a 50% chance of inheriting the COL3A1 pathogenic variant and developing complications of the disorder.
• In the rare occurrence in which an individual has biallelic COL3A1 pathogenic variants, 100% of offspring will inherit one of the variants and may develop complications of the disorder (see Genetically Related Disorders).

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected and/or has the pathogenic variant, the parent's family members may be at risk.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.
• Pregnancy has often been actively discouraged for women with vEDS because of high reported risks of mortality (see Pregnancy Management).

Testing of asymptomatic individuals younger than age 18 years

• The benefits of testing individuals younger than age 18 years for vEDS include: (1) elimination of concern for those children who do not have the familial pathogenic variant; (2) awareness of and preparedness for potential complications; and (3) restriction of high-impact sports and high-risk activities for those with the pathogenic variant.
• Although vEDS is often considered an adult-onset condition, 12%-24% of individuals have a major complication by age 20 years [Pepin et al 2014, Frank et al 2015]. Genetic testing of at-risk children has been controversial because of the concern that there is no preventive treatment. However, awareness of the condition is a key component of appropriate intervention in the occurrence of a major complication and for implementation of risk-reducing behaviors. In this context, 87% of children tested before age 18 years had not experienced a major complication, and the mean age of testing was eight years. Given the opportunity to consider testing for children at 50% risk of having inherited the pathogenic variant, parents usually did not wait until a complication arose or until the child reached majority for a test to be performed. Instead, they requested that the test be performed to clarify the child's status and allow them to anticipate medical risks [PH Byers, personal observation].

In a family with an established diagnosis of vEDS it is appropriate to consider testing symptomatic individuals regardless of age.

Prenatal Testing and Preimplantation Genetic Testing

Molecular genetic testing. Once the COL3A1 pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for vEDS are possible. Given the efficiency of molecular genetic testing and the recognition that essentially all individuals with a biochemical diagnosis of vEDS also have a known COL3A1 pathogenic variant, molecular genetic testing is the recommended approach for prenatal testing. Experience with use of assisted reproductive technologies for women with vEDS is limited [Bergeron et al 2014].

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

COL3A1 encodes collagen alpha-1(III) chains of type III procollagen, a major structural component of skin, blood vessels, and hollow organs. The type III procollagen molecule is a homotrimer, with constituent chains 1,466 amino acids in length. The chains have multiple domains: a signal peptide that directs the nascent protein to the RER lumen; a 10-cysteine domain of the A-terminal propeptide followed by a 36-amino-acid minor triple helical domain characterized by a repeating Gly-Xaa-Yaa triplet in which Xaa and Yaa can be most amino acids; a telopeptide domain that remains attached to the major triple helical (triple domain) and contains a potential propeptide cleavage site and a crosslinking lysine; a 342-triplet-repeat domain of the major triple helical domain; a telopeptide that can be retained after propeptide cleavage; and a 253-amino-acid C-terminal proptide that contains chain-chain recognition sites that lead to chain association with chain selection domains.

More than 1,500 COL3A1 variants that result in a disease-causing phenotype have been identified.

The majority of identified pathogenic variants result in single-amino-acid substitutions for glycines in the Gly-X-Y repeats of the triple helical region of the type III procollagen molecule. The phenotypic effects of these variants vary according to the nature of the substituting residues. Single nucleotide changes in glycine codons can result in substitutions by valine, alanine, aspartic acid, glutamic acid, arginine, serine, cysteine, or phenylalanine with different expected rates and different observed rates. Phenotypes as measured by both longevity and clinical features are generally milder with smaller amino acid substitution. About one quarter of reported pathogenic variants occur at splice sites, most resulting in exon skipping. A smaller number of splice site variants lead to the use of cryptic splice sites with partial-exon exclusion or intron inclusion and/or mRNA instability. The majority of exon-skipping splice site variants have been identified at the 5' donor site, with very few found at the 3' splice site.

Several partial-gene deletions have been reported as well. Less common are variants that create premature termination codons predicted to result in COL3A1 haploinsufficiency ("null" pathogenic variants) [Schwarze et al 2001, Leistritz et al 2011].

Note: At least two classes of COL3A1 variants are underrepresented (in terms of predicted frequency) among individuals with clinical features of vEDS:

• Substitutions of glycine in the triple helical domain by alanine
• Null variants

Thus, some pathogenic variants in COL3A1 may not produce a typical vEDS clinical picture. It is unclear if individuals with these classes of pathogenic variants have attenuated or subclinical phenotypes and present at later ages, or if there is a molecular explanation for the absence of certain pathogenic variant types.

Mechanism of disease causation. Pathogenic variants in COL3A1 typically result in a structural alteration of type III collagen that leads to intracellular storage and impaired secretion of collagen chains. Production of half the normal amount of type III procollagen occurs in a minority of individuals.

COL3A1-specific laboratory technical considerations. For fibrillar collagen genes of the same clade (COL1A1, COL1A2, COL2A1, COL3A1, and COL5A2), there is a "legacy" naming system so that all genes have 52 exons – derived from the structure of COL1A2. In the case of COL3A1, there is fusion of two exons that are equivalent to exons 4 and 5 in COL1A2, and the fusion exon is called exon 4/5. In addition, there is a second "legacy" protein-naming system in which, in addition to the use of the p.Met1 nomenclature, the first glycine of the canonic triple helical domain is referred to as residue 1 in the triple helix. In reports from some laboratories, both systems are used, and the difference in protein position between the two systems is indicated. In older reports from some laboratories, the legacy description for protein position may be used in combination with the standard description for nucleotide position, leading to considerable confusion.

Author Notes

Collagen Diagnostic Laboratory website

Peter H Byers, MD, and Ulrike Schwarze, MD, along with Dru Leistritz, are actively involved in clinical research regarding individuals with different forms of Ehlers-Danlos syndrome, osteogenesis imperfecta, and genetic aortopathies. They would be happy to communicate with persons who have any questions regarding diagnosis of these conditions or other considerations.

Contact Dr Byers or Dr Schwarze to inquire about review of variants of uncertain significance in genes studied at the Collagen Diagnostic Laboratory.

Acknowledgments

We are grateful to the Freudmann Fund, private contributions from a number of families, and to the OI Foundation, the Ehlers-Danlos Society, and the Marfan Foundation for enthusiastic support of the work to support the individual in those organization affected by the conditions.

Author History

Peter H Byers, MD (1999-present)
Mitzi L Murray, MD, MA; University of Washington (2015-2019)
Melanie G Pepin, MS, CGC; University of Washington (1999-2019)

Revision History

• 10 April 2025 (sw) Comprehensive update posted live
• 21 February 2019 (ha) Comprehensive update posted live
• 19 November 2015 (me) Comprehensive update posted live
• 3 May 2011 (me) Comprehensive update posted live
• 7 June 2006 (me) Comprehensive update posted live
• 14 April 2004 (me) Comprehensive update posted live
• 15 April 2002 (me) Comprehensive update posted live
• 2 September 1999 (me) Review posted live
• 6 April 1999 (mp) Original submission

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