NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Familial Exudative Vitreoretinopathy, Autosomal Dominant

Synonym: adFEVR

, PhD, BSc and , PhD, BSc, MBChB, FRCOphth.

Author Information
, PhD, BSc
Royal Society Principal Research Fellow
Honorary Associate Professor
Section of Ophthalmology and Neuroscience
Leeds Institute of Molecular Medicine
University of Leeds
Leeds, United Kingdom
, PhD, BSc, MBChB, FRCOphth
Consultant in Ophthalmology
Hull Royal Infirmary
Kingston upon Hull, United Kingdom

Initial Posting: ; Last Revision: September 22, 2011.

Summary

Disease characteristics. Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is characterized by failure of peripheral retinal vascularization. The visual problems and variable phenotype associated with adFEVR result from secondary complications caused by retinal ischemia. The retinal avascularity is probably present from birth and generates sequelae that stabilize in early adult life or progress in later life. Expressivity may be asymmetric and is highly variable, ranging from mild or asymptomatic to severe (e.g., registered as blind) within the same family.

Diagnosis/testing. The diagnosis of adFEVR is based on a family history compatible with autosomal dominant inheritance and bilateral peripheral retinal avascularity, seen temporally, by indirect ophthalmoscope and scleral indentation, or by fundus fluorescein angiography. Mutations in one of three genes are known to be associated with adFEVR: FZD4, encoding the protein frizzled-4; LRP5, encoding low-density lipoprotein receptor-related protein 5; and TSPAN12, encoding tetraspanin-12. Mutations in these genes are responsible for fewer than 50% of adFEVR cases. Another locus, EVR3, has been mapped; the gene is not known.

Management. Treatment of manifestations: Prophylactic cryotherapy or argon laser photocoagulation to induce regression of new vessel growth caused by ischemia resulting from retinal avascularity; treatment is similar for retinal holes and areas of retinal exudate to prevent retinal detachment; rhegmatogenous retinal detachments produced by retinal traction are repaired surgically using conventional methods and exudative retinal detachments may be stabilized with cryotherapy, but prognosis is guarded for both.

Prevention of secondary complications: Reduced bone density would be expected to benefit from drugs used to treat osteoporosis; however, long-term follow-up data are not yet available.

Surveillance: Regular fundus examination in children to evaluate for neovascularization, traction, or exudate; review of individuals with retinal traction at intervals determined by the clinical findings.

Evaluation of relatives at risk: Fundus examination and fundus fluorescein angiography to identify characteristic lesions to allow early treatment.

Genetic counseling. Autosomal dominant FEVR is inherited in an autosomal dominant manner. Offspring of an affected individual are at a 50% risk of inheriting the mutation, but many individuals with adFEVR can be asymptomatic because of reduced penetrance. Prenatal testing is possible if the disease-causing mutation has been identified in the family.

Diagnosis

Clinical Diagnosis

The diagnosis of autosomal dominant familial exudative vitreoretinopathy (adFEVR) is based on the following:

  • Family history compatible with autosomal dominant inheritance
  • Bilateral peripheral retinal avascularity (Figure 1)
    • Retinal avascularity is usually seen temporally, but may be missed unless an indirect ophthalmoscope and scleral indentation are used.
    • Retinal vascular changes may be more apparent with fundus fluorescein angiography; one small study has suggested that this method identifies 100% of FEVR cases [Ober et al 1980].
Figure 1

Figure

Figure 1. Classic features of FEVR

1A. Fundus fluorescein angiogram showing the temporal retinal periphery of the right eye of a mildly affected person. Black areas to the left of the photograph represent loss of the normal capillary (more...)

Other retinal abnormalities that support the diagnosis:

  • Retinal neovascularization and peripheral brush border anastomoses
  • Peripheral fibrovascular mass
  • Retinal holes/tears that may be associated with retinal detachment
  • Retinal traction (with macular ectopia and/or straightening of vessels at the posterior pole, acute-angle vascular branching) that may be associated with retinal detachment
  • Exudation that may be associated with retinal detachment
  • Falciform retinal folds

Rare retinal features:

  • Retinoschisis
  • Giant retinal tears

No characteristic electrophysiologic features have been identified.

Molecular Genetic Testing

Genes. To date, mutations in one of three genes are known to be associated with adFEVR:

The proportion of adFEVR attributed to mutations in each of the genes varies by study:

Evidence for further locus heterogeneity. A fourth locus for adFEVR, EVR3 (chromosomal locus 11p12-p13), has been mapped; the gene is not yet known [Downey et al 2001].

Clinical testing

  • FZD4. Sequence analysis of FZD4 has identified various types of mutations (missense, nonsense, small deletions, small insertions); no splice mutations have been reported. The mutations appear to be evenly distributed throughout the gene. No mutational hot spots have been identified.
  • LRP5. Sequence analysis of LRP5 has identified many types of mutations (missense, nonsense, small deletions, small insertions, splicing). The mutations appear to be evenly distributed throughout the gene. No mutational hot spots have been identified. Each mutation appears to be family specific.
  • TSPAN12. Sequence analysis of TSPAN12 has identified all types of mutations (missense, nonsense, small deletions, small insertions, splicing). The mutations appear to be evenly distributed throughout the gene. No mutational hot spots have been identified. Each mutation appears to be family specific with the exception of c.709G>C (p.Ala237Pro), which is common in the Netherlands.

Table 1. Summary of Molecular Genetic Testing Used in Familial Exudative Vitreoretinopathy, Autosomal Dominant

Gene 1Proportion of adFEVR Attributed to Mutations in This GeneTest MethodMutations Detected 2
FZD44%-40%Sequence analysis 3Sequence variants
LRP512%-25%
TSPAN123%-10%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm/establish the diagnosis in a proband

  • The diagnosis of adFEVR is based on a family history compatible with autosomal dominant inheritance and bilateral peripheral retinal avascularity, seen temporally, by indirect ophthalmoscope and scleral indentation, or by fundus fluorescein angiography.
  • Molecular genetic testing should begin with sequence analysis of FZD4.
  • If a pathogenic mutation is not identified, sequence analysis of LRP5 should be performed.
  • If a pathogenic mutation is not identified, sequence analysis of TSPAN12 should be performed.
  • Because not all genes associated with adFEVR are known, failure to identify a mutation in FZD4, LRP5 or TSPAN12 does not rule out the 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

All individuals with autosomal dominant familial exudative vitreoretinopathy (adFEVR) have failure of peripheral retinal vascularization, which by itself usually causes no clinical symptoms. The visual problems and variable phenotype associated with adFEVR result from secondary complications caused by retinal ischemia. This region of retinal avascularity is presumed to be present from birth and initially was thought to generate sequelae that stabilized in early adult life [Ober et al 1980, Tasman et al 1981]. Later studies suggested that disease may progress into later life [Shukla et al 2003].

Autosomal dominant FEVR shows highly variable expressivity and may be markedly asymmetric. The phenotype ranges from mild to severe even within the same family. At the mild end of the spectrum, individuals are asymptomatic; at the severe end, children are registered as blind shortly after birth.

Forty-one percent of the individuals reported by Shukla et al [2003] were at the mild end of the spectrum, in which vision is normal; the only manifestation was an asymptomatic sector of peripheral retinal avascularity. A proportion of individuals demonstrate retinal exudates and retinal traction; about 20% develop rhegmatogenous retinal detachment [Miyakubo et al 1984, van Nouhuys 1991]. Individuals with this severe phenotype often present in the first ten years of life with reduced vision, strabismus, and/or leukocoria.

Individuals with adFEVR and mutations in LRP5 have been observed to have reduced bone mass [Toomes et al 2004a, Qin et al 2005]. Preliminary studies indicate that this finding is not seen in individuals with FEVR who have FZD4 mutations or those with other forms of FEVR [Qin et al 2005; Toomes, personal communication]. Reduced bone mass is often evident only upon examination and predisposes affected individuals to bone fractures.

Genotype-Phenotype Correlations

Although the phenotype has appeared to be indistinguishable by gene involved, research suggests that individuals with adFEVR who have mutations within LRP5 may show signs of osteopenia or osteoporosis on dual x-ray absorptiometry (DXA) [Toomes et al 2004a, Qin et al 2005].

Possible complex inheritance of FEVR. A family with mutations in both FZD4 (c.1250G>A; p.Arg417Gln) and LRP5 (c.1330C>T; p.Arg444Cys) in cis configuration on the same chromosome had a more severe phenotype than another unrelated family with the same FZD4 mutation only [Qin et al 2005]. Three of four affected family members with both mutations were blind, whereas three of four affected family members with only the FZD4 mutation were asymptomatic. These findings suggest synergy between the FZD4 mutation (p.Arg417Gln) and the LRP5 mutation (p.Arg444Cys) in the adFEVR phenotype [Qin et al 2005].

In a family with FEVR with an FZD4 mutation c.1463G>A (p.Gly488Asp), one affected individual had an FZD4 sequence variant c.205C>T (p.His69Tyr) in trans configuration associated with a more severe ocular phenotype than that in family members with the p.Gly488Asp mutation only [Kondo et al 2003]. This p.His69Tyr variant was also found in controls and in another family with adFEVR [Omoto et al 2004]. The proband of the family reported by Omoto et al [2004] had a severe phenotype at age six years, while her affected mother and brother had a mild subclinical form of the disease.

Early data suggesting that the factor V Leiden mutation could be modifying the phenotype was not supported by subsequent studies. The cosegregation of an FZD4 mutation c.1502delCT and the factor V Leiden mutation in a family with a severe adFEVR phenotype suggested that the factor V Leiden mutation could be modifying the phenotype [Shastry & Trese 2004]. However, the report of a second family with the same FZD4 mutation and a severe FEVR phenotype but without the Leiden mutation [Bottomley et al 2006] suggested that the cosegregation of these two mutations in the first family was the result of chance alone. This conclusion was further supported by the failure of Bottomley et al [2006] to identify a factor V Leiden mutation in 14 additional families with adFEVR.

Penetrance

When using fluorescein angiography to determine clinical status, penetrance is reported to be 100% because all affected individuals have a sector of avascular peripheral retina [Ober et al 1980].

Using examination of the retina with an indirect ophthalmoscope through a dilated pupil to determine clinical status, penetrance is considered to be about 90% [van Nouhuys 1982].

Using reduced vision or other clinical symptoms to determine clinical status, penetrance as low as 10% is reported.

Prevalence

FEVR is often described as a very rare disorder. The prevalence has not been calculated; however, given that molecular testing has shown that as many as 90% of affected individuals may be asymptomatic, it is likely that the frequency of the disorder is underestimated.

FEVR has been described in all ethnic groups.

Differential Diagnosis

Familial exudative vitreoretinopathy (FEVR) can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. The mode of inheritance cannot be distinguished by clinical examination alone.

Incontinentia pigmenti (IP) is a rare X-linked dominant disorder affecting the skin, hair, teeth, nails, and eyes. The eye phenotype is present in one third of affected individuals and resembles FEVR. The other findings of IP distinguish it from FEVR.

Acquired disorders that resemble adFEVR:

  • Retinopathy of prematurity (ROP), a sporadic disorder, is the best phenocopy for FEVR. ROP is characterized by failure of the peripheral retinal vasculature to develop, partly as a result of premature birth prior to the completion of retinal vascularization. In some infants with ROP, retinal neovascularization and cicatricial sequelae appear similar to those seen in individuals with FEVR. The history of prematurity and the lack of a family history of FEVR help to distinguish ROP from FEVR.
  • Coats disease, persistent fetal vasculature syndrome, and toxocariasis have distinctive clinical pictures that may resemble features of the FEVR phenotype, including peripheral retinal fibrovascular mass, retrolental membranes, and exudative detachment.
    • Coats disease (OMIM 300216) is characterized by severe retinal telangiectasia. Abnormal vessels can be present throughout the fundus, producing massive exudates that may lead to retinal detachment. It is commonly seen unilaterally in boys.
    • Persistent fetal vasculature syndrome or persistent hyperplastic primary vitreous (PHPV) is characterized by retrolental fibrovascular membranes reminiscent of Norrie disease (see NDP-Related Retinopathies). It is observed in full-term infants and is attributed to failure of regression of the hyaloid vasculature. Involvement is usually unilateral but can be bilateral. Occurrence is usually sporadic but occasionally familial. In contrast to FEVR, the involved eyes are often microphthalmic. Clinical features of abnormal hyaloid artery regression, the physiologic process thought to underlie PHPV, are also seen in some persons with FEVR. In one family with autosomal recessive FEVR, affected family members had a tuft of gliotic tissue at the disc (Bergmeister's papillae) or central vitreous opacity extending from the posterior pole to the lens suggestive of a persistent hyaloid artery [Downey et al 2006].
    • Toxocariasis is an acquired, usually unilateral, infestation with the round-worm Toxocara canis. In one form, a peripheral granulomatous mass develops. Retinal traction may ensue, forming a retinal fold. The uveitis that can be associated with toxocariasis is not a feature of FEVR.

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 autosomal dominant familial exudative vitreoretinopathy (adFEVR), the following evaluations are recommended:

  • Ophthalmologic examination, including indirect ophthalmoscopy and scleral depression
  • Fundus fluorescein angiography, which increases the detection rate of peripheral avascularity in asymptomatic affected individuals [Ober et al 1980]

Treatment of Manifestations

Retinal avascularity per se often requires no treatment; however, it can induce ischemia, leading to neovascularization of the retinal periphery, which can be treated with prophylactic cryotherapy or argon laser photocoagulation to attempt to induce regression of the new vessels. Similar treatments are used to treat retinal holes and areas of retinal exudate to prevent retinal detachment.

Rhegmatogenous retinal detachments produced by retinal traction are repaired surgically using conventional methods, but the prognosis is guarded.

Exudative retinal detachments may be stabilized with cryotherapy, but the prognosis is poor.

Prevention of Primary Manifestations

The arc of peripheral retinal avascularity, thought to be an aberration of retinal development, is not preventable using current treatments.

Prevention of Secondary Complications

Patients with FEVR associated with reduced bone density would be expected to benefit from drugs used to treat osteoporosis, although long-term data demonstrating an increase in bone density in these patients is not yet available [Downey et al 2006].

Surveillance

Children who are at risk based on family history should undergo regular fundus examination to evaluate for the development of retinal neovascularization, traction, or exudate.

Asymptomatic individuals with a small region of peripheral avascularity may require annual review only. Those with active neovascularization or exudate may well require treatment and close observation thereafter.

Individuals with retinal traction require review at intervals depending on the degree of stability of the clinical findings. The frequency of the review varies by individual depending on the assessment of the examining clinician.

Evaluation of Relatives at Risk

Relatives at risk benefit from fundus examination and, ideally, fundus fluorescein angiography to identify any characteristic lesions. Prophylaxis in the form of peripheral retinal ablation with laser photocoagulation or cryotherapy depends on the individual's age and the progression of the lesion.

If the pathogenic mutation has been identified in an affected family member, molecular genetic testing of at-risk family members may be useful: relatives who do not have the family-specific mutation do not need regular retinal examinations.

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

Therapies Under Investigation

Vascular endothelial growth factor (VEGF) inhibitors are currently in widespread use for acquired retinal diseases with a neovascular or exudative component. An as-yet unpublished study presented information on six children with FEVR and sight-threatening retinal neovascularization and exudate who had failed to stabilize with conventional treatments [Drenser 2006]. Treatment with pegaptanib sodium intravitreal injection resulted in a sustained decrease in exudate over six months; however, retinal traction continued to progress; in some eyes this appeared to be initiated by VEGF inhibition. The long-term effects of VEGF inhibition on the eye and the effects of VEGF inhibition in a pediatric population are currently unknown.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

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

Autosomal dominant familial exudative vitreoretinopathy (adFEVR) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed with adFEVR have inherited the mutation from a parent who may or may not be affected.
    • Because of reduced penetrance, it is common for such parents to have no visual complications and thus be undiagnosed.
    • The mutation may be in an (as-yet) unidentified gene.
  • A proband with adFEVR may have the disorder as the result of a de novo gene mutation. The proportion of cases caused by de novo mutations is currently unknown.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include examination by fundus fluorescein angiography and molecular genetic testing if a disease-causing mutation has been identified in the family.

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 a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%.
    • If the sib inherits the mutation, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity of symptoms.
    • Initial studies have shown that up to 90% of individuals with adFEVR can be asymptomatic.
  • If a pathogenic mutation has not been identified in the proband and both parents have normal findings on fundus fluorescein angiography, the risk to the sibs of a proband for adFEVR is low.
  • Although no instances of germline mosaicism have been reported, it remains a possibility.

Offspring of a proband

  • Each child of an individual with adFEVR has a 50% chance of inheriting the mutation.
  • If the offspring inherits the mutation, it is not possible to predict whether symptoms will occur. If symptoms do occur, it is not possible to predict the age of onset or severity.
  • Up to 90% of individuals with adFEVR can be asymptomatic.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent has a disease-causing mutation, his or her family members are 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.

Possible complex inheritance of FEVR. While no conclusive evidence is available, some anecdotal findings suggest that the pattern of inheritance of FEVR may be more complex than previously thought (see Genotype-Phenotype Correlations).

Genetic counseling for disorders with reduced penetrance. Reduced penetrance and the likelihood of additional (as-yet unidentified) genes associated with adFEVR result in significant difficulty in determining which at-risk family members have and have not inherited a pathogenic mutation. Early studies suggested that approximately 50% of individuals with adFEVR were asymptomatic [Benson 1995]; however, based on limited data from molecular testing for asymptomatic at-risk family members in research studies, this figure appears to be much higher, perhaps as high as 90%. Additional studies may identify penetrance to be mutation specific.

Genetic counseling for disorders with genetic heterogeneity. Because the autosomal dominant, autosomal recessive, and X-linked forms of FEVR cannot be distinguished by ophthalmologic examination alone, determining the mode of inheritance for a particular family can be difficult, and for the simplex case, may not be possible.

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder and/or the disease causing mutation, it is possible that the proband has a de novo mutation or the parent has reduced penetrance. 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, allelic variants, 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 adFEVR 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.

  • FEVR.NET (Familial Exudative Vitreoretinopathy)
    Email: young1@fevr.net
  • National Eye Institute
    31 Center Drive
    MSC 2510
    Bethesda MD 20892-2510
    Phone: 301-496-5248
    Email: 2020@nei.nih.gov
  • Retina International
    Retina Suisse
    Ausstellungsstrasse 36
    Zurich CH-8005
    Switzerland
    Phone: +41 (0) 44 444 1077
    Fax: +41 (0) 44 444 1070
    Email: christina.fasser@retina-international.org
  • American FEVR Research Consortium Registry
    Moran Eye Center, University of Utah
    65 Medical Drive
    Room 6620-C
    Salt Lake City UT 84112
    Phone: 800-824-2073 ext 51297; 801-585-1297
    Fax: 801-587-7686
    Email: jennifer.harmon@hsc.utah.edu
  • eyeGENE® - National Ophthalmic Disease Genotyping Network Registry
    Phone: 301-435-3032
    Email: eyeGENEinfo@nei.nih.gov

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. Familial Exudative Vitreoretinopathy, Autosomal Dominant: Genes and Databases

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 Familial Exudative Vitreoretinopathy, Autosomal Dominant (View All in OMIM)

133780EXUDATIVE VITREORETINOPATHY 1; EVR1
601813EXUDATIVE VITREORETINOPATHY 4; EVR4
603506LOW DENSITY LIPOPROTEIN RECEPTOR-RELATED PROTEIN 5; LRP5
604579FRIZZLED, DROSOPHILA, HOMOLOG OF, 4; FZD4
605750EXUDATIVE VITREORETINOPATHY 3; EVR3
613138TETRASPANIN 12; TSPAN12
613310EXUDATIVE VITREORETINOPATHY 5; EVR5

Molecular Genetic Pathogenesis

The primary pathologic process in autosomal dominant familial exudative vitreoretinopathy (adFEVR) is believed to be a premature arrest of retinal angiogenesis/vasculogenesis or retinal vascular differentiation, leading to incomplete vascularization of the peripheral retina. To date, mutations in four genes have been shown to cause FEVR: NDP (encoding norrin) (OMIM 300658) (X-linked see NDP-Related Disorders), FZD4 (dominant), LRP5 (dominant and recessive) and TSPAN12 (dominant). Each of the encoded proteins is a component of the norrin/β-catenin signaling pathway (also referred to as the norrin/frizzled-4 pathway). In this pathway, the ligand norrin binds to a receptor complex consisting of the receptor frizzled-4, the co-receptor low-density lipoprotein receptor-related protein-5, and the auxiliary protein tetraspanin-12. In the absence of norrin binding, signaling is not activated. This results in cytoplasmic β-catenin becoming phosphorylated and targeted for degradation through the ubiquitin-proteasome pathway. As a result, prospective target genes remain repressed. Signaling is activated by norrin binding to the frizzled-4, LRP5 and TSPAN12 receptor complex. This complex triggers a signal which inhibits the destruction of β-catenin, allowing its cytoplasmic levels to increase. Subsequently, β-catenin enters the nucleus where it interacts with the T-cell factor (TCF)/lymphoid enhancing factor (LEF) family of transcription factors to turn on the expression of norrin target genes. This signaling pathway shares many similarities to the canonic Wnt/β-catenin pathway except that norrin substitutes Wnt as the ligand and no tetraspanins have been linked to Wnt/β-catenin signaling. Identifying new FEVR-related genes therefore provides an ideal opportunity to discover new components of this important signaling pathway [Xu et al 2004, Junge et al 2009, Ye et al 2010].

FZD4

Gene structure. FZD4 mRNA is 7,394 bp long and comprises two exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. Types of disease-causing mutations identified in FZD4 include missense changes, nonsense changes, insertions, and deletions; no splice site mutations have been identified. The majority of deletions and insertions result in a frameshift error in the mRNA, but it is not known whether these aberrant mRNAs are targeted for nonsense-mediated mRNA decay or if they produce prematurely terminated truncated proteins.

Table 2. Selected FZD4 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.1250G>A 1p.Arg417GlnNM_012193​.3
NP_036325​.2
c.205C>T 2p.His69Tyr
c.1463G>Ap.Gly488Asp
c.1501_1502delCTp.Leu501SerfsTer533

Note on variant classification: Variants listed in the table have been provided by the authors. 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).

1. Associated with a more severe phenotype when in cis with LRP5 c.1330C>T mutation (see Genotype-Phenotype Correlations, Possible complex inheritance of FEVR).

2. Associated with a more severe ocular phenotype when in trans with the c.1463G>A mutation (see Genotype-Phenotype Correlations, Possible complex inheritance of FEVR).

Normal gene product. The 537-amino acid protein frizzled-4 is a member of the frizzled family of seven-pass transmembrane receptors that bind Wnt proteins [Huang & Klein 2004]. However, frizzled-4 is the only member of the frizzled family that functions in the norrin/β-catenin pathway. Evidence suggests that this pathway is the one underlying FEVR and is triggered by the binding of norrin rather than a Wnt ligand to a receptor complex comprising frizzled-4, LRP5, and tetraspanin12 [Xu et al 2004, Junge et al 2009].

Abnormal gene product. Many of the mutations in frizzled-4 result in premature termination codons (PTCs). The most likely outcome for mutations resulting in PTCs is haploinsufficiency induced by nonsense-mediated mRNA decay. However, if the PTC is not followed by a downstream intron, as is the case for all the frameshift mutations identified in frizzled-4, the mRNAs can escape this process, enabling them to be translated into truncated mutant proteins. The precise effect of PTCs on frizzled-4 has not been investigated; thus it is not known whether an abnormal gene product is created. However, a study in which a truncated mutant frizzled-4 protein (p.Leu501fsTer533) was created in vitro showed that the mutant protein is not located in its usual position within the cell membrane but is trapped within the endoplasmic reticulum [Robitaille et al 2002, Kaykas et al 2004]. This mutant protein also trapped the wild-type protein within the cell and appeared to act in a dominant-negative manner [Kaykas et al 2004].

The majority of the frizzled-4 missense mutations appear to be in functional sites, suggesting that they knock out the function of the protein. For example, in vitro experiments have shown that missense mutations in the CRD domain (p.Met105Val and p.Met157Val) reduce the ability of frizzled-4 to bind norrin and to activate the β-catenin pathway [Xu et al 2004].

LRP5

Gene structure. LRP5 mRNA is 5,161 bp long and comprises 23 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic allelic variants. All types of disease-causing mutations have been identified in LRP5: missense changes, nonsense changes, insertions, deletions, and splice site mutations. The majority of deletions, insertions, and splice mutations result in a frameshift error in the mRNA, but it is not known whether these aberrant mRNAs are targeted for nonsense-mediated mRNA decay or if they produce prematurely terminated truncated proteins.

Table 3. Selected LRP5 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.518C>Tp.Thr173MetNM_002335​.2
NP_002326​.2
c.1330C>Tp.Arg444Cys 1
c.4081T>Gp.Cys1361Gly
c.4099G>Ap.Glu1367Lys
c.3502T>Cp.Tyr1168His

Note on variant classification: Variants listed in the table have been provided by the authors. 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).

1. Associated with a more severe phenotype when in cis with FZD4 c.1250G>A mutation (see Genotype-Phenotype Correlations, Possible complex inheritance of FEVR).

Normal gene product. LRP5 encodes a 1,615-amino acid single-pass transmembrane receptor, termed low-density lipoprotein receptor-related protein 5. It partners with frizzled receptors (e.g., frizzled-4) to bind Wnt proteins [He et al 2004]. LRP5 also functions in the norrin/β-catenin pathway. Evidence suggests that this pathway is the one underlying FEVR and is triggered by the binding of norrin rather than a Wnt ligand to a receptor complex comprising frizzled-4, LRP5, and tetraspanin12.

Abnormal gene product. The LRP5 mutations identified in individuals with adFEVR are predicted to result in functional haploinsufficiency of the protein. Most nonsense and frameshift mutations are likely to undergo nonsense-mediated mRNA decay or produce truncated proteins that are incorrectly transported within the cell; however, no direct evidence exists. In vitro cell-based assays have shown that the adFEVR missense mutations p.Tyr1168His and p.Cys1361Gly affect the transduction of β-catenin signaling upon binding of either Wnt or norrin. However, two other adFEVR-related mutations (p.Thr173Met and p.Glu1367Lys) tested in a similar manner did not show any effect. When proteins with the adFEVR-related mutations p.Thr173Met, p.Glu1367Lys, p.Tyr1168His, and p.Cys1361Gly were cotransfected with wild-type LRP5 protein, none of them interfered with wild-type Wnt/β-catenin signaling, arguing against a dominant-negative effect for these mutations on Wnt signaling [Ai et al 2005].

TSPAN12

Gene structure. TSPAN12 mRNA is 2579 bp long and comprises eight exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Pathogenic variants. The types of disease-causing mutations identified in TSPAN12 include missense changes, nonsense changes, insertions, deletions, and splice site mutations. The majority of deletions, insertions, and splice mutations result in a frameshift error in the mRNA, but it is not known whether these aberrant mRNAs are targeted for nonsense-mediated mRNA decay or if they produce prematurely terminated truncated proteins.

Table 4. Selected TSPAN12 Pathogenic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.709G>Cp.Ala237Pro 1NM_012338​.3
NP_036470​.1

Note on variant classification: Variants listed in the table have been provided by the authors. 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).

1. Common in the Netherlands

Normal gene product. TSPAN12 encodes a 305-amino acid protein containing four transmembrane-spanning domains, termed tetraspanin12. It forms a component of the norrin-LRP5-FZD4 signaling complex; cell-based assays have shown that it enhances the level of norrin/β-catenin signaling [Junge et al 2009].

Abnormal gene product. The TSPAN12 mutations identified in individuals with adFEVR are predicted to result in functional haploinsufficiency of the protein. Most nonsense and frameshift mutations are predicted to undergo nonsense-mediated mRNA decay or produce truncated proteins that are incorrectly transported within the cell.

References

Literature Cited

  1. Ai M, Heeger S, Bartels CF, Schelling DK. Clinical and molecular findings in osteoporosis-pseudoglioma syndrome. Am J Hum Genet. 2005;77:741–53. [PMC free article: PMC1271384] [PubMed: 16252235]
  2. Benson WE. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1995;93:473–521. [PMC free article: PMC1312071] [PubMed: 8719692]
  3. Boonstra FN, van Nouhuys CE, Schuil J, de Wijs IJ, van der Donk KP, Nikopoulos K, Mukhopadhyay A, Scheffer H, Tilanus MA, Cremers FP, Hoefsloot LH. Clinical and molecular evaluation of probands and family members with familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2009;50:4379–85. [PubMed: 19324841]
  4. Bottomley HM, Downey LM, Inglehearn CF, Toomes C. Comment on 'cosegregation of two unlinked mutant alleles in some cases of autosomal dominant familial exudative vitreoretinopathy'. Eur J Hum Genet. 2006;14:6–7. [PubMed: 16319824]
  5. Boyden LM, Mao J, Belsky J, Mitzner L, Farhi A, Mitnick MA, Wu D, Insogna K, Lifton RP. High bone density due to a mutation in LDL-receptor-related protein 5. N Engl J Med. 2002;346:1513–21. [PubMed: 12015390]
  6. Chen ZY, Battinelli EM, Fielder A, Bundey S, Sims K, Breakefield XO, Craig IW. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5:180–3. [PubMed: 8252044]
  7. de Crecchio G, Simonelli F, Nunziata G, Mazzeo S, Greco GM, Rinaldi E, Ventruto V, Ciccodicola A, Miano MG, Testa F, Curci A, D'Urso M, Rinaldi MM, Cavaliere ML, Castelluccio P. Autosomal recessive familial exudative vitreoretinopathy: evidence for genetic heterogeneity. Clin Genet. 1998;54:315–20. [PubMed: 9831343]
  8. Downey LM, Bottomley HM, Sheridan E, Ahmed M, Gilmour DF, Inglehearn CF, Reddy A, Agrawal A, Bradbury J, Toomes C. Reduced bone mineral density and hyaloid vasculature remnants in a consanguineous recessive FEVR family with a mutation in LRP5. Br J Ophthalmol. 2006;90:1163–7. [PMC free article: PMC1857417] [PubMed: 16929062]
  9. Downey LM, Keen TJ, Roberts E, Mansfield DC, Bamashmus M, Inglehearn CF. A new locus for autosomal dominant familial exudative vitreoretinopathy maps to chromosome 11p12-13. Am J Hum Genet. 2001;68:778–81. [PMC free article: PMC1274490] [PubMed: 11179025]
  10. Drenser KA. Pharmacologic therapy for pediatric retinal vascular disease. Las Vegas, NV: The Annual Meeting of the American Academy of Ophthalmology; 2006.
  11. Drenser KA, Dailey W, Vinekar A, Dalal K, Capone A, Trese MT. Clinical presentation and genetic correlation of patients with mutations affecting the FZD4 gene. Arch Ophthalmol. 2009;127:1649–54. [PubMed: 20008721]
  12. Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T, Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S, Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA, Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF, Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D, Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H, Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R, Olsen BR, Warman ML. LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development. Cell. 2001;107:513–23. [PubMed: 11719191]
  13. He X, Semenov M, Tamai K, Zeng X. LDL receptor-related proteins 5 and 6 in Wnt/beta-catenin signaling: arrows point the way. Development. 2004;131:1663–77. [PubMed: 15084453]
  14. Huang HC, Klein PS. The Frizzled family: receptors for multiple signal transduction pathways. Genome Biol. 2004;5:234. [PMC free article: PMC463283] [PubMed: 15239825]
  15. Jia LY, Li XX, Yu WZ, Zeng WT, Liang C. Novel frizzled-4 gene mutations in chinese patients with familial exudative vitreoretinopathy. Arch Ophthalmol. 2010;128:1341–9. [PubMed: 20938005]
  16. Jiao X, Ventruto V, Trese MT, Shastry BS, Hejtmancik JF. Autosomal recessive familial exudative vitreoretinopathy is associated with mutations in LRP5. Am J Hum Genet. 2004;75:878–84. [PMC free article: PMC1182117] [PubMed: 15346351]
  17. Junge HJ, Yang S, Burton JB, Paes K, Shu X, French DM, Costa M, Rice DS, Ye W. TSPAN12 regulates retinal vascular development by promoting Norrin- but not Wnt-induced FZD4/beta-catenin signaling. Cell. 2009;139:299–311. [PubMed: 19837033]
  18. Kaykas A, Yang-Snyder J, Heroux M, Shah KV, Bouvier M, Moon RT. Mutant Frizzled 4 associated with vitreoretinopathy traps wild-type Frizzled in the endoplasmic reticulum by oligomerization. Nat Cell Biol. 2004;6:52–8. [PubMed: 14688793]
  19. Kondo H, Hayashi H, Oshima K, Tahira T, Hayashi K. Frizzled 4 gene (FZD4) mutations in patients with familial exudative vitreoretinopathy with variable expressivity. Br J Ophthalmol. 2003;87:1291–5. [PMC free article: PMC1920788] [PubMed: 14507768]
  20. Kondo H, Kusaka S, Yoshinaga A, Uchio E, Tawara A, Hayashi K, Tahira T. Mutations in the TSPAN12 gene in Japanese patients with familial exudative vitreoretinopathy. Am J Ophthalmol. 2011;151:1095–1100. [PubMed: 21334594]
  21. Little RD, Carulli JP, Del Mastro RG, Dupuis J, Osborne M, Folz C, Manning SP, Swain PM, Zhao SC, Eustace B, Lappe MM, Spitzer L, Zweier S, Braunschweiger K, Benchekroun Y, Hu X, Adair R, Chee L, FitzGerald MG, Tulig C, Caruso A, Tzellas N, Bawa A, Franklin B, McGuire S, Nogues X, Gong G, Allen KM, Anisowicz A, Morales AJ, Lomedico PT, Recker SM, Van Eerdewegh P, Recker RR, Johnson ML. A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait. Am J Hum Genet. 2002;70:11–9. [PMC free article: PMC419982] [PubMed: 11741193]
  22. MacDonald ML, Goldberg YP, Macfarlane J, Samuels ME, Trese MT, Shastry BS. Genetic variants of frizzled-4 gene in familial exudative vitreoretinopathy and advanced retinopathy of prematurity. Clin Genet. 2005;67:363–6. [PubMed: 15733276]
  23. Miyakubo H, Hashimoto K, Miyakubo S. Retinal vascular pattern in familial exudative vitreoretinopathy. Ophthalmology. 1984;91:1524–30. [PubMed: 6084219]
  24. Nallathambi J, Shukla D, Rajendran A, Namperumalsamy P, Muthulakshmi R, Sundaresan P. Identification of novel FZD4 mutations in Indian patients with familial exudative vitreoretinopathy. Mol Vis. 2006;12:1086–92. [PubMed: 17093393]
  25. Nikopoulos K, Venselaar H, Collin RW, Riveiro-Alvarez R, Boonstra FN, Hooymans JM, Mukhopadhyay A, Shears D, van Bers M, de Wijs IJ, van Essen AJ, Sijmons RH, Tilanus MA, van Nouhuys CE, Ayuso C, Hoefsloot LH, Cremers FP. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat. 2010a;31:656–66. [PubMed: 20340138]
  26. Nikopoulos K, Gilissen C, Hoischen A, van Nouhuys CE, Boonstra FN, Blokland EA, Arts P, Wieskamp N, Strom TM, Ayuso C, Tilanus MA, Bouwhuis S, Mukhopadhyay A, Scheffer H, Hoefsloot LH, Veltman JA, Cremers FP, Collin RW. Next-generation sequencing of a 40 Mb linkage interval reveals TSPAN12 mutations in patients with familial exudative vitreoretinopathy. Am J Hum Genet. 2010b;86:240–7. [PMC free article: PMC2820179] [PubMed: 20159111]
  27. Ober RR, Bird AC, Hamilton AM, Sehmi K. Autosomal dominant exudative vitreoretinopathy. Br J Ophthalmol. 1980;64:112–120. [PMC free article: PMC1039360] [PubMed: 7362811]
  28. Omoto S, Hayashi T, Kitahara K, Takeuchi T, Ueoka Y. Autosomal dominant familial exudative vitreoretinopathy in two Japanese families with FZD4 mutations (H69Y and C181R). Ophthalmic Genet. 2004;25:81–90. [PubMed: 15370539]
  29. Poulter JA, Ali M, Gilmour DF, Rice A, Kondo H, Hayashi K, Mackey DA, Kearns LS, Ruddle JB, Craig JE, Pierce EA, Downey LM, Mohamed MD, Markham AF, Inglehearn CF, Toomes C. Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy. Am J Hum Genet. 2010;86:248–53. [PMC free article: PMC2820188] [PubMed: 20159112]
  30. Qin M, Hayashi H, Oshima K, Tahira T, Hayashi K, Kondo H. Complexity of the genotype-phenotype correlation in familial exudative vitreoretinopathy with mutations in the LRP5 and/or FZD4 genes. Hum Mutat. 2005;26:104–12. [PubMed: 15981244]
  31. Robitaille J, MacDonald ML, Kaykas A, Sheldahl LC, Zeisler J, Dube MP, Zhang LH, Singaraja RR, Guernsey DL, Zheng B, Siebert LF, Hoskin-Mott A, Trese MT, Pimstone SN, Shastry BS, Moon RT, Hayden MR, Goldberg YP, Samuels ME. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32:326–30. [PubMed: 12172548]
  32. Robitaille JM, Zheng B, Wallace K, Beis MJ, Tatlidil C, Yang J, Sheidow TG, Siebert L, Levin AV, Lam WC, Arthur BW, Lyons CJ, Jaakkola E, Tsilou E, Williams CA, Weaver RG, Shields CL, Guernsey DL. The role of Frizzled-4 mutations in familial exudative vitreoretinopathy and Coats disease. Br J Ophthalmol. 2011;95:574–9. [PubMed: 21097938]
  33. Shastry BS, Trese MT. Familial exudative vitreoretinopathy: further evidence for genetic heterogeneity. Am J Med Genet. 1997;69:217–8. [PubMed: 9056564]
  34. Shastry BS, Trese MT. Cosegregation of two unlinked mutant alleles in some cases of autosomal dominant familial exudative vitreoretinopathy. Eur J Hum Genet. 2004;12:79–82. [PubMed: 14560311]
  35. Shukla D, Singh J, Sudheer G, Soman M, John RK, Ramasamy K, Perumalsamy N. Familial exudative vitreoretinopathy (FEVR). Clinical profile and management. Indian J Ophthalmol. 2003;51:323–8. [PubMed: 14750620]
  36. Tasman W, Augsburger JJ, Shields JA, Caputo A, Annesley WH. Familial exudative vitreoretinopathy. Trans Am Ophthalmol Soc. 1981;79:211–26. [PMC free article: PMC1312184] [PubMed: 7342402]
  37. Toomes C, Bottomley HM, Jackson RM, Towns KV, Scott S, Mackey DA, Craig JE, Jiang L, Yang Z, Trembath R, Woodruff G, Gregory-Evans CY, Gregory-Evans K, Parker MJ, Black GC, Downey LM, Zhang K, Inglehearn CF. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004a;74:721–30. [PMC free article: PMC1181948] [PubMed: 15024691]
  38. Toomes C, Bottomley HM, Scott S, Mackey DA, Craig JE, Appukuttan B, Stout JT, Flaxel CJ, Zhang K, Black GC, Fryer A, Downey LM, Inglehearn CF. Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2004b;45:2083–90. [PubMed: 15223780]
  39. van Nouhuys CE. Dominant exudative vitreoretinopathy and other vascular developmental disorders of the peripheral retina. Doc Ophthalmol. 1982;54:1–414. [PubMed: 6897033]
  40. van Nouhuys CE. Signs, complications, and platelet aggregation in familial exudative vitreoretinopathy. Am J Ophthalmol. 1991;111:34–41. [PubMed: 1985487]
  41. Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, Key L, Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul W. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. 2003;72:763–71. [PMC free article: PMC1180253] [PubMed: 12579474]
  42. Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, Nathans J. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004;116:883–95. [PubMed: 15035989]
  43. Ye X, Wang Y, Nathans J. The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med. 2010;16:417–25. [PMC free article: PMC2963063] [PubMed: 20688566]

Suggested Reading

  1. Toomes C, Downey LM, Bottomley HM, Mintz-Hittner HA, Inglehearn CF. Further evidence of genetic heterogeneity in familial exudative vitreoretinopathy; exclusion of EVR1, EVR3, and EVR4 in a large autosomal dominant pedigree. Br J Ophthalmol. 2005;89:194–7. [PMC free article: PMC1772516] [PubMed: 15665352]

Chapter Notes

Revision History

  • 22 September 2011 (cd) Revision: sequence analysis of TSPAN12 available clinically
  • 14 July 2011 (me) Comprehensive update posted live
  • 11 December 2008 (cd) Revision: clinical and prenatal testing available for mutations in LRP5 and FZD4; prenatal testing available for mutations in FZD4
  • 28 August 2008 (cd) Revision: sequence analysis available clinically
  • 27 August 2007 (me) Comprehensive update posted to live Web site
  • 21 March 2005 (me) Review posted to live Web site
  • 9 September 2004 (ct) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1147PMID: 20301326
PubReader format: click here to try

Views

  • PubReader
  • Print View
  • Cite this Page
  • Disable Glossary Links

Tests in GTR by Gene

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...