Journal of Current Glaucoma Practice

Register      Login

VOLUME 7 , ISSUE 1 ( January-April, 2013 ) > List of Articles


Molecular Diagnostics and Genetic Counseling in Primary Congenital Glaucoma

Muneeb Faiq, Kuldeep Mohanty, Tanuj Dada

Keywords : Primary congenital glaucoma, Molecular diagnostics, Genetics, Genetic counseling

Citation Information : Faiq M, Mohanty K, Dada T. Molecular Diagnostics and Genetic Counseling in Primary Congenital Glaucoma. J Curr Glaucoma Pract 2013; 7 (1):25-35.

DOI: 10.5005/jp-journals-10008-1133

License: CC BY-NC 4.0

Published Online: 01-04-2018

Copyright Statement:  Copyright © 2013; The Author(s).


Primary congenital glaucoma (PCG) is a childhood irreversible blinding disorder with onset at birth or in the first year of life. It is characterized by the classical traid of symptoms viz. epiphora (excessive tearing), photophobia (hypersensitivity to light) and blepharospasm (inflammation of eyelids). The only anatomical defect seen in PCG is trabecular meshwork dysgenesis. PCG shows autosomal recessive mode of inheritance with considerable number of sporadic cases. The etiology of this disease has not been fully understood but some genes like CYP1B1, MYOC, FOXC1, LTBP2 have been implicated. Various chromosomal aberrations and mutations in mitochondrial genome have also been reported. Molecular biology has developed novel techniques in order to do genetic and biochemical characterization of many genetic disorders including PCG. Techniques like polymerase chain reaction, single strand conformational polymorphism and sequencing are already in use for diagnosis of PCG and other techniques like protein truncation testing and functional genomics are beginning to find their way into molecular workout of this disorder. In the light of its genetic etiology, it is important to develop methods for genetic counseling for the patients and their families so as to bring down its incidence. In this review, we ought to develop a genetic insight into PCG with possible use of molecular biology and functional genomics in understanding the disease etiology, pathogenesis, pathology and mechanism of inheritance. We will also discuss the possibilities and use of genetic counseling in this disease.

PDF Share
  1. Hoskins HD Jr, Kass MA. Becker-Shaffer's diagnosis and therapy of the glaucoma 6th ed. St Louis: CV Mosby; 1989. p. 356.
  2. Sarfarazi M, Stoilov I. Molecular genetics of primary congenital glaucoma. Eye (Lond) 2000 Jun;14(Pt 3B):422-428.
  3. Francosis, J. Inheritance in ophthalmology. St Louis: CV Mosby;
  4. p. 218-225.
  5. Jaffar, MS. Care of the infantile glaucoma patient. In: Reineck RD, editor. Ophthalmology Annual. New York: Raven Press; 1988.
  6. Dandona L, Williams JD, Williams BC, Rao GN. Populationbased assessment of childhood blindness in southern India. Arch Ophthalmol 1998 Apr;116(4):545-546.
  7. Gianferrari L, Cresseri A, Maltarello A. Ricerche sulla ereditarieta dell'idroftalmo e della cataratta congenita in paesi delle Prealpi Orobiche. Acta Genet Med Gemellol (Roma) 1954 Jan;3(1):1-15.
  8. Waardenburg PJ, Franceschetti A, Klein D. Genetics and ophthalmology. Vol. 1. Springfield, Ill: Charles C Thomas Publishers; 1961. p. 895-897.
  9. Belkin M, Oliver M, Cohen T. Congenital glaucoma with different clinical manifestations in members of one sibship. J Pediat Ophthalmol 1972;8:266-269.
  10. Merin S, Morin D. Heridity of congenital glaucoma. Br J Opthalmol 1972 May;56(5):414-417.
  11. Briard ML, Feingold J, Kaplan J, Bonaiti C, Aron JJ, Blanck MF, Delthil S, Frezal J. The genetics of congenital glaucoma: a study of 231 cases. J Genet Hum 1976 Nov;24 Suppl:107-123. (Fre).
  12. Kluyskens J. Le glaucoma congenital. Bull Soc Belge Ophthal 1950;94:4-243.
  13. Shaffer, RN.; Weiss, DI. Infantile glaucoma: diagnosis and differential diagnosis. Congenital and Pediatric Glaucomas. St. Louis: CV Mosby; 1970. p. 37-59.
  14. Leighton DA, Phillips CI. Infantile glaucoma. Steroid testing in parents of affected children. Br J Opthalmol 1970 Jan;54(1):27-30.
  15. van der Helm F. Hydorphthalmia and its treatment. A general study based on 630 cases in the Netherlands. Bibl Opthalmol 1963;61:1-64.
  16. Nakajima A, Fujiki K, Tanable U. Genetics of Buphthalmos. 7th Congr. Asia Pacific Acad Opthalmology, Karachi; 1979.
  17. Vogt A. Vererbter hydrothalmus beim kaninchen. Klin Augenheilk 1919;63:233.
  18. Franceschetti, A. Die Vererbung von augenleiden kurzes handbuch der opthalmologie, Vol. 1. Berlin: Springer; 1930. p. 631-855.
  19. Geri G. Considerization e ricerche sull eredita dell idroftalmia nel coniglio. Ricerca Sci 1954;24:2299-2315.
  20. Gong G, Kosoko-Lasaki O, Haynatzki GR, Wilson MR. Genetic dissection of myocilin glaucoma. Hum Mol Genet 2004 Apr;13(Spec No 1): 91R-102R.
  21. Vincent AL, Billingsley G, Buys Y, Levin AV, Priston M, Trope G, Williams-Lyn D, Héon E. Digenic inheritance of early-onset glaucoma: CYP1B1, a potential modifier gene. Am J Hum Genet 2002 Feb;70(2):448-460.
  22. Fingert JH, Stone EM, Sheffield VC, Alward WL. Myocilin glaucoma. Surv Ophthalmol 2002 Nov-Dec;47(6):547-561.
  23. Chen H, Howald WN, Juchau MR. Biosynthesis of all-transretinoic acid from all-trans-retinol: catalysis of all-trans-retinol oxidation by human P-450 cytochromes. Drug Metab Dispos 2000 Mar;28(3):315-322.
  24. Swindell EC, Eichele G. Retinoid metabolizing enzymes in development. Biofactors 1999;10(2-3):85-89.
  25. Tanwar M, Dada T, Sihota R, Dada R. Identification of four novel cytochrome P4501B1 mutations (p.I94X, p.H279D, p.Q340H and p.K433K) in primary congenital glaucoma patients. Mol Vis 2009 Dec;15:2926-2937.
  26. Tanwar M, Dada T, Sihota R, Das TK, Yadav U, Dada R. Mutation spectrum of CYP1B1 in North Indian congenital glaucoma patients. Mol Vis 2009 Jun;15:1200-1209.
  27. Stoilov I, Akarsu AN, Sarfarazi M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum Mol Genet 1997 Apr;6(4):641-647.
  28. Akarsu AN, Tarucli ME, Aktan SG, Barsoum-Homsy M, Chevrette L, Sayli BS, Sarfarazi M. A second locus (GLC3B) for primary congenital glaucoma (Buphthalmos) maps to the 1p36 region. Hum Mol Genet 1996 Aug;5(8):1199-1203.
  29. Stoilov IR, Costa VP, Vasconcellos JP, Melo MB, Betinjane AJ, Carani JC, Oltrogge EV, Sarfarazi M. Molecular genetics of primary congenital glaucoma in Brazil. Invest Ophthalmol Vis Sci 2002 Jun;43(6):1820-1827.
  30. Kubota R, Noda S, Wang Y, Minoshima S, Asakawa S, Kudoh J, Mashima Y, Oguchi Y, Shimizu N. A novel myosin-like protein (myocilin) expressed in the connecting cilium of the photoreceptor: molecular cloning, tissue expression and chromosomal mapping. Genomics 1997 May;41(3):360-369.
  31. Karali A, Russell P, Stefani FH, Tamm ER. Localization of myocilin/trabecular meshwork-inducible glucocorticoid response protein in the human eye. Invest Ophthalmol Vis Sci 2000 Mar;41(3):729-740.
  32. Kaur K, Reddy AB, Mukhopadhyay A, Mandal AK, Hasnain SE, Ray K, Thomas R, Balasubramanian D, Chakrabarti S. Myocilin gene implicated in primary congenital glaucoma. Clin Genet 2005 Apr;67(4):335-340.
  33. Tanwar M, Kumar M, Dada T, Sihota R, Dada R. MYOC and FOXC1 gene analysis in primary congenital glaucoma. Mol Vis 2010 Oct;16:1996-2006.
  34. Sarfarazi M, Stoilov I, Schenkman JB. Genetics and biochemistry of primary congenital glaucoma. Ophthalmol Clin North Am 2003 Dec;16(4):543-554.
  35. MacKinnon JR, Giubilato A, Elder JE, Craig JE, Mackey DA. Primary infantile glaucoma in an Australian population. Clin Experiment Ophthalmol 2004 Feb;32(1):14-18.
  36. Ali M, McKibbin M, Booth A, Parry DA, Jain P, Riazuddin SA, Hejtmancik JF, Khan SN, Firasat S, Shires M, et al. Null mutations in LTBP2 cause primary congenital glaucoma. Am J Hum Genet 2009 May;84(5):664-671.
  37. Narooie-Nejad M, Paylakhi SH, Shojaee S, Fazlali Z, Rezaei Kanavi M, Nilforushan N, Yazdani S, Babrzadeh F, Suri F, Ronaghi M, et al. Loss of function mutations in the gene encoding latent transforming growth factor beta binding protein 2, LTBP2, cause primary congenital glaucoma. Hum Mol Genet 2009 Oct;18(20):3969-3977.
  38. Tanwar M, Dada T, Sihota R, Dada R. Mitochondrial DNA analysis in primary congenital glaucoma. Mol Vis 2010 Mar;16:518-533.
  39. Broughton WL, Rosenbaum KN, Beauchamp GR. Congenital glaucoma and other ocular abnormalities associated with pericentric inversion of chromosome 11. Arch Opthalmol 1983 Apr;101(4):594-597.
  40. Stambolian D, Quinn G, Emanuel BS, Zackai E. Congenital glaucoma associated with a chromosomal abnormality. Am J Opthalmol 1988 Nov;106(5):625-627.
  41. Mandal AK, Gothwal VK, Bagga H, Nutheti R, Mansoori T. Outcome of surgery on infants younger than 1 month with congenital glaucoma. Ophthalmology 2003 Oct;110(10): 1909-1915.
  42. Cohn AC, Kearns LS, Savarirayan R, Ryan J, Craig JE, Mackey DA. Chromosomal abnormalities and glaucoma: a case of congenital glaucoma with trisomy 8q22-qter/monosomy 9p23- pter. Ophthalmic Genet 2005 Mar;26(1):45-53.
  43. Hollander DA, Sarfarazi M, Stoilov I, Wood IS, Fredrick DR, Alvarado JA. Genotype and phenotype correlations in congenital glaucoma. Trans Am Ophthalmol Soc 2006;104:183-195.
  44. Panicker SG, Reddy AB, Mandal AK, Ahmed N, Nagarajaram HA, Hasnain SE, Balasubramanian D. Identification of novel mutations causing familial primary congenital glaucoma in Indian pedigrees. Invest Ophthalmol Vis Sci 2002 May;43(5):1358-1366.
  45. Kan YW, Dozy AM, Varmus HE, Taylor JM, Holland JP, Lie- Injo LE, Ganesan J, Todd D. Deletion of alpha-globin genes in haemoglobin-H disease demonstrates multiple alpha-globin structural loci. Nature 1975 May;255(5505):255-256.
  46. Kan YW, Dozy AM. Antenatal diagnosis of sickle-cell anaemia by DNA analysis of amniotic-fluid cells. Lancet 1978 Oct;2(8096): 910-912.
  47. Mullis K, Faloona F, Scharf S, Saiki R, Horn G, Erlich H. Specific enzymatic amplification of DNA in vitro: the polymerase chain reaction. Cold Spring Harb Symp Quant Biol 1986;51 Pt 1:263-273.
  48. Newton CR, Graham A, Heptinstall LE, Powell SJ, Summers C, Kalsheker N, Smith JC, Markham AF. Analysis of any point mutation in DNA. The amplification refractory mutation system (ARMS). Nucleic Acids Res 1989 Apr;17(7):2503-2516.
  49. Orita M, Iwahana H, Kanazawa H, Hayashi K, Sekiya T. Detection of polymorphisms of human DNA by gel electrophoresis as singlestrand conformation polymorphisms. Proc Natl Acad Sci USA 1989 Apr;86(8):2766-2770.
  50. Ravnik-Glavac M, Glavac D, Dean M. Sensitivity of singlestrand conformation polymorphism and heteroduplex method for mutation detection in the cystic fibrosis gene. Hum Mol Genet 1994 May;3(5):801-807.
  51. Vidal-Puig A, Moller DE. Comparative sensitivity of alternative single-strand conformation polymorphism (SSCP) methods. Biotechniques 1994 Sep;17(3):490-496.
  52. Sheffield VC, Beck JS, Kwitek AE, Sandstrom DW, Stone EM. The sensitivity of single-strand conformation polymorphism analysis for the detection of single base substitutions. Genomics 1993 May;16(2):325-332.
  53. Hayashi K, Yandell DW. How sensitive is PCR-SSCP? Hum Mutat 1993;2(5):338-346.
  54. Nagamine CM, Chan K, Lau YF. A PCR artifact: generation of heteroduplexes. Am J Hum Genet 1989 Aug;45(2):337-339.
  55. White MB, Carvalho M, Derse D, O'Brien SJ, Dean M. Detecting single base substitutions as heteroduplex polymorphisms. Genomics 1992 Feb;12(2):301-306.
  56. Boyd M, Lanyon WG, Connor JM. Screening for molecular pathologies in Lesch-Nyhan syndrome. Hum Mutat 1993;2(2): 127-130.
  57. Spritz RA, Holmes SA. Polymerase chain reaction detection of a novel human KIT (mast/stem cell growth factor receptor) gene polymorphism by single-strand conformation polymorphism analysis or by SmaI or BstNI cleavage. Hum Genet 1993 Sep;92(2):208-209.
  58. Ganguly A, Rock MJ, Prockop DJ. Conformation-sensitive gel electrophoresis for rapid detection of single-base differences in double-stranded PCR products and DNA fragments: evidence for solvent-induced bends in DNA heteroduplexes. Proc Natl Acad Sci USA 1993 Nov;90(21):10325-10329.
  59. Körkkö J, Annunen S, Pihlajamaa T, Prockop DJ, Ala-Kokko, L. Conformation sensitive gel electrophoresis for simple and accurate detection of mutations: comparison with denaturing gradient gel electrophoresis and nucleotide sequencing. Proc Natl Acad Sci USA 1998 Feb;95(4):1681-1685.
  60. Roest PA, Roberts RG, Sugino S, van Ommen GJ, den Dunnen JT. Protein truncation test (PTT) for rapid detection of translationterminating mutations. Hum Mol Genet 1993 Oct;2(10):1719-1721.
  61. Powell SM, Petersen GM, Krush AJ, Booker S, Jen J, Giardiello FM, Hamilton SR, Vogelstein B, Kinzler KW. Molecular diagnosis of familial adenomatous polyposis. N Engl J Med 1993 Dec;329(27):1982-1987.
  62. Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Chappuis P, Sappino AP, Limacher IM, Bron L, Benhattar J, et al. A simple p53 functional assay for screening cell lines, blood and tumors. Proc Natl Acad Sci USA 1995 Apr;92(9):3963-3967.
  63. Kruger WD, Cox DR. A yeast assay for functional detection of mutations in the human cystathionine beta-synthase gene. Hum Mol Genet 1995 Jul;4(7):1155-1161.
  64. Bougeard G, Limacher JM, Martin C, Charbonnier F, Killian A, Delattre O, Longy M, Jonveaux P, Fricker JP, Stoppa-Lyonnet D, et al. Detection of 11 germline inactivating TP53 mutations and absence of TP63 and HCHK2 mutations in 17 French families with Li-Fraumeni or Li-Fraumeni-like syndrome. J Med Genet 2001 Apr;38(4):253-257.
  65. Shapiro D. ‘Report on genetic screening and testing’ [Internet]. (Vol. 1). In: ‘Proceedings of the International Bioethics Committee of UNESCO’; 1995. p. 11-26.
  66. Parker LS. Bioethics for human geneticists: models for reasoning and methods for teaching. Am J Hum Genet 1994 Jan;54(1):137-147.
PDF Share
PDF Share

© Jaypee Brothers Medical Publishers (P) LTD.