April 2004
Volume 45, Issue 4
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Glaucoma  |   April 2004
Correlations of Genotype with Phenotype in Indian Patients with Primary Congenital Glaucoma
Author Affiliations
  • Shirly G. Panicker
    From the Kallam Anji Reddy Molecular Genetics Laboratory, Brien Holden Eye Research Centre, Hyderabad Eye Research Foundation, Hyderabad, India; the
  • Anil K. Mandal
    Jasti V. Ramanamma Children’s Eye Care Centre, Hyderabad, India; the
  • Aramati B. M. Reddy
    From the Kallam Anji Reddy Molecular Genetics Laboratory, Brien Holden Eye Research Centre, Hyderabad Eye Research Foundation, Hyderabad, India; the
  • Vijaya K. Gothwal
    Centre for Sight Enhancement, Vision Rehabilitation Centres, L.V. Prasad Eye Institute, Hyderabad, India; and the
  • Seyed E. Hasnain
    Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India.
Investigative Ophthalmology & Visual Science April 2004, Vol.45, 1149-1156. doi:10.1167/iovs.03-0404
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      Shirly G. Panicker, Anil K. Mandal, Aramati B. M. Reddy, Vijaya K. Gothwal, Seyed E. Hasnain; Correlations of Genotype with Phenotype in Indian Patients with Primary Congenital Glaucoma. Invest. Ophthalmol. Vis. Sci. 2004;45(4):1149-1156. doi: 10.1167/iovs.03-0404.

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      © 2015 Association for Research in Vision and Ophthalmology.

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purpose. To establish the genotype–phenotype correlations of various CYP1B1 (human cytochrome P450) mutations in patients in India with primary congenital glaucoma (PCG).

 

methods. The study cohort comprised 146 patients with PCG from 138 pedigrees. Patients were analyzed for six distinct CYP1B1 mutations by sequencing and polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) methods. A severity index for grading various PCG phenotypes was constructed based on clinical parameters.

 

results. Six mutations were identified in 45 patients analyzed and genotype–phenotype correlations were established for 43 of them. The percentages of severe phenotypes associated with various mutations in at least one eye were: frameshift, 100%; G61E, 66.7%; P193L, 62.5%; E229K, 80%; R368H, 72%; R390C, 83.3%. The frameshift mutation resulted in blindness. Based on the severity index, the disease severity was graded from normal to severe and the prognosis from good to very poor (blind). De novo mutation was identified in one family.

 

conclusions. This is the first study to attempt to devise a severity index for grading various PCG phenotypes and to use genotype as an indicator to predict the prognoses of the disorder. This index may help guide therapy and counseling of the afflicted family regarding the progression of the disorder. All patients with severe phenotypes showed poor prognoses (r = 0.976; P < 0.0001). The data derived from this study could be used as an added clinical tool in disease management. Integrated management of PCG that makes use of a genetic approach could yield better results than medical, surgical, and rehabilitation interventions alone.

Primary congenital glaucoma (PCG) is a severe form of childhood blindness caused by developmental defect(s) in the trabecular meshwork and anterior chamber angle of the eye. These abnormalities cause the obstruction of outflow of aqueous humor, which in turn results in raised intraocular pressure (IOP). If PCG is left untreated, it results in optic nerve damage and subsequent loss of vision. It is usually seen in the age group of birth to 3 years. Clinical manifestations include elevated IOP, enlargement of the globe, edema, and opacification of the cornea, with rupture of Descemet’s membrane, photophobia, blepharospasm, anomalously deep anterior chamber and excessive tearing. It is mostly inherited as an autosomal recessive disorder and, in a few cases, parent-to-child transmission (pseudodominance) of the disease also occurs. 1 Inbred populations show a higher incidence of the disease. It is seen in 1 in 10,000 cases in the West, 2 1 in 3300 in the state of Andhra Pradesh in India, 3 1 in 2500 in Saudi Arabia, 4 and 1 in 2500 in the Slovakian Romany population. 5 Using linkage analysis, PCG (gene symbol GLC3) has been mapped to three different loci, GLC3A (at 2p21), GLC3B (at 1p36), and GLC3C (at 14q24.3) (Stoilov IR, et al. IOVS 2002;43:ARVO E-Abstract 3015). 6 7 Although these three loci have been linked to PCG, only the gene, CYP1B1 (Online Mendelian Inheritance in Man [OMIM] 601771, a member of the cytochrome P450 supergene family) at the GLC3A locus has been identified to date. 
Approximately 45 mutations in the coding region (exons II and III) of this gene (GenBank accession no. U56438; http://www.ncbi.nlm.nih.gov/Genbank; provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD) have now been implicated in the pathogenesis of PCG. These include deletion, insertion, point mutation, missense, nonsense, frameshift, and chain terminator mutations. Membrane-bound cytochromes such as CYP1B1 have a transmembrane domain, which is located at the amino terminal end of the molecule. This is followed by a proline rich “hinge” region, which permits flexibility between the membrane-spanning domain and the cytoplasmic portion of the molecule. The carboxyl terminal region has highly conserved core structures (CCSs) and is required for the proper heme-binding ability of the CYP1B1 molecule. Those mutations at the N-terminus hinge region or C terminus CCSs are expected to interfere with fundamental properties of the cytochrome P450 molecule, such as proper folding, heme binding, and formation of stable hemoprotein complex, substrate accommodation, and interaction with the redox partner, and to decrease significantly the enzyme’s metabolism. 1 8 9 Frameshift mutations causing premature stop codons in the open reading frames would result in functional null alleles. 1 10 Several CYP1B1 mutations would cause conformational changes in the DNA which in turn affect the structure function relationship of CYP1B1. 11 12 This conformational change could result in disease manifestation. Though a wide spectrum of the aforementioned mutations in CYP1B1 were reported in various ethnic populations, 1 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 scant information is available on the genotype–phenotype correlations of this devastating childhood blinding disorder. 10 22 Genotype–phenotype correlations could play a significant role in managing the disease. We have screened 146 patients with PCG from 138 pedigrees and reported six distinct CYP1B1 mutations from 45 patients with PCG from India. 10 27 These include four novel mutations: ins 376A or Ter@223(frameshift), P193L, E229K, R390C, and two known mutations, G61E and R368H. 
Herein, we describe the results of genotype–phenotype correlations of 43 Indian patients with PCG, its implications in disease prognoses and the de novo mutation identified. In addition, we report the severity index developed for grading various congenital glaucoma phenotypes that occur in India. 
Methods
Selection and Evaluation of Study Subjects
This investigation followed the tenets of the Declaration of Helsinki. The Institute’s Ethics Committee approved the research. After obtaining informed consent, both consanguineous and nonconsanguineous subjects (n = 146) from 138 pedigrees were recruited. All subjects (both familial and sporadic cases) were clinically evaluated by a glaucoma specialist (AKM) and diagnosed with PCG by slit lamp biomicroscopy, gonioscopy, measurement of IOP, and perimetry wherever possible. About half (51.5%) of the families recruited were of a nonconsanguineous group; sporadic cases accounted for 80%. All subjects enrolled were followed up for several years, and samples were collected over 2 years in the Children’s Eye Care Centre at the Institute. The various clinical parameters of PCG subjects and the ranges observed are given in Table 1 . The quantitative clinical data of PCG study subjects are given in Table 2 2
Mutation Screening of CYP1B1 Gene and Direct Sequencing
Genomic DNA was prepared from peripheral lymphocytes. The coding regions (1.6 Kb) spanning exons, II and III of CYP1B1 gene 28 (GenBank accession no. U56438) were amplified from genomic DNA of patients and control samples using three sets of primers as described earlier. 21 The amplicons were sequenced directly, and the patient and control sequences were compared, to identify the mutations. 
PCR-RFLP Analysis
All six mutations identified earlier resulted in restriction site changes and, based on this polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) method were developed 10 27 for further screening of the samples. All the PCR-RFLP–positive samples were sequenced again to confirm the respective mutations using an automated DNA sequencer (Prism 3700; Applied Biosystems, Foster City, CA) using dye terminator chemistry sequencing (Big Dye; Applied Biosystems). Seventy healthy volunteers without any history of eye disorders were used as normal control subjects. 
Statistical Analysis
Because there was asymmetric phenotype between both eyes of several patients analyzed, severe phenotype exhibited in at least one eye was considered for calculating the percentage of severity of disease against each mutation. Correlation between severity and prognosis was estimated using Spearman’s rank correlation coefficient, and P < 0.05 was considered to be statistically significant. 
Microsatellite Analysis
Microsatellite analysis was performed to assess paternity in pedigree 0017 using 11 highly polymorphic short tandem repeat (STR) markers from the X- and Y-chromosomes and from the autosomes. The markers used were from a PCR amplification kit (AmpFlSTR Profiler Plus; Applied Biosystems, Foster City, CA). This kit coamplifies the repeat regions of the following 11 short tandem repeat loci and their respective chromosomal locations are given in parentheses: D3S1358 (3p), vWA (12p12-pter), FGA (4q28), D8S1179 (8), D21S11 (21), D18S51 (18q21.3), D5S818 (5q21-31), D13S317 (13q22-31), D7S820 (7q11.21-22), and (X:p22.1-22.3; Y:p11.2). A segment of the X-Y homologous gene amelogenin was also amplified for gender identification. One primer of each locus-specific primer pair was labeled with either the 5-FAM, JOE, or NED NHS-ester dye, which was detected as blue, green, and yellow, respectively, on the sequencer (Prism 3700; Applied Biosystems). 
Results
Identification of De Novo Mutation
It is notable that de novo mutation was identified in one of the families. Mutation in family 0017 was confirmed by sequencing, and cosegregation of mutant alleles with disease phenotype was ascertained by PCR-RFLP analysis (Fig. 1) . An interesting instance was observed in family 0017, in which the affected male child (proband-II.1) was homozygous for R368H, whereas their mother (I.2) was heterozygous (carrier) for the same mutation. No sequence change was detected in the father (I.1), after several rounds of sequencing and PCR-RFLP analyses. He was found homozygous for the wild-type allele (normal) and the proband (II.1) had both carrier (II.2) and normal (II.3) siblings. Usually, for the manifestation of an autosomal recessive disease, both parents are expected to be carriers, but in this family only one of the parents (the mother, II.2) was found to be a carrier, and the first male child (proband II.1) was affected by PCG. Hence, we reasoned that the absence of mutation in the father could be due to nonpaternity or occurrence of paternal de novo mutation in the germline. 
A similar instance of a paternal de novo homozygous germline mutation (G365W) was reported in an American family. 11 Their line of evidence also corroborates our findings. Paternity in this nonconsanguineous family was established by analyzing 11 highly polymorphic short tandem repeat (STR) markers (AmpFlSTR Profiler Plus Loci Kit; applied Biosystems) from the X and Y-chromosomes and from the autosomes (data not shown). For the Y-linked markers, the father and affected son (proband II.2) shared an identical haplotype, whereas, for the X-linked markers, the father and daughter shared another haplotype. Also, none of the autosomal markers showed any evidence of incompatibility in this pedigree. Therefore, no evidence for nonpaternity was found by our investigation. Moreover, the genomic DNA used for screening was obtained from peripheral leukocytes; hence, we interpreted this as a case of de novo mutation in the germline. 
Severity Index for Grading PCG
Several cases of PCG with varying severity and manifestations have been identified in India. Hence, a severity index was constructed for grading various phenotypes. The phenotypes were graded from normal to severe, using the clinical parameters given in Table 3 . A phenotype was graded “very severe” when the last recorded vision ranged between less than 20/400 and no perception of light (NPL), or total blindness. The severe phenotypes associated with various mutations are given in Table 4
Genotype–Phenotype Correlations
By direct sequencing and PCR-RFLP methods six distinct CYP1B1 mutations were identified in 43 Indian patients with PCG. 10 27 The respective genotype–phenotype correlations are shown in Table 5 . The six mutations identified comprise of four novel mutations: ins 376A or Ter@223 (frameshift), P193L, E229K, R390C, and two known mutations, G61E and R368H. All these patients had bilateral PCG. The prognosis of the disease was assessed for each patient based on his or her last recorded vision. The prognosis was graded into four categories: good, fair, poor, and very poor. 
Depending on the combination of alleles, the genotype–phenotype correlations varied (Table 5) . The worst phenotype was seen with frameshift mutation (0004p and 0004s) followed by R390C homozygous mutation (Table 5) . All the patients with R390C homozygous mutation (0005f, 0012p, 0012s, 0018p, and 0092p) showed very severe phenotype and very poor prognosis compared with heterozygous mutation (0005p). Of all the mutations identified herein, the predominant one was R368H, which appeared in 25 patients. Six patients had the R390C mutation, followed by E229K, five; P193L, four; G61E, three; and frameshift, two (Table 4) . With all mutations, severe phenotypes were observed in at least one eye of the patients. The percentages of severe phenotypes seen in at least one eye against various mutations were frameshift, 100%, G61E, 66.7%; P193L, 62.5%; E229K, 80%; R368H, 72%; and R390C, 83.3% (Table 4) . All patients with frameshift and G61E had homozygous mutations, whereas all E229K-bearing patients were heterozygous. Patients with P193L, R368H, and R390C had both homozygous and heterozygous mutations. Thirty-two percent of patients with the R368H mutation showed asymmetric phenotypes between eyes (Table 5) . Good correlation was found between the severity and prognosis of the disorder (r = 0.976; P < 0.0001). 
Discussion
We reported the direct association of CYP1B1 mutations with PCG phenotypes from India. 10 Subsequently, in the current study, we screened by direct sequencing and PCR-RFLP analyses a large PCG cohort (146 subjects from 138 pedigrees) and identified six distinct mutations in 45 patients. We also found R368H to be the predominant mutation causing PCG in India. 27 This allele was earlier rarely reported from Middle East and Brazil, 17 22 but in India 16.2% of the patients screened had the mutation. 27 This indicates that the mutation frequency varies, depending on the geographical location as well as ethnic background. Though a spectrum of CYP1B1 mutations from various ethnic backgrounds 1 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 have been implicated in the pathogenesis of PCG, only a very few studies have reported genotype–phenotype correlations. 21 22 In this investigation, we describe the genotype–phenotype correlations of 43 patients and their prognoses. Although PCG with varying phenotypes have been identified, this is first severity index for grading the various PCG phenotypes that has been developed. It enables grading of PCG from normal to very severe phenotypes (Table 3)
Severe phenotypes were associated with all six mutations described in this study, but the percentage of severity varied with each mutation. For the different mutations, the associated percentages of severe phenotypes in at least one eye of the patient were: G61E, 66.7%; P193L, 62.5%; E229K, 80%; R368H, 72%; R390C, 83.3%; and frameshift, 100% (Table 4)
Of all the mutations studied, frameshift and R390C homozygous mutations were found to be associated with very severe phenotypes and very poor prognoses. Even though multiple surgical interventions were performed in two patients (0004p and 0004s) with frameshift mutations, both eventually became blind (Table 5) . This could be because the frameshift mutation resulted in a functional null allele lacking all domains of CYP1B1. 10 Whether surgery was performed at 1 week or 4 weeks, all five patients (0005f, 0012p, 0012s, 0018p, and 0092p) with R390C homozygous mutations exhibited uniformly very severe phenotypes and had very poor prognoses (Table 5) . This indicates that probably clinical interventions in these patients had limited value. However, another study in a group of patients shows that early and prompt surgical interventions resulted in better prognosis. 29 30 Probably these patients had mutations that were different from those reported in the current study, and they may be less severe. This study gives the genotype–phenotype correlations of a large number of patients with PCG (25 patients) with R368H mutation. It was found that 72% of them had severe phenotype in at least one eye. Both R368H and R390C residues are highly conserved across various members of the cytochrome P450 superfamily (data not shown). These residues map to helix K, which is one of the highly conserved core structures (CCSs) and is thought to be involved in proper protein folding and in active heme binding. Therefore, these mutations could lead to severe phenotypes. 1 10 17  
The highly conserved glycine residue at position 61 is in a left-handed helical conformation and is in a very unique position, where the peptide chain takes a sharp turn. 10 The G61E mutation 12 is adjacent to the N-terminal proline-rich region of CYP1B1, is also likely to affect proper protein function, and hence results in disease manifestation. The proline-proline-glycine-proline motif may serve to join the membrane-binding N terminus to the globular region of P450 protein. 13 14 18 24 Mutations in the hinge region have been reported to interfere with the proper folding and heme-binding properties of cytochrome P450 molecules. 1 8 It has been shown that this mutation significantly reduces the enzyme’s metabolism. 9  
P193 and E229 amino acid (aa) residues are also conserved among various members of the cytochrome P450 superfamily. 10 A molecular simulation study has shown that P193L and E229K mutations could bring conformational changes in the protein (Achary MS, et al., unpublished observation, 2002). The P193 aa residue in CYP1B1 comes in the N-capping region of the helix E (aa 173-210) and is most suited for proline. The replacement of proline with leucine at this position (P193L) could disrupt the helical structure and cause severe conformational change in the mutant protein. Similarly, E229 is in the middle of the helix F (218 to 234) and the replacement of this residue at position 229 could cause conformational change. This is also associated with the premature termination of the F helix at this position 10 (Achary MS, et al., unpublished observation, 2002). Hence, it is possible that the conformational changes caused by P193L and E229K mutations impairs the structure–function relationship of CYP1B1 and in turn results in manifestation of disease. 
Mutational analyses of CYP1B1 coding exons revealed homozygous mutations in 30 of 43 Indian patients described in this study. Two patients (0001 and 0035) showed compound heterozygous mutations, whereas in 11 patients, only single heterozygous mutations were detected. Because we could not identify the second mutation in 11 heterozygous patients, we conclude that it could be due to mutations in (1) CYP1B1 promoter or control region; (2) genes linked to other PCG loci such as GLC3B and GLC3C; (3) other glaucoma genes such as FOXC1 and MYOC, resulting in digenic inheritance; or (4) some other unknown genes causing glaucoma. Mutations in the forkhead transcription factor gene FOXC1 (formerly called FKHL7) could also contribute to the development of PCG. 31 Hence, it is possible that PCG can be due to mutations in multiple genes (such as CYP1B1 and FOXC1, CYP1B1 and MYOC, genes linked to GLC3B and C or some other loci). Digenic inheritance in glaucoma has been shown recently in two instances, such as in early-onset glaucoma in humans and also in mice with PCG. 32 33 CYP1B1 and MYOC mutations were identified in early-onset glaucoma in humans, 32 whereas mutations in CYP1B1 and FOXC1 were detected in mice with PCG.34 This points to the fact that mutations in genes other than CYP1B1 can cause PCG, because all these genes could contribute to the development of anterior chamber angle. PCG is caused by unknown developmental defect(s) in trabecular meshwork and anterior chamber angle of the eye. 1 Angle structures are mainly derived from the neural crest cells; hence, defects in genes expressed in neural crest cells could also contribute to PCG. 
The genotype/phenotype correlation varies, depending on the combination of alleles. The PCG phenotypes associated with heterozygous mutations varied from mild to severe, and this variation could be due to the various combinations of alleles (Table 5) . The phenotypic heterogeneity of this disorder seen in India could reflect the underlying genetic heterogeneity of the disorder. We screened 146 well-characterized patients with PCG for CYP1B1 mutations and detected mutations in only 45 of them. This indicates that mutations in non-CYP1B1 genes in other loci could also cause this disorder and also highlights the genetic complexity of PCG in India. 
This is the first study to describe the genotype–phenotype correlations of a large number of patients with PCG. A severity index for grading congenital glaucoma has been developed for the first time. This is the second report demonstrating the occurrence of de novo mutation in CYP1B1 gene causing PCG. This study also indicates that probably genotype could be used as an indicator in predicting the prognosis of the disease—for instance, in the case of frameshift and R390C mutations described in this study. Because PCG results in high life-long morbidity, genetic counseling and rehabilitation of the patient are very important in reducing the burden of the afflicted family, and may improve the quality of life. An integrated management of PCG using genetic approach along with medical, surgical, and rehabilitation interventions could yield better results in tackling this devastating blinding disease of childhood. In sum, the data derived from this study could be used as an added clinical tool in managing the disease better. 
Establishing genotype–phenotype correlations of PCG may aid in knowing the prognosis of the disease, in guiding therapy and in counseling the afflicted families. Therefore, further studies involving large number of families from various ethnic backgrounds would be required in establishing the genotype–phenotype correlations of this blinding disorder in children. 
Furthermore, the molecular consequences of the mutations found to date, provide a framework for genotype–phenotype correlation and suggest future studies in light of results of investigation of normal and mutant CYP1B1. 
 
Table 1.
 
Clinical Data Ranges Observed in PCG Study Subjects
Table 1.
 
Clinical Data Ranges Observed in PCG Study Subjects
Clinical Parameters Ranges Observed
Age of onset By birth–3 years
Age of diagnosis By birth–30 years
IOP (mm Hg) 24–55
Cup-to-disc ratio of the optic nerve 0.3:1 (total cupping)
Corneal diameter (mm) 11–17
Last recorded vision 6/6-NPL (normal-blind)
Corneal changes Corneal scar, Haab’s striae, edema, buphthalmos, megalocornea
Treatments (n) Medical-surgical (1–3)
Table 2.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Table 2.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Serial Number Pedigree ID Age of Onset Age of Diagnosis Corneal Diameter (mm) and Clarity at Diagnosis (OD; OS) IOP at Diagnosis (mm Hg OD; OS) Last C/D Ratio (OD; OS) Last Visual Acuity (OD; OS) Treatments (OD; OS)
1 0004p By birth 5 mo 12; 12.5 36; 38 0.9; NA NPL OU Medical and 1× Trab/Trab OU; 1× PK , * OD
Buphthalmos, Haab’s striae, hazy cornea, and edema OU
2 0004s By birth 3 mo NA OU NA OU NA OU NPL OU Medical and 1× Trab/Trab OU
Buphthalmos, hazy cornea, and atrophic OU
3 0093p By birth By birth 15.5; 13 35; 30 NA OU 20/160; 20/80 1× Trab/Trab OU
Hazy cornea and edema OU
4 0093s By birth By birth 14.5; 16 26; 30 0.5 OU 20/130; 20/960 Medical and 1× Trab/Trab OU
Hazy cornea and edema OU
5 0011p By birth 2 wk 12; 12.5 30 OU 0.3; 0.6 20/50 OU Medical and 1× Trab/Trab OU; 2× Trab/Trab OS
Corneal edema OU
6 0058p By birth By birth 13 32 OU 0.5; 0.6 20/360 1× Trab/Trab OU
Hazy cornea and corneal scar OU
7 0001p By birth 5 y NA 24 OU 0.8; 0.6 20/25 OU Medical treatment OU
Clear OU
8 0001m Late onset in OD; >3 years 30 y NA Clear OD, hazy OS 34; 50 0.8; 0.9 20/20; NPL in OD Medical treatment OD
9 0069p By birth By birth 14 OU 26; 24 0.6 OU 20/300; 20/120 Medical treatment OU; 1× Trab/Trab OU
Hazy cornea and edema OU
10 0024p By birth By birth 11.5 OU 28; 31 NA OU 20/80 OU Medical treatment OU; 1× Trab/Trab OD
Hazy cornea OU
11 0037p 1 y 5 y 14 OD; enucleated OS 26; NA NA OU PL in OD 3× Trab/Trab OD
megalocornea, corneal scar OU, edema OD
12 0047p By birth By birth NA OU 25; 32 0.4; 0.8 20/126; PL 3× Trab/Trab OU and 3× molteno implants
Corneal scar OU
13 0125p 1 wk 1 wk 13.5; 14 20; 28 0.6; 0.4 20/670 OU 1× Trab/Trab OU; 1× Trab OD
Haab’s striae and hazy cornea OU
14 0002p By birth 2 wk 13 OU NA OU 0.9 OU 20/30; PL 3× Trab/Trab OU; retinal reattachment surgery OS, and medical treatment OD
Haab’s striae, buphthalmos and hazy cornea OU
15 0006p By birth 9 mo 13; 12.5 26; 30 0.3 OU 20/40; 20/300 1× Trab/Trab OU
Megalocornea, corneal edema OU, and hazy cornea OS
16 0017p By birth By birth 13.5 OU 26; 24 0.9 OU NPL; 20/160 1× Trab/Trab OS
Megalocornea, corneal edema OU and hazy cornea OS
17 0040p By birth By birth 13; 12 32; 26 0.6 OU Fixing and following light 1× Trab/Trab OU
Buphthalmos OU, corneal scar OD and hazy cornea OS
18 0076p By birth By birth 12 OU 26; 30 0.2 OU 20/400; 20/30 1× Trab/Trab OU; 1× Trab/Trab OS
Buphthalmos and hazy cornea OU
19 0079p 4 mo 4 mo 13.5; 13 22; 28 NA OU Fixing and following light 1× Trab/Trab OU
Corneal edema OD, Haab’s striae OS, and buphthalmos OU
20 0130p By birth 2.6 y 12; 13.5 12; 28 0.3; 0.9 Fixing and following light 1× Trab/Trab OS
Megalocornea OS
21 0137p By birth 1 mo 14.5 OU 26; 28 NA; 0.5 20/60 OU 1× Trab/Trab OU
Corneal scar OD and hazy cornea OS
22 0144p By birth By birth 11 OU 36; 30 NA; 0.5 20/260 OU 1× Trab/Trab OU
Corneal scar and edema OD
23 0006s By birth 3 mo 15 OU 32 OU NA OU PL; HM Medical and 1× Trab/Trab OU
Corneal edema and scar OU
Table 2A.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Table 2A.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Serial Number Pedigree ID Age of Onset Age of Diagnosis Corneal Diameter (mm) and Clarity at Diagnosis (OD; OS) IOP at Diagnosis (mm Hg OD; OS) Last C/D Ratio (OD; OS) Last Visual Acuity (OD; OS) Treatments (OD; OS)
24 0022p 6 mo 8 mo 14 OU 34; 35 NA 20/600 OU 1× Trab/Trab OU; 1× Trab/Trab OD
Megalocornea, corneal edema, scar and hazy OU
25 0035p By birth 28 d 11 OU 26 OU NA OU 20/960 OU 2× Trab/Trab OU
Corneal edema and hazy OU
26 0051p By birth 4 mo 13 OU 28; 26 0.3; 0.4 20/250 OU 1× Trab/Trab OU
Haab’s striae and hazy cornea OU
27 0071p By birth By birth 11.5; 11 28; 26 NA 20/200 OU 1× Trab/Trab OU
Corneal scar OD, corneal edema and hazy OU
28 0071s By birth By birth 13 OU 28; 20 NA Fixing and following light 1× Trab/Trab OU
Corneal scar OD and hazy OU
29 0075p By birth By birth 14 OU 34; 38 NA 20/2400 OU 1× Trab/Trab OU
Buphthalmos, corneal scar, and edema OU
30 0150p By birth 3 mo 13 OU 28; 30 0.2 OU 20/200; 20/60 1× Trab/Trab OU
Megalocornea OU
31 0136p By birth 3 mo 13; 14 32; 34 0.2 OU 20/180 OU 1× Trab/Trab OU
Haab’s striae OS
32 0067p By birth By birth 15; 14 16; 12 NA 20/60 OU 1× Trab/Trab OU; 3× Trab OD; 7× Trab OS
Haab’s striae OD, corneal scar, and edema OS
33 0025p By birth 10 y 16; 14 50; 55 1.0 OU 20/200 OU 1× Trab/Trab OD
OU Haab’s striae, buphthalmos OU, and megalocornea OD
34 0035m By birth 8 y NA OU NA OU NA OU PL in OU 2× Trab/Trab OU; 1× PK OS; 1× Iridencleisis OU
Megalocornea, corneal edema, scar and hazy OU
35 0095p 1 y 1 y 12 OU 38; 36 0.4; 0.3 PL in OU 1× Trab/Trab OU
Megalocornea and hazy cornea OU
36 0100p By birth 4 mo 12; 12.5 OU 20 OU NA 20/20; 20/200 OU 1× Trab/Trab OU; 1× Trab OD; 1× Trab OS; and medical treatment
Haab’s striae, buphthalmos OU, and megalocornea OD
37 0039p By birth By birth NA OU 19; 18 0.4; 0.5 20/20; 20/25 Medical treatment OD; 1× Trab OS
NA OU
38 0005p By birth By birth 12 OU 40; 42 0.3 OU 20/120 OU 1× Trab/Trab OU
Corneal edema OU
39 0005f By birth By birth NA OU 18 OU NA OU NPL OU 1× Trab/Trab OU; 1× Trab OD; iridencleisis OU
Buphthalmos, megalocornea, and corneal edema OU
40 0012p By birth By birth 12; 12.5 32; 34 NA OU 20/400 OU 1× Trab/Trab OU; 1× PK OD
Buphthalmos, corneal scar, and corneal edema OU
41 0012s By birth By birth 12 OU 28; 32 0.3 OU CF in OU 1× Trab/Trab OU
Buphthalmos, megalocornea, corneal scar and hazy OU
42 0018p By birth By birth 13 OU 28; 30 NA OU NA OU 1× Trab/Trab OU
Buphthalmos, megalocornea, and hazy OU
43 0092p By birth By birth 12.5; 13 22; 24 NA OU 20/600; 20/960 1× Trab/Trab OU
OU Buphthalmos, megalocornea, and hazy OU
Figure 1.
 
PCR-RFLP analyses of the cosegregation of mutant allele with the disease phenotype. Filled square: Affected individual; arrow: proband; dot in open symbol: carriers; DNA molecular weight marker (lane M) in base pairs (left); allele sizes (right); control (lane C); patient (patient); mutant allele (arrowhead). Restriction site changes and mutations (nucleotide as well as amino acid changes) are shown at the bottom of the gel. Restriction digestion of wild-type allele in the control generated 507- and 200-bp fragments (lane C). Mutation abolishes the TaaI site. In carriers, in addition to the wild-type allele, a mutant allele of 352 bp was present. In the disease phenotype (homozygous) a mutant allele of 352 bp was present. The father’s DNA (I.1) was the same as the control DNA and he bore no mutant allele of 352 bp.
Figure 1.
 
PCR-RFLP analyses of the cosegregation of mutant allele with the disease phenotype. Filled square: Affected individual; arrow: proband; dot in open symbol: carriers; DNA molecular weight marker (lane M) in base pairs (left); allele sizes (right); control (lane C); patient (patient); mutant allele (arrowhead). Restriction site changes and mutations (nucleotide as well as amino acid changes) are shown at the bottom of the gel. Restriction digestion of wild-type allele in the control generated 507- and 200-bp fragments (lane C). Mutation abolishes the TaaI site. In carriers, in addition to the wild-type allele, a mutant allele of 352 bp was present. In the disease phenotype (homozygous) a mutant allele of 352 bp was present. The father’s DNA (I.1) was the same as the control DNA and he bore no mutant allele of 352 bp.
Table 3.
 
Severity Index Used for Grading Various Indian PCG Phenotypes
Table 3.
 
Severity Index Used for Grading Various Indian PCG Phenotypes
Clinical Parameters Used for Grading Normal Mild Moderate Severe/Very Severe*
Corneal diameter (mm) Up to 10.5 >10.5–12 >12–13 >13
IOP (mm Hg) Up to 16 >16–20 >20–30 >30
C/D ratio 0.3–0.4 >0.4–0.6 >0.6–0.8 >0.8
Last recorded visual acuity 20/20 <20/20–20/60 <20/60–20/200 <20/200–20/400, <20/400–NPL (blind)*
Corneal clarity No edema Mild edema Severe edema Severe edema and Haab’s striae
Table 4.
 
Severe Phenotypes Associated with CYP1B1 Mutations in Indian PCG Patients
Table 4.
 
Severe Phenotypes Associated with CYP1B1 Mutations in Indian PCG Patients
Serial Number Pedigrees/Patients (n) Mutations Identified Eyes with Severe Phenotypes (n) (Eyes Evaluated, %) Eyes with Very Poor Prognoses (n) (Eyes Assessed; n, %)
1 1 (2) Ter@223 4/4 (100) Very poor (100)*
2 2 (3) G61E 4/6 (66.7) Very poor (66.7)
3 3 (4) P193L 5/8 (62.5) Very poor (1/8, 12.5)*
Very poor (4/8, 50)
4 5 (5) E229K 8/10 (80) Very poor (80)
5 22 (25) R368H 36/50 (72) Very poor (72)
6 4 (6) R390C 10/12 (83.3) Very poor (2/12, 16.6)*
Very poor (8/12, 66.6)
Table 5.
 
Genotype–Phenotype Correlations of CYP1B1 Mutations in Indian PCG Patients
Table 5.
 
Genotype–Phenotype Correlations of CYP1B1 Mutations in Indian PCG Patients
Serial Number Pedigree ID Age at Intervention Mutations Identified Severity by Eye Prognoses by Eye
1 0004p 5 mo Ter@223 Very severe OU Very poor OU*
2 0004s 3 mo Ter@223 Very severe OU Very poor OU*
3 0093p 1 mo G61E Severe OU Poor OU
4 0093s 2 mo G61E Severe OD Poor OD
Very severe OS Poor OD
5 0011p 2 wk G61E Mild OU Good OU
6 0058p 1 wk P193L Severe OU Poor OU
7 0001p ND P193L (h) Mild OU Good OU
E229K (h)
8 0001m ND P193L (h) Normal OD Good OD
Very severe OS Very poor OS*
9 0069p 1.6 y P193L (h) Very severe OU Very poor OU
10 0024p 1 mo E229K (h) Very severe OU Very poor OU
11 0037p 5 y E229K (h) Very severe OU Very poor OU
12 0047p 10 y E229K (h) Very severe OU Very poor OU
13 0125p 3 mo E229K (h) Severe OU Poor OU
14 0002p 35 d R368H Mild OD Good OD
Severe OS Poor OS
15 0006p 8 mo R368H Mild OD Good OD
Severe OS Poor OS
16 0017p 9 y R368H Very severe OD Very poor OD*
Severe OS Poor OS
17 0040p 5 mo R368H Very severe OD Very poor OD
Severe OS Poor OS
18 0076p 1 y R368H Severe OD Poor OD
Moderate OS Fair OS
19 0079p 3 mo R368H Very severe OD Very poor OD
Severe OS Poor OS
20 0130p 3 y R368H Severe OD Poor OD
Very severe OS Very poor OS
21 0137p 1 mo R368H Severe OD Poor OD
Moderate OS Fair OS
22 0144p 1 mo R368H Severe OD Poor OD
Moderate OS Fair OS
23 0006s 4 mo R368H Severe OU Poor OU
24 0022p 6 mo R368H Very severe OU Very poor OU
25 0035s 28 d R368H Very severe OU Very poor OU
26 0051p 5 mo R368H Very severe OU Very poor OU
27 0071p 2 wk R368H Severe OU Poor OU
28 0071s 2 wk R368H Severe OU Poor OU
29 0075p 1 wk R368H Very severe OU Very poor OU
30 0150p 1 mo R368H Moderate OU Fair OU
31 0136p 2 mo R368H Moderate OU Fair OU
32 0067p 2 mo R368H Severe OU Poor OU
33 0025p 10 y R368H (h) Very severe OU Very poor OU
34 0035p 8 y R368H (h) Very severe OU Very poor OU
35 0095p 1.2 y R368H (h) Very severe OU Very poor OU
36 0100p 1.3 y R368H (h) Moderate OD Fair OD
Severe OS Poor OS
37 0039p 21 d R368H (h) Moderate OU Fair OU
38 0005p 29 d R368H (h) Moderate OU Fair OU
R390C (h)
39 0005f 2 mo R390C Very severe OU Very poor OU*
40 0012p 4 mo R390C Very severe OU Very poor OU
41 0012s 2 mo R390C Very severe OU Very poor OU
42 0018p 1 wk R390C Very severe OU Very poor OU
43 0092p 29 d R390C Very severe OU Very poor OU
The authors thank the patients and their families for their participation in this study; the Clinical Biochemistry Services and the Jasti V. Ramanamma Children’s Eye Care Center staff at L. V. Prasad Eye Institute (LVPEI) for their assistance in sample collection; Dorairajan Balasubramanian and Gullapalli N. Rao, LVPEI, for encouragement and support; Rishita Nutheti, International Center for Advancement of Rural Eye Care (ICARE), for assistance in statistical analysis; Hampapathalu A. Nagarajaram and colleagues, Center for DNA Fingerprinting and Diagnostics, Hyderabad, for the microsatellite analysis and for their unpublished data on molecular dynamics, respectively; and the anonymous reviewers for their constructive comments. 
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Figure 1.
 
PCR-RFLP analyses of the cosegregation of mutant allele with the disease phenotype. Filled square: Affected individual; arrow: proband; dot in open symbol: carriers; DNA molecular weight marker (lane M) in base pairs (left); allele sizes (right); control (lane C); patient (patient); mutant allele (arrowhead). Restriction site changes and mutations (nucleotide as well as amino acid changes) are shown at the bottom of the gel. Restriction digestion of wild-type allele in the control generated 507- and 200-bp fragments (lane C). Mutation abolishes the TaaI site. In carriers, in addition to the wild-type allele, a mutant allele of 352 bp was present. In the disease phenotype (homozygous) a mutant allele of 352 bp was present. The father’s DNA (I.1) was the same as the control DNA and he bore no mutant allele of 352 bp.
Figure 1.
 
PCR-RFLP analyses of the cosegregation of mutant allele with the disease phenotype. Filled square: Affected individual; arrow: proband; dot in open symbol: carriers; DNA molecular weight marker (lane M) in base pairs (left); allele sizes (right); control (lane C); patient (patient); mutant allele (arrowhead). Restriction site changes and mutations (nucleotide as well as amino acid changes) are shown at the bottom of the gel. Restriction digestion of wild-type allele in the control generated 507- and 200-bp fragments (lane C). Mutation abolishes the TaaI site. In carriers, in addition to the wild-type allele, a mutant allele of 352 bp was present. In the disease phenotype (homozygous) a mutant allele of 352 bp was present. The father’s DNA (I.1) was the same as the control DNA and he bore no mutant allele of 352 bp.
Table 1.
 
Clinical Data Ranges Observed in PCG Study Subjects
Table 1.
 
Clinical Data Ranges Observed in PCG Study Subjects
Clinical Parameters Ranges Observed
Age of onset By birth–3 years
Age of diagnosis By birth–30 years
IOP (mm Hg) 24–55
Cup-to-disc ratio of the optic nerve 0.3:1 (total cupping)
Corneal diameter (mm) 11–17
Last recorded vision 6/6-NPL (normal-blind)
Corneal changes Corneal scar, Haab’s striae, edema, buphthalmos, megalocornea
Treatments (n) Medical-surgical (1–3)
Table 2.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Table 2.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Serial Number Pedigree ID Age of Onset Age of Diagnosis Corneal Diameter (mm) and Clarity at Diagnosis (OD; OS) IOP at Diagnosis (mm Hg OD; OS) Last C/D Ratio (OD; OS) Last Visual Acuity (OD; OS) Treatments (OD; OS)
1 0004p By birth 5 mo 12; 12.5 36; 38 0.9; NA NPL OU Medical and 1× Trab/Trab OU; 1× PK , * OD
Buphthalmos, Haab’s striae, hazy cornea, and edema OU
2 0004s By birth 3 mo NA OU NA OU NA OU NPL OU Medical and 1× Trab/Trab OU
Buphthalmos, hazy cornea, and atrophic OU
3 0093p By birth By birth 15.5; 13 35; 30 NA OU 20/160; 20/80 1× Trab/Trab OU
Hazy cornea and edema OU
4 0093s By birth By birth 14.5; 16 26; 30 0.5 OU 20/130; 20/960 Medical and 1× Trab/Trab OU
Hazy cornea and edema OU
5 0011p By birth 2 wk 12; 12.5 30 OU 0.3; 0.6 20/50 OU Medical and 1× Trab/Trab OU; 2× Trab/Trab OS
Corneal edema OU
6 0058p By birth By birth 13 32 OU 0.5; 0.6 20/360 1× Trab/Trab OU
Hazy cornea and corneal scar OU
7 0001p By birth 5 y NA 24 OU 0.8; 0.6 20/25 OU Medical treatment OU
Clear OU
8 0001m Late onset in OD; >3 years 30 y NA Clear OD, hazy OS 34; 50 0.8; 0.9 20/20; NPL in OD Medical treatment OD
9 0069p By birth By birth 14 OU 26; 24 0.6 OU 20/300; 20/120 Medical treatment OU; 1× Trab/Trab OU
Hazy cornea and edema OU
10 0024p By birth By birth 11.5 OU 28; 31 NA OU 20/80 OU Medical treatment OU; 1× Trab/Trab OD
Hazy cornea OU
11 0037p 1 y 5 y 14 OD; enucleated OS 26; NA NA OU PL in OD 3× Trab/Trab OD
megalocornea, corneal scar OU, edema OD
12 0047p By birth By birth NA OU 25; 32 0.4; 0.8 20/126; PL 3× Trab/Trab OU and 3× molteno implants
Corneal scar OU
13 0125p 1 wk 1 wk 13.5; 14 20; 28 0.6; 0.4 20/670 OU 1× Trab/Trab OU; 1× Trab OD
Haab’s striae and hazy cornea OU
14 0002p By birth 2 wk 13 OU NA OU 0.9 OU 20/30; PL 3× Trab/Trab OU; retinal reattachment surgery OS, and medical treatment OD
Haab’s striae, buphthalmos and hazy cornea OU
15 0006p By birth 9 mo 13; 12.5 26; 30 0.3 OU 20/40; 20/300 1× Trab/Trab OU
Megalocornea, corneal edema OU, and hazy cornea OS
16 0017p By birth By birth 13.5 OU 26; 24 0.9 OU NPL; 20/160 1× Trab/Trab OS
Megalocornea, corneal edema OU and hazy cornea OS
17 0040p By birth By birth 13; 12 32; 26 0.6 OU Fixing and following light 1× Trab/Trab OU
Buphthalmos OU, corneal scar OD and hazy cornea OS
18 0076p By birth By birth 12 OU 26; 30 0.2 OU 20/400; 20/30 1× Trab/Trab OU; 1× Trab/Trab OS
Buphthalmos and hazy cornea OU
19 0079p 4 mo 4 mo 13.5; 13 22; 28 NA OU Fixing and following light 1× Trab/Trab OU
Corneal edema OD, Haab’s striae OS, and buphthalmos OU
20 0130p By birth 2.6 y 12; 13.5 12; 28 0.3; 0.9 Fixing and following light 1× Trab/Trab OS
Megalocornea OS
21 0137p By birth 1 mo 14.5 OU 26; 28 NA; 0.5 20/60 OU 1× Trab/Trab OU
Corneal scar OD and hazy cornea OS
22 0144p By birth By birth 11 OU 36; 30 NA; 0.5 20/260 OU 1× Trab/Trab OU
Corneal scar and edema OD
23 0006s By birth 3 mo 15 OU 32 OU NA OU PL; HM Medical and 1× Trab/Trab OU
Corneal edema and scar OU
Table 2A.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Table 2A.
 
Quantitative Clinical Data of PCG Subjects Used for Genotype–Phenotype Correlations
Serial Number Pedigree ID Age of Onset Age of Diagnosis Corneal Diameter (mm) and Clarity at Diagnosis (OD; OS) IOP at Diagnosis (mm Hg OD; OS) Last C/D Ratio (OD; OS) Last Visual Acuity (OD; OS) Treatments (OD; OS)
24 0022p 6 mo 8 mo 14 OU 34; 35 NA 20/600 OU 1× Trab/Trab OU; 1× Trab/Trab OD
Megalocornea, corneal edema, scar and hazy OU
25 0035p By birth 28 d 11 OU 26 OU NA OU 20/960 OU 2× Trab/Trab OU
Corneal edema and hazy OU
26 0051p By birth 4 mo 13 OU 28; 26 0.3; 0.4 20/250 OU 1× Trab/Trab OU
Haab’s striae and hazy cornea OU
27 0071p By birth By birth 11.5; 11 28; 26 NA 20/200 OU 1× Trab/Trab OU
Corneal scar OD, corneal edema and hazy OU
28 0071s By birth By birth 13 OU 28; 20 NA Fixing and following light 1× Trab/Trab OU
Corneal scar OD and hazy OU
29 0075p By birth By birth 14 OU 34; 38 NA 20/2400 OU 1× Trab/Trab OU
Buphthalmos, corneal scar, and edema OU
30 0150p By birth 3 mo 13 OU 28; 30 0.2 OU 20/200; 20/60 1× Trab/Trab OU
Megalocornea OU
31 0136p By birth 3 mo 13; 14 32; 34 0.2 OU 20/180 OU 1× Trab/Trab OU
Haab’s striae OS
32 0067p By birth By birth 15; 14 16; 12 NA 20/60 OU 1× Trab/Trab OU; 3× Trab OD; 7× Trab OS
Haab’s striae OD, corneal scar, and edema OS
33 0025p By birth 10 y 16; 14 50; 55 1.0 OU 20/200 OU 1× Trab/Trab OD
OU Haab’s striae, buphthalmos OU, and megalocornea OD
34 0035m By birth 8 y NA OU NA OU NA OU PL in OU 2× Trab/Trab OU; 1× PK OS; 1× Iridencleisis OU
Megalocornea, corneal edema, scar and hazy OU
35 0095p 1 y 1 y 12 OU 38; 36 0.4; 0.3 PL in OU 1× Trab/Trab OU
Megalocornea and hazy cornea OU
36 0100p By birth 4 mo 12; 12.5 OU 20 OU NA 20/20; 20/200 OU 1× Trab/Trab OU; 1× Trab OD; 1× Trab OS; and medical treatment
Haab’s striae, buphthalmos OU, and megalocornea OD
37 0039p By birth By birth NA OU 19; 18 0.4; 0.5 20/20; 20/25 Medical treatment OD; 1× Trab OS
NA OU
38 0005p By birth By birth 12 OU 40; 42 0.3 OU 20/120 OU 1× Trab/Trab OU
Corneal edema OU
39 0005f By birth By birth NA OU 18 OU NA OU NPL OU 1× Trab/Trab OU; 1× Trab OD; iridencleisis OU
Buphthalmos, megalocornea, and corneal edema OU
40 0012p By birth By birth 12; 12.5 32; 34 NA OU 20/400 OU 1× Trab/Trab OU; 1× PK OD
Buphthalmos, corneal scar, and corneal edema OU
41 0012s By birth By birth 12 OU 28; 32 0.3 OU CF in OU 1× Trab/Trab OU
Buphthalmos, megalocornea, corneal scar and hazy OU
42 0018p By birth By birth 13 OU 28; 30 NA OU NA OU 1× Trab/Trab OU
Buphthalmos, megalocornea, and hazy OU
43 0092p By birth By birth 12.5; 13 22; 24 NA OU 20/600; 20/960 1× Trab/Trab OU
OU Buphthalmos, megalocornea, and hazy OU
Table 3.
 
Severity Index Used for Grading Various Indian PCG Phenotypes
Table 3.
 
Severity Index Used for Grading Various Indian PCG Phenotypes
Clinical Parameters Used for Grading Normal Mild Moderate Severe/Very Severe*
Corneal diameter (mm) Up to 10.5 >10.5–12 >12–13 >13
IOP (mm Hg) Up to 16 >16–20 >20–30 >30
C/D ratio 0.3–0.4 >0.4–0.6 >0.6–0.8 >0.8
Last recorded visual acuity 20/20 <20/20–20/60 <20/60–20/200 <20/200–20/400, <20/400–NPL (blind)*
Corneal clarity No edema Mild edema Severe edema Severe edema and Haab’s striae
Table 4.
 
Severe Phenotypes Associated with CYP1B1 Mutations in Indian PCG Patients
Table 4.
 
Severe Phenotypes Associated with CYP1B1 Mutations in Indian PCG Patients
Serial Number Pedigrees/Patients (n) Mutations Identified Eyes with Severe Phenotypes (n) (Eyes Evaluated, %) Eyes with Very Poor Prognoses (n) (Eyes Assessed; n, %)
1 1 (2) Ter@223 4/4 (100) Very poor (100)*
2 2 (3) G61E 4/6 (66.7) Very poor (66.7)
3 3 (4) P193L 5/8 (62.5) Very poor (1/8, 12.5)*
Very poor (4/8, 50)
4 5 (5) E229K 8/10 (80) Very poor (80)
5 22 (25) R368H 36/50 (72) Very poor (72)
6 4 (6) R390C 10/12 (83.3) Very poor (2/12, 16.6)*
Very poor (8/12, 66.6)
Table 5.
 
Genotype–Phenotype Correlations of CYP1B1 Mutations in Indian PCG Patients
Table 5.
 
Genotype–Phenotype Correlations of CYP1B1 Mutations in Indian PCG Patients
Serial Number Pedigree ID Age at Intervention Mutations Identified Severity by Eye Prognoses by Eye
1 0004p 5 mo Ter@223 Very severe OU Very poor OU*
2 0004s 3 mo Ter@223 Very severe OU Very poor OU*
3 0093p 1 mo G61E Severe OU Poor OU
4 0093s 2 mo G61E Severe OD Poor OD
Very severe OS Poor OD
5 0011p 2 wk G61E Mild OU Good OU
6 0058p 1 wk P193L Severe OU Poor OU
7 0001p ND P193L (h) Mild OU Good OU
E229K (h)
8 0001m ND P193L (h) Normal OD Good OD
Very severe OS Very poor OS*
9 0069p 1.6 y P193L (h) Very severe OU Very poor OU
10 0024p 1 mo E229K (h) Very severe OU Very poor OU
11 0037p 5 y E229K (h) Very severe OU Very poor OU
12 0047p 10 y E229K (h) Very severe OU Very poor OU
13 0125p 3 mo E229K (h) Severe OU Poor OU
14 0002p 35 d R368H Mild OD Good OD
Severe OS Poor OS
15 0006p 8 mo R368H Mild OD Good OD
Severe OS Poor OS
16 0017p 9 y R368H Very severe OD Very poor OD*
Severe OS Poor OS
17 0040p 5 mo R368H Very severe OD Very poor OD
Severe OS Poor OS
18 0076p 1 y R368H Severe OD Poor OD
Moderate OS Fair OS
19 0079p 3 mo R368H Very severe OD Very poor OD
Severe OS Poor OS
20 0130p 3 y R368H Severe OD Poor OD
Very severe OS Very poor OS
21 0137p 1 mo R368H Severe OD Poor OD
Moderate OS Fair OS
22 0144p 1 mo R368H Severe OD Poor OD
Moderate OS Fair OS
23 0006s 4 mo R368H Severe OU Poor OU
24 0022p 6 mo R368H Very severe OU Very poor OU
25 0035s 28 d R368H Very severe OU Very poor OU
26 0051p 5 mo R368H Very severe OU Very poor OU
27 0071p 2 wk R368H Severe OU Poor OU
28 0071s 2 wk R368H Severe OU Poor OU
29 0075p 1 wk R368H Very severe OU Very poor OU
30 0150p 1 mo R368H Moderate OU Fair OU
31 0136p 2 mo R368H Moderate OU Fair OU
32 0067p 2 mo R368H Severe OU Poor OU
33 0025p 10 y R368H (h) Very severe OU Very poor OU
34 0035p 8 y R368H (h) Very severe OU Very poor OU
35 0095p 1.2 y R368H (h) Very severe OU Very poor OU
36 0100p 1.3 y R368H (h) Moderate OD Fair OD
Severe OS Poor OS
37 0039p 21 d R368H (h) Moderate OU Fair OU
38 0005p 29 d R368H (h) Moderate OU Fair OU
R390C (h)
39 0005f 2 mo R390C Very severe OU Very poor OU*
40 0012p 4 mo R390C Very severe OU Very poor OU
41 0012s 2 mo R390C Very severe OU Very poor OU
42 0018p 1 wk R390C Very severe OU Very poor OU
43 0092p 29 d R390C Very severe OU Very poor OU
Copyright 2004 The Association for Research in Vision and Ophthalmology, Inc.
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