INTRODUCTION — This monograph summarizes the interpretation of germline genetic testing of COL3A1, the gene associated with vascular type Ehlers-Danlos syndrome (vascular EDS [VEDS], previously called EDS type IV) . Affected individuals are heterozygous for a pathogenic variant in COL3A1.
Evaluation and management of VEDS are discussed in detail separately. (See 'Resources' below.)
Clinical characteristics of VEDS — There are several distinct types of EDS with different genetic causes and different clinical characteristics (table 1). (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Classification'.)
Neonates may present with clubfoot, hip dislocation, and/or amniotic bands . Unless identified as part of a family study or known family history of the condition, presentation in most individuals who are unaware of their diagnosis occurs in early adulthood (late 20s to early 30s) with a major complication [3,4].
Presenting findings can be catastrophic, including sudden death, shock, stroke, acute abdomen due to intestinal perforation or rupture, or uterine rupture during delivery. There is a 5 percent risk of maternal death during pregnancy, although pregnancy does not appear to affect overall survival in VEDS .
Other clinical manifestations include thin, translucent skin; easy bruising; thin vermillion of the lips; narrow nose; prominent eyes; and hypermobility of the small joints, often mild.
VEDS complications include [2,5,6]:
●Arterial aneurysm, dissection, or rupture, most commonly affecting the thorax and abdomen. Head, neck, and extremities can also be involved
●Gastrointestinal perforation, especially in the sigmoid colon, but also affecting small intestine, stomach, and iatrogenic (during colonoscopy)
●Uterine rupture during late pregnancy and delivery, as well as uterine or vaginal tears and wound dehiscence
●Liver or spleen rupture (rare)
●Carotid-cavernous sinus fistula
●Severe bruising, sometimes unrelated to trauma or in unusual sites
Morbidity from arterial and internal organ rupture can be severe; the median life expectancy is slightly >50 years. (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes", section on 'Vascular EDS'.)
The diagnosis is generally suspected on clinical grounds and established by genetic testing that identifies a pathogenic variant in COL3A1. If a COL3A1 variant cannot be identified, it may be possible to make the diagnosis using biochemical analysis of type III procollagen from cultured fibroblasts and to identify unusual splicing events. (See 'Caveats for COL3A1 genetic testing' below.)
COL3A1 gene — COL3A1 encodes the proα1(III) chain of type III procollagen, an extracellular fibrillar collagen with important roles in embryogenesis, stabilizing the extracellular matrix that surrounds blood vessels and hollow viscera, and providing structural integrity of the skin [7,8]. Type III collagen is a homotrimer of α1(III) chains .
Approximately 1000 heterozygous pathogenic variants in COL3A1 have been identified in individuals with VEDS. In many cases, genotype correlates with disease severity :
●Heterozygous null variants, which result in haploinsufficiency, tend to be less severe because one-half the normal amount of type III procollagen is produced, with no abnormal proα1(III) chains.
●Variants that alter protein sequence (and hence structure) tend to be more severe because seven of every eight type III procollagen molecules will incorporate one or more abnormal chains. The majority of these variants result in substitutions for glycine residues in the triple helical domain (characterized by the repeating Gly-Xaa-Yaa triplet). Most of the remainder have in-frame deletions that generally result from exon skipping.
Approximately one-half of individuals with a pathogenic variant in COL3A1 inherit it from an affected parent and one-half have a de novo mutation. Thus, a negative family history cannot be used to exclude the diagnosis. (See 'Caveats for COL3A1 genetic testing' below.)
Transmission is autosomal dominant; heterozygosity for a pathogenic variant in the COL3A1 gene is sufficient to cause VEDS. In genetically characterized kindreds, disease penetrance is close to 100 percent, although the age of presentation and nature of the characteristic complications can vary .
How to read the report — Confirm that the result applies to the tested individual and determine whether testing was performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory (or other nationally certified laboratory); if this is not the case, testing should be repeated in a certified laboratory if it was performed as part of research or in a noncertified laboratory.
These and other caveats are summarized in the checklist (table 2).
Caveats for COL3A1 genetic testing
●If a familial variant is known (in a parent or sibling), analysis for that specific variant is generally sufficient to determine whether the individual is predisposed to manifestations of VEDS.
●If the diagnosis is suspected based on personal or family history but a familial variant has not been identified, genetic testing involves targeted gene sequencing or a gene panel that investigates variants in known EDS genes or genes known to predispose to arterial aneurysms or dissection/rupture, including COL3A1 and others. Vascular events can occur in VEDS as well as other types of EDS and other syndromic or nonsyndromic vascular disorders. The choice of targeted versus panel testing will vary based upon the clinical presentation of the individual or expertise of the practitioner.
●If the diagnosis of VEDS is suspected on clinical criteria, COL3A1 sequencing can be used to detect small intragenic insertions or deletions, point mutations, and splice site variations, which account for >95 percent of pathogenic variants. An affected individual should be tested before asymptomatic family members. Deep intronic alterations that change RNA splicing and cause mRNA instability are the most challenging to identify; specialized techniques may be required to characterize the cause of mRNA instability. Whole genome sequencing has the potential to identify rare mechanisms of deficiency of type III procollagen causing VEDS, but interpretation remains incomplete and warrants further investigation.
EVALUATION AND MANAGEMENT
Pathogenic variant in COL3A1 — Optimal management for individuals with a pathogenic variant in COL3A1 involves a multidisciplinary team with experience managing VEDS. This can include a primary care physician, vascular surgeon, general surgeon, genetics expert, and cardiologist. (See 'Locating an expert' below.)
●Evaluations – Data are lacking regarding the benefits of regular surveillance, and the risk/benefit calculation is evolving. In general, the following may be appropriate :
•Monitor blood pressure regularly.
•Noninvasive imaging is preferred for surveillance of vascular abnormalities (ultrasound, magnetic resonance angiography [MRA], computed tomography angiography [CTA]). The approach to imaging can vary depending on patient age at diagnosis and mode of presentation (table 3). The usual approach is MRA or CTA in the late teens or early 20s (or after the first event, if the diagnosis was unknown).
Subsequent evaluations depend on initial findings. In individuals with negative imaging, repeated evaluations at 18- to 24-month intervals appear reasonable . Family history or type of genetic variant can inform the frequency of surveillance.
•Avoid invasive diagnostic testing that could cause vascular or organ injury (invasive arteriography or routine colonoscopy (table 3); virtual colonoscopy may have similar risks ) unless indicated based on life-threatening bleeding or prior to surgical interventions.
Noninvasive colon cancer screening can be considered depending on the clinical situation. If endoscopy is chosen, the higher perforation rate must be discussed at the time of consent . Close consultation with the endoscopist is essential to determine if alternatives to endoscopy exist and to ensure that the diagnosis of VEDS is not confused with the more common (but less risk-prone) hypermobility type of EDS.
●Management – There are no proven specific interventions or medications to reduce risks of arterial rupture or rupture of a visceral organ. Management is generally supportive, as summarized in the table (table 3).
•Create a care team centered around the patient, with a primary care physician and appropriate specialists (general surgeon; vascular surgeon; geneticist; and perhaps a pulmonologist, neurosurgeon, obstetrician in the case of pregnancy).
•Provide education about VEDS and the importance of avoiding trauma (collision sports) or large increases in blood pressure (heavy lifting, extreme weight training). Elective procedures (surgery, endoscopy) should be avoided unless no good alternative exists.
•Advise patients to carry documentation of their diagnosis and the implications (medic-alert bracelet, wallet card).
•Instruct patients to seek medical attention immediately for symptoms of vascular or visceral organ rupture, including sudden unexplained pain.
•Treat hypertension to reduce the risk of arterial complications. Prophylactic medications to maintain blood pressure and heart rate at the low end of the normal range has been proposed but has not been tested or demonstrated to confer protection in randomized trials.
•Medical or surgical intervention may be needed for arterial complications. Decisions about elective aneurysm repair (timing, indications, approach) are individualized based on personal risk/benefit assessments . If surgery is required, exploration should be minimized; gentle underhydration may be helpful .
•Emergency surgery may be required for arterial dissection or rupture, or rupture of an internal organ. Embolization has been used. Stenting is increasingly considered.
VUS or negative genetic testing — Management of individuals with negative genetic testing depends on the likelihood of disease.
●Negative genetic testing for a known familial pathogenic variant in COL3A1 very likely excludes VEDS, with caveats noted above. (See 'How to read the report' above.).
●If VEDS is suspected based on personal or family history and a familial variant in COL3A1 has not been characterized, then negative testing of COL3A1 makes it unlikely that the person has VEDS but cannot be used to exclude the disorder. Consultation with an expert in connective tissue disorders or a genetics expert is advised to determine the next steps, which may include a clinical examination by the expert, gene panel testing for other genes, more extensive testing of COL3A1, or in vitro collagen analysis and evaluation for splice site abnormalities.
●A variant of uncertain significance (VUS) means the pathogenicity of the variant has not been determined. Management is based on personal and family history of VEDS manifestations. In our experience, VUSs in COL3A1 are rare, although numerous VUSs in COL3A1 are listed in the ClinVar database. Individuals with a VUS may benefit from consultation with an expert in connective tissue disorders or a genetics expert to assist in determining the pathogenicity of the variant.
First-degree relatives — All first-degree relatives of an individual with a pathogenic variant in COL3A1 should be offered genetic counseling and testing for the variant (algorithm 1).
Testing is appropriate at any age, as vascular complications can occur in childhood. The parents of the proband should be tested if future childbearing is possible. It is also possible that a parent may be affected but undiagnosed.
Each child of an affected parent has a 50 percent chance of inheriting the COL3A1 variant and being at risk for developing complications of VEDS. Reproductive counseling should be provided to discuss reproductive options. Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "In vitro fertilization: Overview of clinical issues and questions", section on 'When are donor oocytes used?' and "Donor insemination" and "Preimplantation genetic testing".)
Information about EDS
•Diagnosis – (See "Clinical manifestations and diagnosis of Ehlers-Danlos syndromes".)
•Treatment – (See "Overview of the management of Ehlers-Danlos syndromes".)
•Guidelines – (See "Society guideline links: Ehlers-Danlos syndromes and joint hypermobility".)
●Differential diagnosis of VEDS (other connective tissue disorders with aortic aneurysm) – (See "Epidemiology, risk factors, pathogenesis, and natural history of thoracic aortic aneurysm and dissection", section on 'Genetic predisposition' and "Genetics, clinical features, and diagnosis of Marfan syndrome and related disorders", section on 'Differential diagnosis'.)
●EDS society – https://www.ehlers-danlos.com/
●Ehlers-Danlos support UK – https://www.ehlers-danlos.org/
Locating an expert
●Ehlers-Danlos Society – The Healthcare Professionals Directory (https://www.ehlers-danlos.com/healthcare-professionals-directory/) lists experts from around the world.
●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG).
●Genetic counselors – National Society of Genetic Counselors (NSGC). Genetic testing laboratories may also provide online or telephone access to a genetic counselor.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟