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VCAN-Related Vitreoretinopathy

Includes: Wagner Vitreoretinal Degeneration (Wagner Syndrome), Erosive Vitreoretinopathy (ERVR)

, PhD and , MD, PhD.

Author Information
, PhD
Institute of Medical Molecular Genetics
University of Zurich and ETH Zurich
Department of Biology
ETH Zurich
Zurich, Switzerland
, MD, PhD
University Hospital Eye Clinic
University of Zurich
Zurich, Switzerland

Initial Posting: ; Last Update: August 16, 2012.

Summary

Disease characteristics. VCAN-related vitreoretinopathy, which includes Wagner syndrome and erosive vitreoretinopathy (ERVR), is characterized by “optically empty vitreous” on slit-lamp examination and avascular vitreous strands and veils, mild or occasionally moderate to severe myopia, presenile cataract, night blindness of variable degree associated with progressive chorioretinal atrophy, retinal traction and retinal detachment at advanced stages of the disease, and reduced visual acuity. Optic nerve inversion has also been described. Systemic abnormalities are not observed. The first signs usually become apparent during early adolescence, but onset can be as early as age two years.

Diagnosis/testing. The clinical diagnosis of VCAN-related vitreoretinopathy is established based on typical clinical findings and a family history consistent with autosomal dominant inheritance. VCAN (previously known as CSPG2) is the only gene in which mutations are known to cause Wagner syndrome and ERVR.

Management. Treatment of manifestations: Refractive error is corrected by spectacles or contact lenses; visually disabling cataract is treated by cataract surgery, preferably by an experienced surgeon. Retinal breaks without retinal detachment are treated with laser retinopexy or cryocoagulation. Vitreoretinal surgery is indicated for retinal detachment, vitreoretinal traction involving the macula, or epiretinal membranes involving the macula.

Surveillance: Annual ophthalmologic examination by a vitreoretinal specialist.

Evaluation of relatives at risk: For the purpose of early diagnosis and treatment of ophthalmologic complications in at-risk relatives: molecular genetic testing if the disease-causing mutation has been identified in the family; otherwise, ophthalmologic evaluation.

Genetic counseling. VCAN-related vitreoretinopathy is inherited in an autosomal dominant manner. Most individuals diagnosed with VCAN-related vitreoretinopathy have an affected parent. Each child of an affected individual has a 50% chance of inheriting the mutation. Prenatal testing is possible for families in which the disease-causing mutation is known.

Diagnosis

Clinical Diagnosis

VCAN-related vitreoretinopathy is characterized by:

  • “Optically empty vitreous” on slit-lamp examination and avascular vitreous strands and veils
  • Mild or occasionally moderate to severe myopia
  • Presenile cataract
  • Night blindness of variable degree associated with progressive chorioretinal atrophy
  • Retinal traction and detachment at advanced stages of the disease
  • Reduced visual acuity resulting from the above manifestations
  • Absence of systemic abnormalities

The clinical diagnosis of VCAN-related vitreoretinopathy is established based on typical clinical findings and a family history consistent with autosomal dominant inheritance. Not every clinical finding listed above is observed in every affected individual. The hallmark, however, is the empty vitreous. The presence of several affected family members facilitates diagnosis by identifying the mode of inheritance and spectrum of ocular findings among affected family members at different ages. In general, it is the pattern of ocular findings in an individual or a family rather than a specific ocular finding that helps establish the diagnosis. Establishing the diagnosis may be more difficult in a simplex case (i.e., a single occurrence in a family).

Molecular Genetic Testing

Gene. VCAN (previously known as CSPG2), encoding the large extracellular matrix proteoglycan versican, is the only gene in which mutations are known to cause Wagner syndrome and erosive vitreoretinopathy (ERVR) [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006, Meredith et al 2007, Brezin et al 2011, Kloeckener-Gruissem et al 2012].

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in VCAN-Related Vitreoretinopathy

Gene Symbol Test MethodMutations DetectedMutation Detection Frequency by Test Method 1
VCANSequence analysisSequence variants 210/12 families with VCAN-related vitreoretinopathy 3
Deletion / duplication analysis 4Exonic, multiexonic, or whole-gene deletion / duplicationUnknown; none reported 5

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. In ten of twelve families with VCAN-related vitreoretinopathy, sequence analysis of the entire VCAN coding region and flanking introns identified mutations; in two families no mutation was found [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006, Meredith et al 2007].

4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. No deletions or duplications of VCAN have been reported to cause VCAN-related vitreoretinopathy. (Note: By definition, deletion/duplication analysis identifies rearrangements that are not identifiable by sequence analysis of genomic DNA.)

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

1.

Because all VCAN mutations to date associated with Wagner syndrome and ERVR are found in the splice acceptor or splice donor site of introns 7 and 8, respectively, sequencing of this DNA region is recommended as a first step.

2.

If no mutation is found, sequencing of the entire VCAN coding region is recommended.

Of note, the presence of characteristic connective tissue abnormalities in the patient or relatives could prompt genetic testing for Stickler syndrome rather than or in addition to testing for VCAN mutations. See Differential Diagnosis.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Clinical Description

Natural History

VCAN-related vitreoretinopathy comprises the phenotypic continuum of Wagner vitreoretinal degeneration (Wagner syndrome) and erosive vitreoretinopathy (ERVR), two disorders that were previously thought to be distinct entities based on clinical findings. Wagner syndrome, the first reported inherited vitreoretinal degeneration, was described by Wagner [1938]. ERVR was described in 1994 as a new clinical entity with some features that overlapped with Wagner syndrome [Brown et al 1994].

Vitreoretinal degeneration. As described by Wagner [1938], the hallmark of VCAN-related vitreoretinopathy is progressive degenerative changes of the vitreous (syneresis) and the vitreoretinal interface beginning at a young age. Syneresis can lead to massive liquefaction of the vitreous such that on slit-lamp examination the vitreous cavity appears optically empty ("empty vitreous") with pockets of liquefied vitreous that are usually lined by avascular strands and veils. Preretinal vitreous membranes that span the whole equator of the eye are characteristic. Ocular changes show considerable inter- and intrafamilial variability.

The first signs usually become apparent during early adolescence, but onset can be as early as age two years [Miyamoto et al 2005].

No gender-specific difference in the occurrence or frequency of any particular ocular features has been observed.

The vitreous degeneration, which is assumed to be the primary pathology, leads to a number of secondary changes, including presenile cataract, degeneration and atrophy of the retina, and the underlying retinal pigment epithelium (RPE) and choroid, and retinal detachment [Wagner 1938, Jansen 1962, Graemiger et al 1995, Zech et al 1999, Miyamoto et al 2005, Mukhopadhyay et al 2006, Meredith et al 2007].

Common Ocular Features (≤60% of Affected Individuals)

Myopic refractive error (nearsightedness) results from axial myopia (a developmental mismatch of the refractive power and length of the globe) and/or index myopia (a change in the refractive index of the progressively cataractous lens). Axial myopia is common, although severity varies. In the family reported by Wagner, most affected members had mild myopia and only a few had moderate to severe myopia. In contrast, in the Dutch family all members had high myopia with astigmatism [Jansen 1962].

Presenile cataract (progressive loss of transparency of the ocular lens) is a common finding and a common cause of decline in visual acuity over time. The types of cataract vary. Small spherical opacities and posterior subcapsular cataract affected 43% of eyes in the original family reported by Wagner [Graemiger et al 1995]. In the Dutch families, cataract types included moderate cortical cataract, anterior and posterior cortical cataract, and posterior subcapsular cataract [Mukhopadhyay et al 2006]. Nuclear cataract without any posterior subcapsular opacity was described in a British family [Meredith et al 2007].

In a Japanese family, approximately 50% of affected individuals underwent cataract surgery; the oldest was age 35 years [Miyamoto et al 2005]. In a French family, cataract affected 55% of individuals [Zech et al 1999]. Of note, even after cataract extraction and correction of the refractive error, visual acuity was not normal, typically ranging from 6/12 (20/40) to 6/24 (20/80).

Nonspecific reactive changes of the retinal pigment epithelium and overlying retina (pigment condensation, vascular sheathing, pigmented lattice degeneration, and later chorioretinal atrophy in the retinal periphery) occur. Affected individuals may experience nyctalopia (night blindness) and visual field constriction that are not as severe as those seen in retinitis pigmentosa. Nyctalopia may or may not progress. In some cases the chorioretinal atrophy is so severe that it resembles choroideremia. Diffuse retinal pigmentary changes and patchy chorioretinal atrophy are observed in some, but not all family members affected by Wagner syndrome [Meredith et al 2007, Ronan et al 2009].

The full-field electroretinogram (ERG) becomes attenuated. Typically both the amplitudes of the a-waves (response of the photoreceptor layer) and the b-waves (response of the bipolar cell layer) are reduced. The rod and cone systems (as measured by the scotopic and photopic response, respectively) are affected to varying degrees but in a family-specific manner, as demonstrated by the Swiss family originally reported by Wagner, the Japanese family, and the British family [Graemiger et al 1995, Miyamoto et al 2005, Meredith et al 2007]. No ERG measurements were reported from the French and Dutch families [Zech et al 1999, Mukhopadhyay et al 2006].

Abnormal retinal vessels or poor vascularization of the peripheral retina were found in approximately 50% of individuals from the family reported by Wagner [Graemiger et al 1995], but only in a few individuals of the Dutch families [Mukhopadhyay et al 2006]. No details about retinal vessel characteristics were given for the other reported families [Zech et al 1999, Miyamoto et al 2005, Meredith et al 2007].

Retinal detachment was initially found to be associated with increasing age; however, a recent report indicates that detachments can occur earlier (average of 9.5 years) [Ronan et al 2009]. Caused by shrinkage of the preretinal membranes and the vitreous strands and veils, retinal detachment is either tractional or rhegmatogenous.

  • Tractional retinal detachment is caused by tangential shortening of the adhering membranes. The detached retina is rigid; successful surgical repair requires meticulous removal of the membranes and vitreoretinal adhesions and, most often, extensive retinotomies to relieve the traction. Tractional retinal detachment is not a particularly common feature of Wagner syndrome.
  • Rhegmatogenous retinal detachment is caused by retinal breaks associated with the preretinal membranes. Liquefied vitreous fluid enters the potential subretinal space through one or more retinal tears caused by shrinking membranes. The retinal detachment is typically bullous; surgical repair primarily relies on closure of all retinal breaks. Of note, rhegmatogenous retinal detachment associated with hereditary vitreoretinal degeneration in young individuals in a considerable number of cases presents with only minor changes of the vitreous. Consequently, large retinal tears in young persons should raise the suspicion of a hereditary disease, and should prompt examination of other family members and eventually molecular genetic analysis.

In the original publication by Wagner the incidence of retinal detachment at age 20 years was one in four, whereas in the Dutch pedigrees published by Jansen bilateral retinal detachment was a frequent finding at a young age. Of note, follow-up publications of the original Wagner pedigree reported an incidence of retinal detachment more than one in two. Of the few retinal detachments described in the Swiss family reported originally by Wagner and the Dutch families reported by Jansen, some were peripheral tractional [Graemiger et al 1995, Mukhopadhyay et al 2006]. Further tractional effects were observed as situs inversus [Wagner 1938]. Recently, affected individuals were described with inversion of the papilla as a possible consequence of tractional forces [Ronan et al 2009].

In the Japanese family reported by Miyamoto et al [2005], most of the retinal detachments were rhegmatogenous. No retinal detachments were observed in the only two affected individuals reported in a British family [Meredith et al 2007].

Occasional Ocular Features

The following features have been reported rarely. Some may not be part of VCAN-related vitreoretinopathy but rather occur coincidentally.

Spherophakia, a spherical deformation of the ocular lens, has been observed sporadically in persons with VCAN-related vitreoretinopathy [Graemiger et al 1995].

Cataract can induce a change of the refractive index of the lens nucleus, further attenuating the myopic refractive error (index myopia).

Posterior vitreous detachment (PVD), detachment of the posterior vitreous membrane from the retinal surface, is caused by shrinkage of the vitreous body and the pathological vitreoretinal interface. In contrast to the usual age-related PVD, the PVD in VCAN-related vitreoretinopathy initially affects the peripheral rather than the central posterior vitreous. None of the individuals from the original family described by Wagner or the French family showed PVD [Graemiger et al 1995, Zech et al 1999].

Ectopic fovea, manifesting as an increased angle kappa (the angle between the visual axis and the pupillary axis), has occasionally been reported [Graemiger et al 1995, Miyamoto et al 2005, Meredith et al 2007].

Phthisis bulbi (painful shrinking of the ocular globe as a result of loss of intraocular pressure) can occur and may require enucleation of the eye. Retinal detachment that has not been repaired successfully and retinal detachment associated with proliferative retinal vitreoretinopathy (PVR) are risk factors for phthisis bulbi. The decrease in intraocular pressure is caused by decreased aqueous production by the ciliary body epithelium, which becomes compromised by the pathologic vitreoretinal membranes because of the primary vitreal changes, the PVR, or both.

Synchysis scintillans (bilateral accumulation of cholesterol crystals in the vitreous, which may or may not be associated with recurrent vitreous hemorrhage), may or may not occur with increased frequency in VCAN-related vitreoretinopathy, as it was only observed in a few older affected individuals [Graemiger et al 1995, Zech et al 1999].

Optic atrophy was found in only a few of the older individuals from the original Wagner family. These individuals had advanced chorioretinal atrophy, suggesting that optic atrophy is secondary to the massive loss in retinal ganglion cells [Graemiger et al 1995].

Glaucoma may not be a common feature of Wagner syndrome, as only a few individuals with VCAN-related vitreoretinopathy have been reported with glaucoma, none of them having primary open-angle glaucoma (one had congenital glaucoma, two had chronic angle-closure glaucoma, and three had neovascular glaucoma).

Exudative vitreoretinopathy with vascular abnormalities has only been reported in one French family [Brezin et al 2011]; in fact, familial exudative vitreoretinopathy (FEVR) was the initial diagnosis suspected in this family.

Uveitis is also a rare feature observed in individuals with Wagner syndrome. A case was reported in a French [Brezin et al 2011] and a British [Meredith et al 2007] family.

Systemic Findings

To date, no systemic abnormalities associated with VCAN-related vitreoretinopathy have been reported, and consequently VCAN-related vitreoretinopathy is considered an isolated vitreoretinal degeneration.

Note: Recording blood pressure in persons with vitreoretinopathy may reveal possible systemic complications.

Genotype-Phenotype Correlations

Because of the highly variable frequency of findings and the low number of mutations identified to date, no definite genotype-phenotype correlations have been established so far.

Penetrance

Penetrance appears to be complete. Within families reported to date, no unaffected individuals had a VCAN mutation.

Anticipation

Anticipation is not observed.

Nomenclature

Once the molecular basis of Wagner syndrome, originally described by Wagner in 1938, and ERVR, originally described by Brown and colleagues in 1994, was identified, the high similarity of the clinical phenotypes and the fact that both were caused by mutations in the same gene led to the conclusion that both were descriptions of the same disorder, which has been called VCAN-related vitreoretinopathy in this GeneReview [Brown et al 1994, Brown et al 1995, Mukhopadhyay et al 2006].

The predominantly ocular, or nonsyndromic, phenotype of Stickler syndrome, associated with specific mutations in exon 2 of COL2A1, encoding the alpha 1 chain of collagen type II [Richards et al 2000], can readily be distinguished from Wagner syndrome because of its distinctive vitreous phenotype [Snead & Yates 1999]. However, some authors have referred to this form of Stickler syndrome as Wagner syndrome type II and have designated the VCAN-related phenotype as vitreoretinochoroidopathy (VRCP) Wagner syndrome type I [Gupta et al 2002].

Syndrome alias: hyaloideoretinal degeneration of Wagner

Prevalence

Wagner syndrome is a very rare disorder. After the first Swiss pedigree reported by Wagner in 1938, several additional families, some of them very large, have been reported. Including families with ERVR, not more than 50 families or simplex cases of VCAN-related vitreoretinopathy have been reported.

Wagner syndrome has been reported in families of various ethnic backgrounds including white, northern European, Japanese, and Chinese.

Differential Diagnosis

Syndromes with overlapping features. A recent review summarizes the clinical features of inherited vitreoretinopathies and points out the importance of consulting an expert ophthalmologist in diagnostic assessment of the disease [Edwards 2008].

Autosomal Dominant Vitreoretinopathies

Snowflake vitreoretinal degeneration (SVD) (OMIM 193230). Both SVD and VCAN-related vitreoretinopathy exhibit vitreous abnormalities including fibrillar condensation, gel liquefaction, and marked thickening of the cortical vitreous. In SVD, however, membranous degeneration of the vitreous with avascular strands and veils is not observed. Retinal defects start in the superficial retinal layers, whereas in VCAN-related vitreoretinopathy they start in the deep retinal layers and choroid; retinal detachment is uncommon; and the retinal crystalline snowflake-like deposits that give the disease its name are common. Mutations in KCNJ13 are causative [Hejtmancik et al 2008].

Stickler syndrome, or hereditary arthroophthalmopathy, is most often a systemic disorder associated with a skeletal dysplasia (spondyloepiphyseal dysplasia) and craniofacial abnormalities, including cleft palate. Retinal detachment is much more common in Stickler syndrome (50%) than in VCAN-related vitreoretinopathy (15%). Abnormal dark adaptation associated with alterations in the ERG that is common in VCAN-related vitreoretinopathy has not been described in Stickler syndrome. Two different and specific vitreoretinal phenotypes have been described in Stickler syndrome (Stickler syndrome type 1 and type 2). The type 1 vitreoretinal phenotype is caused by mutations in COL2A1 encoding type II procollagen. For certain mutations in COL2A1, a predominantly ocular or nonsyndromic phenotype can result. Usually, however, these patients can be readily distinguished from patients with Wagner syndrome because of the specific vitreous anomaly associated with type 1 Stickler syndrome. However, some authors have referred to this form of Stickler syndrome as Wagner syndrome type II [Gupta et al 2002].

Autosomal dominant vitreoretinochoroidopathy (ADVIRC) (OMIM 193220). Only a few families with vitreoretinochoroidopathy (VRCP) have been described. Affected individuals show the following findings that seem to progress more slowly than those of VCAN-related vitreoretinopathy:

  • Fibrillar condensation of the vitreous, but not optically empty vitreous
  • Chorioretinal hyperpigmentation with peripheral pigmentary clumping
  • Macular atrophy
  • Breakdown of the blood retinal barrier (observed in one family)
  • Normal full-field (Ganzfeld) ERG but altered multifocal ERG pattern
  • Cataract

High myopia and retinal detachment do not appear to be part of VRCP [Oh & Vallar 2006]. Mutations in VMD2, the gene encoding bestrophin, are causative. It appears that splicing defects may cause VRCP, whereas mutations in the coding region result in Best disease [Yardley et al 2004].

Autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV). Bennett et al [1990] reported a six-generation family with an autosomal dominant vitreoretinopathy in which the prevailing clinical features were severe anterior and posterior segment inflammation; neovascular proliferations and related complications, in particular tractional retinal detachment and neovascular glaucoma; and a selective loss of the b-wave amplitude on the ERG early in the disease. Mutations in VMD2 are causative. ADNIV and ADVIRC may be considered to belong to a disease spectrum of VMD2-related autosomal dominant vitreoretinopathies.

Autosomal Recessive Vitreoretinopathies

Goldmann-Favre syndrome (included in enhanced S-cone syndrome). Mutations in NR2E3 (nuclear receptor subfamily 2, group E, member 3) have been identified in Goldmann-Favre syndrome, enhanced S-cone syndrome (ESCS), and clumped pigmentary retinal degeneration [Haider et al 2000]. All these clinical entities are usually associated with night blindness and visual field constriction. Electroretinography characteristically reveals a severe reduction in rod function and a relatively enhanced function of the short-wavelength-sensitive cones.

The classic Goldmann-Favre phenotype includes progressive vitreous changes (vitreous liquefaction and fibrillar strands and veils); night blindness and severe reduction in the ERG in early childhood; chorioretinal atrophy and pigmentary retinal degeneration later in the disease course resulting in marked visual field loss; retinoschisis in the periphery, macula, or both; presenile cataract; and a hyperopic rather than myopic refractive error.

Although ESCS lacks the marked vitreous changes typical of the Goldmann-Favre phenotype, vitreous cells are a very common feature, and more prominent vitreous changes including vitreous opacities, haze, and veils can occur. Peripheral retinal schisis has been observed in ESCS, and foveal schisis, eventually associated with cystoid changes, may even be a common feature. The fundus appearance varies, and features are overlapping with clumped pigmentary retinal degeneration, in which the retinal pigmentary changes are the most prominent feature of the phenotype [Audo et al 2008].

Knobloch syndrome (OMIM 267750). Knobloch syndrome is a syndromic vitreoretinopathy in which ocular changes similar to those of VCAN-related vitreoretinopathy are associated with occipital encephalocele. Mutations in COL18A1, the gene encoding the alpha 1 chain of collagen type 18, are causative [Menzel et al 2004, Keren et al 2007].

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with VCAN-related vitreoretinopathy, the following evaluations are recommended:

  • Baseline ophthalmologic examination including best corrected visual acuity, assessment of intraocular pressure, slit-lamp examination of the anterior segment, and biomicroscopy and indirect ophthalmoscopy of the posterior segment
  • Family history
  • Visual field examination
  • Photographic fundus documentation
  • Optical coherence tomography (OCT), if available. While not mandatory, OCT scan is useful assessing the vitreoretinal interface, quantifying atrophic changes of the central retina, and evaluating for cystoid macular edema.
  • ERG examination
  • Orthoptic assessment

Treatment of Manifestations

Refractive error is corrected by spectacles or contact lenses.

Visually disabling cataract is treated by cataract surgery. Phacoemulsification and implantation of an intraocular lens in the capsular bag has become the widely adopted standard procedure; however, as emphasized by Edwards, cataract surgery in patients with vitreoretinopathy and possibly preceding vitrectomy can be difficult and should be performed by an experienced surgeon [Miyamoto et al 2005, Edwards 2008].

Posterior capsule opacification after cataract surgery is treated with YAG laser capsulotomy.

Retinal breaks are treated with laser retinopexy or cryocoagulation if no retinal detachment is present.

Vitreoretinal surgery is indicated for retinal detachment, vitreoretinal traction involving the macula, or epiretinal membranes involving the macula.

Surveillance

Annual ophthalmologic examination by a vitreoretinal specialist is indicated.

Evaluation of Relatives at Risk

Family mutation known. If the disease-causing mutation has been identified in at least one affected family member, it is appropriate to offer molecular genetic testing to at-risk relatives in order to reduce morbidity by early diagnosis and treatment of ophthalmologic complications.

Family mutation not known. If the disease-causing mutation in the family is not known, it is appropriate to offer ophthalmologic evaluations to those family members at risk in order to identify individuals who presumably will benefit from regular ophthalmologic examinations and early treatment of ophthalmologic complications.

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

Therapies Under Investigation

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Genetic Counseling

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. —ED.

Mode of Inheritance

VCAN-related vitreoretinopathy is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with VCAN-related vitreoretinopathy have an affected parent.
  • A proband with VCAN-related vitreoretinopathy may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is not known.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include ophthalmologic evaluation of both parents. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: (1) Although most individuals diagnosed with VCAN-related vitreoretinopathy have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. (2) If the parent is the individual in whom the mutation first occurred, s/he may have somatic mosaicism for the mutation and may be mildly/minimally affected.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the proband’s parents.
  • If a parent of the proband has VCAN-related vitreoretinopathy, the risk to the sibs is 50%.
  • When the parents are clinically unaffected and/or the disease-causing mutation found in the proband has not been found in the parents, the risk to the sibs of a proband appears to be low.
  • If the disease-causing mutation cannot be found in the proband’s parents, the occurrence of a de novo mutation in the proband is presumed. Germline mosaicism has not been described but remains a possibility.

Offspring of a proband. Each child of an individual with VCAN-related vitreoretinopathy has a 50% chance of inheriting the mutation.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected, his or her 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.

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 maternity (e.g., with assisted reproduction) 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.
  • 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.

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.

Prenatal Testing

If the disease-causing mutation has been identified in the family, prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks’ gestation) or chorionic villus sampling (usually performed at ~10-12 weeks’ gestation).

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for conditions such as VCAN-related vitreoretinopathy are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Wagner Syndrome
    PO Box 501
    Tilburg
    Netherlands
    Phone: 00 31 13 580 14 22
    Email: info@wagnersyndrome.eu
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • Prevent Blindness America
    211 West Wacker Drive
    Suite 1700
    Chicago IL 60606
    Phone: 800-331-2020 (toll-free)
    Email: info@preventblindness.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. VCAN-Related Vitreoretinopathy: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
VCAN5q14​.2-q14.3Versican core proteinVCAN @ LOVDVCAN

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for VCAN-Related Vitreoretinopathy (View All in OMIM)

118661VERSICAN; VCAN
143200WAGNER VITREORETINOPATHY; WGVRP

Molecular Genetic Pathogenesis

Since VCAN is expressed in many human tissues, mutations in VCAN could be expected to interfere with functions in tissues and organs other than the eye; the cardiovascular system in particular would seem a likely candidate, as versican, the protein product of VCAN, is a component of the extracellular matrix of the blood vessels [Yao et al 1994, Lemire et al 1999]. A possible explanation for the absence of consequences of VCAN mutations in non-ocular tissues is that splicing of the VCAN transcripts may be tissue-specific.

Normal allelic variants. The genomic region (109,399 nucleotides) of VCAN includes 15 exons (NCBI Genbank accession number NM_004385.3). The two largest exons, 7 (2961 nucleotides) and 8 (5262 nucleotides), are subject to alternative splicing, yielding four naturally occurring splice variants (named V0, 1, 2, and 3) that exhibit a tissue-specific expression pattern. The respective exon-intron boundaries show the consensus sequences for splice acceptor and splice donor sites.

Pathologic allelic variants. Five different point mutations, all located in conserved splice sites of introns 7 and 8, are associated with the phenotype [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006, Meredith et al 2007, Ronan et al 2009, Brezin et al 2011]. In some cases, identical mutations have been found in different, unrelated families (Table 2). No exonic mutations have been found. In several patients, it was shown that the mutations can lead to aberrant splice products and/or to quantitative changes of the naturally occurring splice variants lacking exon 8.

Table 2. Selected VCAN Pathologic Allelic Variants

DNA Nucleotide Change 1Protein Amino Acid ChangeReference SequencesNumber of Families with Mutation 2Reference
c.9265+1G>A/T
(IVS 8 splice donor)
--NM_004385​.4 NP_004376​.22 Kloeckener-Gruissem et al [2006], Meredith et al [2007], Ronan et al [2009]
c.9265+2T>A--2Kloeckener-Gruissem et al [2012]
c.4004-1G>A
(IVS 7 splice acceptor)
--1 Mukhopadhyay et al [2006]
c.4004-1G>C--1Kloeckener-Gruissem et al [2012]
c.4004-2A>G/T
(IVS 7 splice acceptor)
--1 Miyamoto et al [2005], Brezin et al [2011]
c.4004-5T>C
(IVS 7 splice acceptor)
--4 Mukhopadhyay et al [2006]
c.4004-5T>A
(IVS 7 splice acceptor)
--2 Mukhopadhyay et al [2006]

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. IVS: Intervening sequence; N>N refers to the respective nucleotide exchange.

2. VCAN mutations were identified in eight of ten families with vitreoretinopathy.

Normal gene product. The extracellular matrix proteoglycan (chondroitin sulfate proteoglycan type 2), also named versican, is found in many different tissues in the human body, including the eye [White & Bruzzone 2000]. Four naturally occurring variants accumulate tissue-specifically. They are products of alternative splicing of exons 7 and 8 (see Figure 1). A central domain of the protein, encoded by both exons 7 and 8, carries glycosaminoglycan (GAG) residue modifications, which may be involved in preventing collagen fibrils from sticking together and thus ensuring gel-like properties of the vitreous content.

Figure 1

Figure

Figure 1. Vitreoretinopathy-associated mutations in VCAN and their effects on naturally occurring splice variants and protein isoforms. Under normal conditions, differential splicing leads to four transcript variants and protein isoforms V0, V1, V2, or (more...)

Abnormal gene product. Mutations in splice recognition sequences result in skipping of exon 8 and in the production of aberrant splice products [Miyamoto et al 2005, Kloeckener-Gruissem et al 2006, Mukhopadhyay et al 2006]. One consequence is increased accumulation of isoforms V2 (no exon 8) and V3 (no exon 7 and 8) [Mukhopadhyay et al 2006] and most likely also of the protein isoforms. This may result in severe reduction of GAG modification, which will render the physical properties of the vitreous, leading to a process of premature liquefaction.

References

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Chapter Notes

Acknowledgments

The authors would like to thank Drs. Wolfgang Berger and John Neidhardt for critical reading of the manuscript.

Revision History

  • 16 August 2012 (me) Comprehensive update posted live
  • 3 February 2009 (me) Review posted live
  • 18 April 2008 (bkg) Original submission
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