 |
|
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
Diagnosis/testing. COL3A1 is the only gene associated with EDS, vascular type. The diagnosis of EDS, vascular type is based on clinical findings and confirmed by biochemical (protein-based) and/or molecular genetic testing. Biochemical studies in affected individuals demonstrate abnormalities of type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility. Molecular genetic testing is available to individuals with the biochemically confirmed diagnosis of EDS, vascular type for genetic counseling purposes.
Management. Treatment may include surgery for arterial or bowel complications/rupture. Pregnant women with the vascular type of EDS should be followed in a high-risk obstetrical program. Affected individuals should be instructed to seek immediate medical attention for sudden unexplained pain. A MedicAlert® bracelet should be worn. Surveillance may include periodic arterial screening through venous subtraction angiography and MRI or CT without contrast material. However, arteriograms are not recommended because of the risk of vascular injury. Affected individuals should minimize risk of trauma by avoiding contact sports, heavy lifting, and weight training. Elective surgery is discouraged.
Genetic counseling. The vascular type of EDS is inherited in an autosomal dominant manner. About 50% of affected individuals have inherited the COL3A1 mutation from an affected parent and about 50% of affected individuals have a de novo disease-causing mutation. The risk to the sibs depends upon the genetic status of the proband's parents. If a parent of the proband is affected, the risk to the sibs is 50%. Offspring of an affected individual have a 50% chance of inheriting the mutation and developing the disorder. Both parental somatic mosaicism and parental germline mosaicism have been reported. Prenatal testing is clinically available for fetuses at 50% risk in families in which the underlying biochemical abnormality of type III collagen or the disease-causing mutation in COL3A1 has been identified.
Diagnostic criteria and standardized nomenclature for the Ehlers-Danlos syndromes were suggested by a medical advisory group in a conference sponsored by the Ehlers-Danlos Foundation (USA) and the Ehlers-Danlos Support Group (UK) at Villefranche in 1997 [Beighton et al 1998]. Criteria are modified here to reflect the authors' experience.
The diagnosis of the vascular type of EDS is considered in different clinical settings: following characteristic complications (see below), in the presence of a positive family history, or on the basis of one or more of the minor diagnostic findings listed below.
The combination of any two of the major diagnostic criteria should have a high specificity for EDS, vascular type; biochemical testing is strongly recommended to confirm the diagnosis.
The presence of one or more minor criteria supports the diagnosis of the vascular type of EDS but is not sufficient to establish the diagnosis.
Major diagnostic criteria for the vascular type of EDS include:
Arterial rupture
Intestinal rupture
Uterine rupture during pregnancy
Family history of the vascular type of EDS
Minor diagnostic criteria for the vascular type of EDS include:
Thin, translucent skin (especially noticeable on the chest/abdomen)
Easy bruising (spontaneous or with minimal trauma)
Characteristic facial appearance (thin lips and philtrum, small chin, thin nose, large eyes)
Acrogeria (an aged appearance to the extremities, particularly the hands)
Hypermobility of small joints
Tendon/muscle rupture
Early-onset varicose veins
Arteriovenous carotid-cavernous sinus fistula
Pneumothorax/pneumohemothorax
Chronic joint subluxations/dislocations
Congenital dislocation of the hips
Talipes equinovarus (clubfoot)
Gingival recession
Biochemical (protein-based) testing. Biochemical testing for EDS, vascular type requires cultured dermal fibroblasts. Proteins synthesized by these cells are biosynthetically labeled with radioactive-labeled proline and the proteins synthesized by the cells are assessed by sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE). The amount of type III procollagen synthesized, the quantity secreted into the medium, and the electrophoretic mobility of the constituent chains are assessed. Cells from individuals with EDS, vascular type have abnormalities of type III procollagen production, intracellular retention, reduced secretion, and/or altered mobility.
Biochemical testing for the vascular type of EDS probably identifies more than 95% of individuals with structural alterations in the proteins synthesized, but may be less sensitive in identifying vascular EDS that is a consequence of mutations that decrease production [Pepin et al 2000, Schwarze et al 2001].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. COL3A1 is the only gene associated with EDS, vascular type.
Molecular genetic testing: Clinical uses
Molecular genetic testing: Clinical method
Sequence analysis. Two methods to identify mutation in the COL3A1 gene are available. The choice of method depends on the available biological samples.
If analysis of type III procollagen synthesized by cultured cells identifies an abnormality in chain mobility, sequence of COL3A1 cDNA provides a substrate for mutation detection.
Direct analysis of the COL3A1 gene provides an alternative approach when a blood sample or other source of genomic DNA is the only sample available. (When this approach is used, some classes of mutations may be missed, particularly small genomic deletions of single or multiple exons.)
| Test Method | Mutations Detected | Mutation Detection Rate | Test Availability |
|---|---|---|---|
| cDNA or genomic DNA sequence analysis | COL3A1 sequence alterations | 98-99% | Clinical
 |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
Biochemical and direct genetic analysis are alternative and complementary approaches to diagnosis and may be determined by the most readily available clinical sample. The relative sensitivities of each are probably similar; different classes of mutations are less easily recognized by each.
Protein-based studies may be less sensitive for the identification of mutations that decrease production but do not alter structure of type III procollagen.
Genomic analysis misses single or multiple exon deletions or allele deletion and identifies variants of unknown significance, the role of which may be defined by study of proteins.
Ehlers-Danlos syndrome, hypermobility type (EDS III). A single report of a family with clinical features of EDS III and a COL3A1 mutation typically associated with the vascular type of EDS (G637S) [Narcisi et al 1994] led to the suspicion of a causative relationship between COL3A1 mutations and EDS III; however, biochemical studies of collagen synthesis have not identified a type III collagen defect in other families with EDS III. Given the relatively young ages of most individuals in the reported family and sparse history, reassessment is warranted.
Familial aortic aneurysm. A COL3A1 glycine substitution mutation was identified in one family with familial aortic aneurysm [Kontusaari, Tromp, Kuivaniemi, Ladda et al 1990] and in another family with aortic aneurysm [Kontusaari, Tromp, Kuivaniemi, Romanic et al 1990]. One of the reported families likely had the vascular type of EDS that had gone undetected prior to identification of the mutation. It is possible that the second family with aortic aneurysm represents the milder end of a clinical spectrum caused by mutations in the COL3A1 gene. However, studies of other families with familial and nonfamilial aneurysm have revealed no evidence of causative type III collagen mutations [Kuivaniemi et al 1993, Tromp et al 1993].
A retrospective review of the health history of more than 400 individuals with the vascular type of EDS confirmed by biochemical and/or molecular genetic testing delineated the natural history of the disorder [Pepin et al 2000]. Among individuals ascertained as a result of complications, 25% had experienced a significant medical complication by age 20 years and more than 80% by age 40 years. In a population ascertained on the basis of major complications or clinical criteria alone, in which all had evidence of abnormal type III procollagen production in cultured dermal fibroblasts, the median age of death is 48 years.
About 12% of neonates with the vascular type of EDS have clubfoot and three percent have congenital dislocation of the hips. In childhood, inguinal hernia, pneumothorax, and recurrent joint dislocation or subluxation are common. Affected individuals often have a lifelong history of easy bruising. Keratoconus [Kuming & Joffe 1977], periodontal disease, and venous varicosities have been reported [Tsipouras et al 1986]. Most children with the vascular type of EDS have few complications and, in families with negative family history, the disease is often unrecognized in childhood.
Vascular rupture or dissection and gastrointestinal perforation or organ rupture are the presenting signs in 70% of adults with the vascular type of EDS. Such complications are dramatic and unexpected, often presenting as sudden death, stroke and its neurological sequelae, acute abdomen, retroperitoneal bleeding, uterine rupture at delivery, and/or shock. The average age for the first major arterial or gastrointestinal complication is 23 years.
Vascular complications include rupture, aneurysm, and/or dissection of major or minor arteries. Arterial rupture may be preceded by aneurysm, arteriovenous fistulae, or dissection, but also may occur spontaneously. The sites of arterial rupture are the thorax and abdomen (50%), head and neck (25%), and extremities (25%). Although uncommon, the vascular type of EDS is a cause of stroke in young adults. The mean age of intracranial aneurysmal rupture, spontaneous carotid-cavernous sinus fistula, and cervical artery aneurysm is 28 years [North et al 1995].
Rupture of the gastrointestinal tract occurs in about 25% of affected individuals. The majority of GI perforations occur in the sigmoid colon. Rupture of the small bowel and stomach have been reported, though infrequently. Bowel rupture is rarely lethal (3%) [Pepin et al 2000]. Recurrent bowel rupture proximal to the first sigmoid tear is common.
Surgical intervention for bowel rupture is necessary and usually lifesaving. Complications during and following surgery are related to tissue and vessel friability, which result in recurrent arterial or bowel tears, fistulae, poor wound healing, and suture dehiscence. Individuals who survive a first complication may experience recurrent rupture. The timing and site of repeat rupture cannot be predicted by the first event.
Rare complications include organ rupture that may involve the heart, with ventricular rupture, the spleen, or the liver [Pepin et al 2000, Ng & Muiesan 2005].
Pregnancy for women with the vascular type of EDS has as much as a 12% risk for death from peripartum arterial rupture or uterine rupture [Pepin et al 2000].
The majority (~2/3) of identified mutations result in substitution of other amino acids for glycine residues in the [Gly-X-Y]343 triplets of the triple helical domain. Most of the remaining mutations affect splice sites and usually result in exon skipping, but other more complex outcomes can occur. A small number of mutations that lead to mRNA instability of the products of the allele or to failure of chain association in the trimer have been identified. The phenotypic effects of substitutions for glycine and exon-skipping events are similar.
Individuals with COL3A1 null mutations may have a delay in the onset of first symptoms. The number of families described with COL3A1 null mutations is small [Schwarze et al 2001].
The marked acrogeroid phenotype appears to reflect the presence of mutations that alter sequences in the carboxyl-terminal end of the type III collagen triple helix [Johnson et al 1995].
In families identified on the basis of clinical complications, penetrance of the vascular EDS phenotype appears to be close to 100%; however, the age of detection of the phenotype may vary.
In the analysis of the mutations identified in the COL3A1 gene to this point, at least two classes of mutations — substitutions of glycine in the triple helical domain by alanine and introduction of premature termination codons — are under-represented among individuals with vascular EDS. Thus, some mutations in COL3A1 may not produce a vascular EDS phenotype.
Anticipation does not occur.
The following terms have been used to describe the vascular type of EDS:
Status dysvascularis: introduced by Sack (1936), never used extensively
Familial acrogeria: used by Gottron (1940); probably included some individuals with vascular EDS
Sack-Barabas syndrome or the Sack-Barabas type of Ehlers-Danlos syndrome: used after Barabas (1967) introduced the disorder to the English language literature
Over the last 15 years, the authors have identified about 800 affected individuals in families in the US, consistent with a minimum prevalence of about 1:250,000. [P Byers & M Pepin, personal observation].
Because many families with the vascular type of EDS are identified only after a severe complication or death, it is likely that individuals/families with COL3A1 mutations with a mild phenotype do not come to medical attention and therefore go undetected.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Other forms of Ehlers-Danlos syndrome should be considered in individuals with easy bruising, joint hypermobility, and/or chronic joint dislocation who have normal collagen III biochemical studies. The disorders in which clinical findings overlap with the vascular type of EDS include the following:
Ehlers-Danlos syndrome, classic type is an autosomal dominant disorder characterized by soft, doughy, stretchy skin, abnormal scars, and significant large-joint hypermobility without accompanying blood vessel, bowel, or organ rupture. The diagnosis is based on clinical and family history findings. Approximately 50% of individuals with EDS, classic type have an identifiable mutation in the COL5A1 or COL5A2 gene.
Ehlers-Danlos syndrome VI (kyphoscoliotic form) is an autosomal recessive disorder characterized by progressive scoliosis, hypotonia, easy bruising and tissue fragility, and fragility of the globe. Vascular rupture may be a feature of this type of EDS. EDS, kyphoscoliotic form is caused by mutations in the PLOD1 gene, which encodes lysyl hydroxylase 1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1). The diagnosis of EDS, kyphoscoliotic form relies upon the demonstration of an increased ratio of deoxypyridinoline to pyridinoline crosslinks in urine measured by HPLC.
Ehlers-Danlos syndrome VIII (periodontal form) is a rare connective tissue disorder including features of the classic type and the vascular type, but with the additional findings of early periodontal friability. Recent studies suggest that a gene for a variety of this type of EDS is located on the short arm of chromosome 12.
Isolated arterial aneurysm is usually NOT the result of a type III collagen defect. Familial forms of arterial aneurysm have been linked to at least three different loci.
Loeys-Dietz syndrome is an autosomal dominant disorder characterized by aneurysms that result from mutations in the genes TGFBR1 and TGFBR2, encoding the TGFβ receptor. The clinical presentation may be heterogeneous and include aneurysm and rupture in the first year of life, craniofacial abnormalities, a Marfan-like physical presentation, or familial aortic aneurysm. One group of individuals has clinical features that overlap with vascular EDS. The diagnosis is made by sequence analysis of the two genes.
Other causes of arterial rupture include localized trauma and collagen vascular disease.
Polycystic kidney disease, autosomal dominant is characterized by progressive cyst development and bilaterally enlarged polycystic kidneys. Cysts also occur in liver, seminal vesicles, pancreas, and arachnoid membrane. Non-cystic abnormalities include intracranial aneurysms and dolichoectasias, dilatation of the aortic root and dissection of the thoracic aorta, mitral valve prolapse, and abdominal wall hernias. The renal manifestations of ADPKD include renal function abnormalities, hypertension, renal pain, and renal insufficiency. ADPKD is caused by mutations in the PKD1 gene in 85% of affected individuals; in 15% of individuals, mutations in PKD2 are causative. This disorder should be considered in individuals with intracranial aneurysm.
Marfan syndrome should be considered if the presenting vascular complication is an aortic aneurysm or dissection. The vascular type of EDS and Marfan syndrome can be distinguished relatively easily on physical examination. Individuals with Marfan syndrome typically have dolichostenomelia and arachnodactyly, lens dislocation, and dilatation or aneurysm of only the aorta. Marfan syndrome is a clinical diagnosis based upon family history and the observation of characteristic findings in multiple organ systems. It is caused by mutations in FBN1.
Gastrointestinal entities to be considered in individuals of any age with large or small bowel rupture are perforated diverticulitis, irritable bowel disease, or inflamed Meckel's diverticulum. Isolated gastrointestinal bleeding, as seen in pseudoxanthoma elasticum and hereditary hemorrhagic telangectasia, is not part of the usual presentation of EDS, vascular type.
Currently, no consensus exists regarding the extent of evaluation at the time of initial diagnosis. Evaluation often depends on the circumstances in which the diagnosis is made.
If the diagnosis is considered or made at the time of assessment for and surgical treatment of bowel rupture, usually little additional assessment is necessary.
If the diagnosis is made at the time of arterial rupture, the remainder of the arterial tree is often assessed by CAT or MRI in the process of identifying the site of hemorrhage.
For the asymptomatic adult or child identified on the basis of family studies, it is not clear that additional assessment is required. However, it has been suggested that a noninvasive evaluation of the arterial tree could help to pinpoint locations of future arterial tears. No data to assess this idea currently exist.
When surgery is required for the treatment of arterial or bowel complications or other health problems, it is appropriate to minimize surgical exploration and intervention [Oderich et al 2005]. In general, surgical procedures are more likely to be successful when the treating physician is aware of the diagnosis of the vascular type of EDS and its associated tissue fragility.
Prompt surgical intervention of bowel rupture: bowel continuity can be restored successfully in most instances either at the time of initial surgery or in a subsequent repair of a colostomy.
The recurrence of bowel tears proximal to the original site and the risk of complications resulting from repeat surgery have led some to recommend distal colectomy to reduce the risk for recurrent bowel rupture. Some physicians and affected individuals consider total colectomy as a prophylactic measure to avoid recurrent bowel complications and the need for repeat surgery [Freeman et al 1996, Fuchs & Fishman 2004].
It is prudent to follow pregnant women with the vascular type of EDS in a high-risk obstetrical program. It is not known if the potential benefits of elective caesarian section (decreasing the risk of mortality) outweigh the potential risks (increasing morbidity). Educating the pregnant individual as to possible complications and the need for close monitoring is recommended.
Affected individuals should be instructed to seek immediate medical attention for sudden unexplained pain.
A MedicAlert® bracelet should be worn.
No measures to prevent arterial vessel tears are known.
Treatment of hypertension, if present, is essential.
The necessity for periodic arterial screening is uncertain and can only be determined by a detailed study. If such screening is undertaken, arteriograms are not recommended because arterial tear/dissection may result at the site of entry of the catheter; and injection pressure may lead to arterial aneurysms. Preferable modes of surveillance include venous subtraction angiography and MRI or CT scan without contrast material.
Trauma. Because of inherent tissue fragility, it is prudent for individuals with the vascular type of EDS to minimize the risk of trauma by avoiding collision sports (e.g., football), heavy lifting, and weight training. No evidence suggesting that moderate recreational exercise is detrimental exists.
Elective surgery. Increased tissue fragility results in a higher risk of surgical complications; thus, elective surgery for individuals with the vascular type of EDS is discouraged. In general, avoidance of surgery in favor of more conservative management is advised. For example, bleeding from a small vessel into a confined space is often best treated conservatively.
Arteriograms. Because arterial tear/dissection may result at the site of entry of the catheter, arteriograms are not recommended; injection pressure may lead to arterial aneurysms.
The genetic status of at-risk relatives should be clarified through clinical evaluation and/or genetic testing. For those found to be affected, management is the same as for individuals identified through clinical findings.
A clinical trial of the effectiveness of β-adrenergic blockage for the reduction of risk of arterial rupture or dissection is currently underway in Europe.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
The vascular type of EDS is inherited in an autosomal dominant manner.
Parents of a proband
About 50% of affected individuals have inherited the COL3A1 mutation from an affected parent and about 50% of affected individuals have a de novo disease-causing mutation.
Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include physical examination and molecular genetic testing as the rate of parental mosaicism in families with EDS IV is as high as 20%.
Parental somatic mosaicism for COL3A1 mutations that includes the germline has been documented in eleven families in which affected individuals have been born to unaffected parents; mosaicism that is apparently limited to the germline has been reported in two families [Kontusaari et al 1992, Richards et al 1992, Milewicz et al 1993, Byers et al 2003, Palmeri et al 2003].
Note: Although many individuals diagnosed with the vascular type of EDS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members or later onset of the disease in the affected parent.
Sibs of a proband
The risk to the sibs depends upon the genetic status of the proband's parents.
If a parent of the proband is affected, the risk to the sibs is 50%.
If the parents are clinically unaffected and/or the proband's disease-causing mutation cannot be detected in DNA extracted from the leukocytes of either parent, there remains a chance that one parent is mosaic in his or her germline. In this instance the composite risk (which combines the risk of parental mosaicism and de novo mutation in the proband) is greater than 0 but less than 7.8% [Byers et al 2003].
Offspring of a proband. Each child of an individual with the vascular type of EDS has a 50% chance of inheriting the mutation and developing the disorder.
Other family members of a proband
Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or undisclosed adoption could also be explored.
Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
Testing of at-risk asymptomatic individuals during childhood. In the case of the vascular form of EDS, the benefits of testing individuals during childhood include (1) elimination of concern for those children who do not have the COL3A1 mutant allele identified and (2) improved surveillance, awareness of treatment for potential complications, and appropriate restriction of high-impact sports for those with the mutant allele.
Testing of apparently asymptomatic individuals during childhood for disorders in which most of the complications occur in adulthood raises ethical considerations. Consensus holds that individuals at risk for adult-onset disorders should not be tested during childhood in the absence of symptoms if the testing can have no positive consequences, such as intervention or improved surveillance.The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications [Bloch & Hayden 1990, Harper & Clarke 1990]. (See also the National Society of Genetic Counselors resolution on genetic testing of children and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.)
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Biochemical testing. Prenatal diagnosis is possible for fetuses at increased risk in families in which the underlying biochemical abnormality of type III collagen has been identified. Prenatal diagnosis using the biochemical assay can only be performed on cultured cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks' gestation.
Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see
.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
| Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|
| COL3A1 | 2q31 | Collagen alpha-1(III) chain | COL3A1 |
| 120180 | COLLAGEN, TYPE III, ALPHA-1; COL3A1 |
| 130050 | EHLERS-DANLOS SYNDROME, TYPE IV, AUTOSOMAL DOMINANT |
Normal allelic variants: The COL3A1 cDNA comprises 51 exons distributed over 44 kb of genomic DNA.
Pathologic allelic variants: Over 400 mutations in the COL3A1 gene that result in a disease-causing phenotype have been identified. The majority of identified mutations are point mutations that result in single amino acid substitutions for glycine in the GLY-X-Y repeat of the triple helical region of the type III collagen molecule. About one-third of the known mutations occur at splice sites, and most result in exon skipping. A smaller number of splice mutations lead to the use of cryptic splice sites with partial exon exclusion or intron inclusion. The vast majority of exon-skipping splice site mutations have been identified at the 5' donor site with very few found at the 3' splice site [Schwarze et al 1997]. Several partial gene deletions have been reported as well. Less common are mutations that create new chain termination codons and result in COL3A1 haploinsufficiency ("null" mutations) [Schwarze et al 2001]. The consequence is synthesis of about one-half the amount of normal type III procollagen. (See collagen database of human type I and type III collagen mutations.)
Normal gene product: Collagen proα1 (III) chain. The COL3A1 gene encodes the 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 1,467 amino acids in length.
Abnormal gene product: Mutations of the COL3A1 gene typically result in a structural alteration of type III collagen that leads to intracellular storage and impaired secretion of collagen chains.
See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals. GeneTests provides information about selected organizations and resources for the benefit of the reader; GeneTests is not responsible for information provided by other organizations.—ED.
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
7 June 2006 (me) Comprehensive update posted to live Web site
25 January 2005 (cd) Revision: change in availability of clinical testing
14 April 2004 (me) Comprehensive update posted to live Web site
15 April 2002 (me) Comprehensive update posted to live Web site
2 September 1999 (me) Review posted to live Web site
6 April 1999 (mp) Original submission
