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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. The diagnosis of PCG is based on clinical findings. CYP1B1, the gene encoding cytochrome P450 1B1, is the only gene currently known to be associated with PCG. Two other loci, GLC3B on 1p36 and GLC3C on 14q24.3, have been linked to PCG, but the causative genes are not known. Sequence analysis of the two coding exons of CYP1B1 is available on a clinical basis. In general, the probability of identifying mutations in CYP1B1 increases with the presence of bilateral and severe disease, and a positive family history for the disease, and parental consanguinity.
Management. Treatment of manifestations: surgery (goniotomy, trabeculotomy, or trabeculectomy) as early as possible or use of drainage implants or cyclodestruction if surgery fails; medication preoperatively and postoperatively to help control IOP; routine treatment of refractive errors and amblyopia. Prevention of secondary complications: discontinuation of medications such as phospoline (ecothiopate) iodide before surgery to prevent prolonged apnea. Surveillance: lifelong monitoring to ensure control of IOP. Agents/circumstances to avoid: alpha-2 agonists because of risk of apnea and bradycardia. Testing of relatives at risk: molecular genetic testing of at-risk sibs as soon as possible after birth if both mutations have been identified in the family in order to establish the diagnosis and avoid repeated examinations under anesthesia in young children.
Genetic counseling. PCG caused by CYP1B1 mutations is inherited in an autosomal recessive manner. Heterozygotes (carriers) are asymptomatic. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Prenatal diagnosis for pregnancies at increased risk is possible if both disease-causing alleles of an affected family member have been identified.
Clinical criteria diagnosis of primary congenital glaucoma (PCG) include the following:
Elevated intraocular pressure (IOP) in an infant or child typically under age one year. An IOP greater than 21 mm Hg (mercury) in one or both eyes as measured by applanation tonometry on at least two occasions is considered abnormally elevated. In general, normal eye pressures range from about ten to 21 mm Hg.
Enlargement of the (infantile) globe (buphthalmos)
Increased corneal diameter
Anomalously deep interor chamber
The classic clinical characteristics of PCG include the following:
Photophobia, blepharospasm, and excessive tearing (hyperlacrimation) (in infants)
Edema and opacification of the cornea with rupture of Descemet's membrane, known as Haab's striae
Thinning of the anterior sclera and atrophy of the iris (in infants)
Structurally normal posterior segment except for progressive optic atrophy
Absence of structural changes in the anterior chamber that are consistent with a diagnosis of anterior segment dysgenesis
The typical findings may not be equally present in both eyes of an affected individual. It is also possible that some affected individuals have mild presentation with subtle clinical findings.
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. CYP1B1, on locus GLC3A, encodes the protein cytochrome P450 1B1. It is the only gene currently known to be associated with PCG.
Other gene. Recent findings suggest that mutations in MYOC, the gene encoding myocillin, may in conjunction with mutations in CYP1B1 increase the clinical severity of glaucoma in individuals with juvenile primary congenitalopen-angle glaucoma (POAG). Indeed, individuals who are heterozygous for mutations in both MYOC and CYP1B1 seem to have a more severe POAG phenotype than those who are heterozygous for mutations in MYOC alone [Vincent et al 2002].
It was further suggested that MYOC may be associated with the molecular pathogenesis of PCG. Kaur et al (2005) presented evidence in a single individual that a heterozygous mutation in MYOC, combined with a heterozygous mutation in CYP1B1, was associated with PCG, suggesting digenic inheritance.
The role of MYOC mutations alone in the molecular etiology of PCG is also unclear. A recent report of a Chinese family segregating both POAG and PCG, suggested that homozygous MYOC mutations may cause PCG [Zhuo et al 2006]. However, further studies are needed before a clear link can be established between MYOC mutations and PCG.
Other loci. The following two loci have also been linked to PCG; the causal genes and mutations are not known.
GLC3B on 1p36.2-p36.1 [Akarsu et al 1996]
GLC3C on 14q24.3 [Stoilov 2002]
Clinical testing
Sequence analysis of the two coding exons of CYP1B1. The frequency of CYP1B1 disease-causing mutations in PCG is variable. In general, the probability of identifying mutations in CYP1B1 increases with the presence of a positive family history for the disease, parental consanguinity, and bilateral and severe disease. However, differences in the number of individuals studied, the methods of ascertainment (familial vs simplex cases [i.e., only one affected individual in a family], unilateral disease vs bilateral disease), and the molecular genetic testing methods used make accurate estimates and comparisons of mutation detection frequency among ethnic groups difficult.
CYP1B1 mutations are responsible for 100% of familial cases of PCG in the Rom (Gypsies) in Slovakia [Plasilova et al 1999], 94% of familial cases in Saudi Arabia [Bejjani et al 1998], and 50%-80% of cases in populations in which consanguinity is common, such as in the Indian subcontinent [Panicker et al 2002]. In other populations in which both familial and simplex cases of PCG were tested, CYP1B1 mutations are responsible for 50% of cases in Brazil [Stoilov et al 2002] and 20%-30% of cases in Japan and in ethnically mixed populations [Kakiuchi-Matsumoto et al 2001, Mashima et al 2001].
It is estimated that the frequency of CYP1B1 mutations decreases to 10%-15% in simplex cases [Mashima et al 2001, Stoilov et al 2002, Curry et al 2004].
| Test Method | Mutations Detected | Mutation Detection Frequency 1 | Test Availability | |
|---|---|---|---|---|
| Familial Cases | Simplex Cases 2 | |||
| Sequence analysis | CYP1B1 sequence variants | 20%-100% | 10%-15% | Clinical
 |
Interpretation of test results
For issues to consider in interpretation of sequence analysis results, click here.
Autosomal recessive transmission is established if homozygous or compound heterozygous mutations in CYP1B1 are identified in an affected individual.
The absence of CYP1B1 mutations suggests either that the disease results from other genetic or undetermined causes or that the clinical diagnosis is incomplete or inaccurate (e.g., the affected individual has anterior segment dysgenesis with glaucoma). In such cases, the mode of inheritance remains unclear.
The identification of a single mutation on one allele of CYP1B1 in an individual with PCG makes genetic counseling difficult.
Confirmation of the diagnosis in a proband Molecular genetic testing can be used, particularly in at-risk neonates, to establish a diagnosis early and avoid repeated examinations under anesthesia.
Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.
Note: Carriers are heterozygotes for an autosomal recessive disorder and are not at risk of developing the disorder.
Prenatal diagnosis for at-risk pregnancies requires prior identification of the disease-causing mutation in the family.
Peters anomaly. Mutations in CYP1B1 have been described in Peters anomaly (OMIM 604229), a uni- or bilateral developmental disorder of the anterior chamber that is distinct from PCG. Clinical findings in Peters anomaly include central corneal opacity associated with corneal stromal thinning, absence of varying lengths of central Descemet's membrane, and irido-corneal and/or kerato-lenticular.
Juvenile open-angle glaucoma. CYP1B1 mutations have also been implicated in three individuals with juvenile open-angle glaucoma (JOAG) (OMIM 137750) [Vincent et al 2002]. In that study, a family with autosomal dominant glaucoma showed co-segregation of mutations in MYOC (the gene encoding myocilin) and CYP1B1 in an individual with more severe disease. These results suggest that CYP1B1 may act as a modifier of MYOC expression and that these two genes may interact through a common pathway [Vincent et al 2002]. In addition, Acharya et al (2006 suggested that on rare occasions homozygous CYP1B1 mutations alone (i.e., without MYOC mutations) may cause JOAG.
Primary congenital glaucoma (PCG) is characterized by developmental defect(s) of the trabecular meshwork and anterior chamber angle that prevent adequate drainage of aqueous humor, resulting in elevated IOP and stretching of the sclera that produces an enlarged globe (buphthalmos). By definition, congenital glaucoma is present at birth; it is typically diagnosed in the first year of life. PCG is more common in males (65%) and is bilateral in 70% of individuals.
The clinical signs and symptoms depend primarily on the age of onset and the severity of the disease [Ho & Walton 2004]. The classic symptoms include tearing, photophobia, and irritability. Occasionally, parents may notice cloudy and/or unusually large corneas in their child caused by corneal edema, which usually does not occur after age three years [Ho & Walton 2004].
The most severe clinical features are typically seen in the newborn, who may present with corneal opacity, increased corneal diameter, increased IOP, and an enlarged globe [Walton 1998]. In 35 newborns with PCG, corneal edema was present in 100% of the eyes, either as diffuse (90% of cases) or localized (10%) opacity [Walton 1998].
Early detection and appropriate treatment of congenital glaucoma can improve visual outcome. In contrast to the permanent optic nerve cupping and visual field loss seen in adults with adult-onset glaucoma, the pressure-induced optic nerve cupping in infants and young children with PCG is reversible, particularly in the early stages of the disease. This favorable outcome is believed to be a result of the highly elastic nature of the tissues of the optic nerves of infants and young children [Allingham et al 2005]. A delay in treatment can result in reduced visual acuity and/or restricted visual fields. In untreated cases, blindness invariably occurs.
The ultimate visual outcome depends on the severity of the disease at diagnosis, the presence of other associated ocular abnormalities, response to surgical treatment, and success of control of IOP upon follow-up. The earlier the onset of clinical manifestations of glaucoma, the worse the prognosis.
Despite early treatment and multiple surgical interventions, some individuals with severe disease evident at birth develop significant visual impairment from corneal opacification, advanced glaucomatous damage, or amblyopia, and may eventually become legally blind.
Individuals with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.
The IOP is a significant prognostic factor for postoperative visual function, with substantially better vision observed in individuals with IOPs lower than 19 mm Hg.
No consistent correlation has been observed between the severity of the glaucoma phenotype and the molecular CYP1B1 genotype. In fact, the phenotype can vary significantly in the same individual (one eye being more severely affected than the other) [Walton 1998], among individuals with identical mutations within the same family [Bejjani et al 1998], and among families with identical mutations [Bejjani et al 1998, Bejjani et al 2000].
Evidence shows that the severity of the phenotype may be influenced by genetic factors [Bejjani et al 2000, Libby et al 2003]. Individual reports suggest that truncating mutations resulting in null alleles tend to cause a more severe phenotype than missense mutations [Vincent et al 2001, Panicker et al 2002].
No information is available on correlation between the success of surgical therapy and the type of CYP1B1 mutation detected.
PCG occurs in all ethnic groups. The birth prevalence, however, varies worldwide:
1:5,000-22,000 in western countries
1:2500 in the MiddleEast
1:1,250 in the Rom (Gypsy) population of Slovakia [Plasilova et al 1998]
1:3,300 in the Indian state of Andhra Pradesh, where the disease accounts for approximately 4.2% of all childhood blindness [Dandona et al 2001].
In Saudi Arabia and in the Rom population of Slovakia, PCG is the most common cause of childhood blindness [Plasilova et al 1998, Bejjani et al 2000].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Before the diagnosis of primary congenital glaucoma (PCG) is established, the nonspecific findings of tearing and redness of the eyes may mimic more common conditions such as conjunctivitis or congenital nasolacrimal duct obstruction. Similarly, ocular irritation with photophobia and redness may mimic the more frequent problem of corneal abrasion.
Congenital glaucoma can be subcategorized by age of onset into the following three types:
Primary "newborn"-type congenital glaucoma: the most severe type; clinically apparent between birth and age one month
Primary "infantile" glaucoma (or infantile PCG, as described by Walton & Katsavounidou (2005): clinically recognized between age one month and two years
"Juvenile" ("late-recognized") primary infantile glaucoma: onset is clinically apparent after age two years
The types do not correlate with a specific genetic cause, although primary "newborn"-type congenital glaucoma is more likely to be caused by CYP1B1 mutations.
In the older child with juvenile onset, or in less severe cases, the increase in IOP is gradual; thus, corneal edema and opacity may be less obvious than in the newborn type. Progressive enlargement of the globe or "buphthalmos" usually does not occur after age three to four years [Ho & Walton 2004, Allingham et al 2005].
Conditions/syndromes associated with infantile glaucoma. A number of well-recognized conditions and syndromes may present with infantile glaucoma, along with other ocular and/or systemic findings. Some conditions may not be compatible with life (e.g. trisomy 13 and trisomy 18, Walker-Warburg syndrome, and Zellweger syndrome); others may be less severe or confined only to the eye.
It is important to establish the diagnosis of an associated syndrome because of the implications for genetic counseling and treatment.
Associated syndromes:
Aniridia is characterized by complete or partial iris hypoplasia with associated foveal hypoplasia, resulting in reduced visual acuity and nystagmus, presenting in early infancy. It is frequently associated with other ocular abnormalities, often of later onset, including cataract, glaucoma, and corneal opacification and vascularization. Inheritance is autosomal dominant.
Anterior segment dysgenesis syndromes are a heterogeneous group of disorders that are usually inherited in an autosomal dominant manner with decreased penetrance. In general, they appear to be phenotypically and genotypically distinct from PCG, although some cases of severe or advanced PCG are difficult to distinguish clinically from some of the anterior segment dysgenesis syndromes such as Peters anomaly.
Axenfeld-Rieger (A-R) anomaly is an anterior segment disorder that presents with posterior embryotoxon and one or more of the following: iris strands adherent to Schwalbe's line, iris hypoplasia, focal iris atrophy, and ectropion uveae. Glaucoma develops in approximately half of individuals with A-R anomaly, but is more common in those with central iris changes and marked anterior iris insertion. A-R anomaly is always bilateral, but may be distinctly asymmetric. A-R anomaly may occur in the setting of Rieger syndrome, which can include developmental defects of the teeth and facial bones, pituitary anomalies, cardiac disease, oculocutaneous albinism, and redundant periumbilical skin. A-R anomaly and Rieger syndrome are inherited in an autosomal dominant manner.
Microcornea is defined by a corneal diameter less than 10 mm. It can be associated with glaucoma and other ocular anomalies including congenital cataracts, sclerocornea, and corneal plana, or may be a feature of systemic syndromes.
Congenital hereditary endothelial dystrophy (CHED) is characterized by bilateral corneal opacification and may be difficult to distinguish from microcornea. However, the corneal diameter and IOP are usually normal in CHED. Both autosomal dominant. and autosomal recessive inheritance are observed. Autosomal recessive CHED (CHED2) is associated with mutations of SLC4A11 [Kumar et al 2007]. The primary defect in the corneal endothelium leads to corneal edema and opacification. CHED and congenital glaucoma are known to coexist, but the exact incidence is unknown [Ramamurthy et al 2007].
Lowe syndrome (oculocerebral renal syndrome) affects males only and is characterized by generalized hypotonia at birth, absence of deep tendon reflexes, and some degree of intellectual impairment. Infantile glaucoma, present in approximately half of affected males, is difficult to control. All boys have impaired vision; corrected acuity is rarely better than 20/100. Slowly progressive glomerulosclerosis and end-stage renal disease (ESRD) are often noted after age ten years. Inheritance is X-linked.
Neurofibromatosis type 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris Lisch nodules. Learning disabilities are common. Less common but potentially more serious manifestations include plexiform neurofibromas, optic and other central nervous system gliomas, malignant peripheral nerve sheath tumors, osseous lesions, and vasculopathy. Congenital glaucoma is rarely observed in individuals with NF1. Inheritance is autosomal dominant.
Nance-Horan syndrome is an X-linked disorder characterized by cataract, microcornea, and skeletal features.
Sturge-Weber syndrome (SWS) is characterized by nevus flammeus of the face and angioma of the meninges. Congenital glaucoma with associated angle anomalies may be seen in as many as 60% of affected individuals.
To establish the extent of disease in an individual diagnosed with primary congenital glaucoma (PCG), examination under anesthesia or sedation is warranted to make a complete assessment of both eyes. The examination includes the following:
Measurement of IOP within the first few minutes of anesthesia
Measurement of corneal diameter
Examination of the anterior segment
Direct gonioscopy to rule out secondary glaucomas
Dilated fundus examination to evaluate for optic nerve damage
If the cornea is opaque, ultrasound biomicroscopy to aid in evaluating the anterior segment structures
Note: If the child is examined under anesthesia, consent may be obtained to perform the appropriate surgical procedure after evaluation under anesthesia.
The primary goal of treatment is to decrease IOP to prevent vision-threatening complications such as corneal opacification and glaucomatous optic atrophy. Early treatment to control IOP will reverse some of these complications in children.
Surgical treatment. PCG is almost always managed surgically. The primary goal of surgery is to eliminate the resistance to aqueous outflow caused by the structural abnormalities in the anterior chamber angle. This goal may be accomplished through an internal approach (goniotomy) or through an external approach (trabeculotomy or trabeculectomy). Glaucoma drainage implants or cyclodestruction may be used to control IOP when initial surgical procedures have failed.
More than one surgical intervention may be necessary to control IOP; thus, significant morbidity is associated with both PCG and the currently available surgical treatment options. Patients with milder forms of disease who present later in childhood often do well with a single surgical procedure and have an excellent visual prognosis later in life.
In goniotomy, the surgeon visualizes the anterior chamber structures through a special lens (goniolens) to create openings in the trabecular meshwork. The goal of the procedure is to eliminate any resistance imposed by the abnormal trabecular meshwork. A clear cornea is necessary for direct visualization of the anterior chamber structures during this procedure.
In trabeculotomy, the trabecular meshwork is incised by cannulating Schlemm's canal with a metal probe or suture via an external opening in the sclera. In trabeculectomy, a section of trabecular meshwork and Schlemm's canal is removed under a partial thickness sclera flap to create a wound fistula. In contrast to goniotomy, these procedures can be performed in individuals with advanced glaucoma and cloudy corneas.
Clarity of the cornea and other ocular media, control of the ocular dimensions (corneal diameters and axial lengths), and optic nerve damage are important indicators of the course of the disease following surgery. Reported success rates for each (initial) procedure are approximately 80%. Infants with elevated IOP and cloudy corneas at birth have the poorest prognosis. The most favorable outcome is seen in infants in whom surgery is performed between the second and eighth month of life. With increasing age, surgery is less effective in preserving vision.
Medications. Beta-blockers (timolol), parasympathomimetics (pilocarpine), sympathomimetics (adrenergic agonists and alpha-2 adrenergic receptor agonists), carbonic anhydrase inhibitors, and prostaglandin agonists have all been used. These medications, particularly the alpha-2 adrenergic receptor agonists, may have severe side effects and must be used with caution in infants and children.
Surgery should not be delayed in an attempt to achieve medical control of IOP.
Medication may be used preoperatively to lower the IOP to prevent optic nerve damage, to reduce the risk of sudden decompression of the globe, and to clear the cornea for better visualization during examination and surgery.
Postoperatively, medication may help control IOP until the success of the surgical procedure is established.
Medical therapy is also used in difficult cases in which surgery may be life-threatening or has led to incomplete control of the glaucoma [deLuise & Anderson 1983].
Treatment of refractive errors. Amblyopia from uncorrected refractive errors often associated with PCG must be treated to obtain optimal visual function.
Medications such as phospoline (ecothiopate) iodide need to be discontinued before surgery, especially if succinylcholine is used because of the prolonged apnea.
Lifelong monitoring is necessary to ensure control of IOP to preserve remaining vision and to prevent further loss of vision.
The intervals at which monitoring need to be performed vary depending on the severity of disease and control of IOP.
Once IOP is controlled and the child is visually rehabilitated, follow-up is typically every three months to keep IOP at the "target" level, which depends on the severity of the glaucomatous optic nerve damage and the age of the patient. Standard clinical follow-up tests include optic nerve photography and visual field testing. The complete ophthalmic evaluation often requires examination under anesthesia or sedation in infants and in young and uncooperative children. This process may be challenging to the patient, the family, and the treating physician.
Alpha-2 agonists should be avoided in children in the treatment of elevated IOP because of the risk of apnea and bradycardia.
Testing at-risk sibs in the neonatal period may be helpful in establishing the diagnosis of PCG early and in avoiding repeated examinations under anesthesia in at-risk young children. Molecular genetic testing alone is appropriate in sibs of affected individuals in whom both mutations have been identified. If no definitive exclusion of the disease is possible by molecular testing, then repeated IOP measurements under anesthesia may be necessary.
Note: The literature is unclear as to timing of the onset of glaucoma, especially in families in whom mutations have been identified. In this high-risk group, it may be appropriate to perform yearly glaucoma screening into young adulthood.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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 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.
Primary congenital glaucoma (PCG) caused by CYP1B1 mutations is inherited in an autosomal recessive manner.
Parents of a proband
The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
Heterozygotes (carriers) are asymptomatic.
Sibs of a proband
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
Heterozygotes (carriers) are asymptomatic.
Offspring of a proband. The offspring of an individual with PCG caused by CYP1B1 mutations are obligate heterozygotes (carriers) for a disease-causing mutation.
Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.
Carrier testing for at-risk family members is available on a clinical basis once the mutations have been identified in the proband.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
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
for a list of laboratories offering DNA banking.
Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15-18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. Both disease-causing alleles 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.
Requests for prenatal testing for conditions such as PCG 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, careful discussion of these issues is appropriate.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutations have 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.
| Locus Name | Gene Symbol | Chromosomal Locus | Protein Name | Locus Specific | HGMD |
|---|---|---|---|---|---|
| GLC3A | CYP1B1 | 2p22-p21 | Cytochrome P450 1B1 | CYP1B1 @ Human Cytochrome P450 (CYP) Allele Nomenclature Committee | CYP1B1 |
| GLC3B | Unknown | 1p36.2-p36.1 | Unknown | ||
| GLC3C | Unknown | 14q24.3 | Unknown |
| 231300 | GLAUCOMA 3, PRIMARY CONGENITAL, A; GLC3A |
| 600975 | GLAUCOMA 3, PRIMARY INFANTILE, B; GLC3B |
| 601771 | CYTOCHROME P450, SUBFAMILY I, POLYPEPTIDE 1; CYP1B1 |
Normal allelic variants: CYB1B1 spans 12 kb, contains three exons (exons 2 and 3 only are coding exons), and produces a 1,631-base mRNA product.
Pathologic allelic variants: More than 55 mutations are known; almost all are point mutations or small (1-13 bp) rearrangements that include deletions, insertions, and duplications. Some mutations are more common in specific ethnic groups. For example, p.Glu387Lys is responsible for all the mutations in the Rom Slovakian individuals [Plasilova et al 1999], and p.Gly61Glu accounts for 72% of the mutations in Saudi Arabian populations [Bejjani et al 1998]. Other mutations have also been associated with specific ethnic groups, but with lower frequencies [Belmouden et al 2002, Panicker et al 2002].
Normal gene product: Cytochrome P450 1B1 is a "drug-metabolizing enzyme" that is responsible for phase I metabolism of diverse substrates [Sutter et al 1994]. It could play a role in modulating bio-organic molecules that affect growth and development. Four intragenic protein polymorphisms (p.Arg48Gly, p.Ala119Ser, p.Val432Leu, p.Asn453Ser) are thought to modulate the normal enzymatic activity of the protein [Shimada et al 1999].
Abnormal gene product: Mutations can affect the enzymatic activity of CYP1B1 by interfering with normal protein folding or stability [Jansson et al 2001].
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.
No specific guidelines regarding genetic testing for this disorder have been developed.
3 December 2007 (me) Comprehensive update posted to live Web site
30 September 2004 (me) Review posted to live Web site
3 June 2004 (bab) Original submission
