Clinical and genetic analysis of Indian patients with NDP-related retinopathies



NDP-related retinopathies are a group of X-linked disorders characterized by degenerative and proliferative changes of the neuroretina, occasionally accompanied with varying degrees of mental retardation and sensorineural hearing loss. NDP is the predominant gene associated with NDP-related retinopathies. The purpose of this study was to report the clinical and genetic findings in three unrelated patients diagnosed with NDP-related retinopathies.


The patients underwent complete ophthalmic examination followed by genetic analyses. NDP gene was screened by direct sequencing approach. Targeted resequencing of several other ocular genes was carried out in patient samples that either indicated NDP gene deletion or tested negative for NDP mutation. Gene quantitation analysis was performed using real-time PCR.


The whole NDP gene was deleted in patient I, while a missense NDP mutation, c.205T>C, was identified in patient II, and both had classical Norrie disease ocular phenotype (with no other systemic defects). Patient III who was diagnosed with familial exudative vitreoretinopathy did not show any mutation in the known candidate genes as well as in other ocular genes tested.


The patient with whole NDP gene deletion did not exhibit any apparent extraocular defects (like mental retardation or sensorineural hearing loss) during his first decade of life, and this is considered to be a notable finding. Our study also provides evidence emphasizing the need for genetic testing which could eliminate ambiguities in clinical diagnosis and detect carrier status, thereby aiding the patient and family members during genetic counseling.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4


  1. 1.

    Sims KB (1999) NDP-Related Retinopathies. In: Pagon RA, Adam MP, Ardinger HH et al (eds) GeneReviews®. University of Washington, Seattle, pp 1993–2016 Updated 2014

    Google Scholar 

  2. 2.

    Warburg M (1961) Norrie’s disease: a new hereditary bilateral pseudotumor of the retina. Acta Ophthalmol 39:757–772

    Article  Google Scholar 

  3. 3.

    Warburg M (1996) Norrie’s disease. A congenital progressive oculoacoustico-cerebral degeneration. Acta Ophthalmol (Copenh) Suppl 89:1–47

    Google Scholar 

  4. 4.

    Parving A, Warburg M (1977) Audiological findings in Norrie’s disease. Audiology 16:124–131

    Article  PubMed  CAS  Google Scholar 

  5. 5.

    Criswick VG, Schepens CL (1968) Familial exudative vitreoretinopathy. Am J Ophthalmol 68:578–594

    Article  Google Scholar 

  6. 6.

    Black GC, Perveen R, Bonshek R et al (1999) Coat’s disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Hum Mol Genet 8:2031–2035

    Article  PubMed  CAS  Google Scholar 

  7. 7.

    Gibson DL, Sheps SB, Uh SH et al (1990) Retinopathy of prematurity-induced blindness: birth weight specific survival and the new epidemic. Pediatrics 86:405–412

    PubMed  CAS  Google Scholar 

  8. 8.

    Shastry BS (2009) Persistent hyperplastic primary vitreous: congenital malformation of the eye. Clin Exp Ophthalmol 37:884–890

    Article  PubMed  Google Scholar 

  9. 9.

    Chen ZY, Battinelli EM, Fielder A et al (1993) A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet 5:180–183

    Article  PubMed  CAS  Google Scholar 

  10. 10.

    Shastry BS, Pendergast SD, Hartzer MK et al (1997) Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol 115:651–655

    Article  PubMed  CAS  Google Scholar 

  11. 11.

    Aponte EP, Pulido JS, Ellison JW et al (2009) A novel NDP mutation in an infant with unilateral persistent fetal vasculature and retinal vasculopathy. Ophthalmic Genet 30(2):99–102

    Article  PubMed  CAS  Google Scholar 

  12. 12.

    Berger W, Meindl A, van de Pol TJR et al (1992) Isolation of a candidate gene for Norrie disease by positional cloning. Nature Genet 1:199–203

    Article  PubMed  CAS  Google Scholar 

  13. 13.

    Smith SE, Mullen TE, Graham D et al (2012) Norrie disease: extraocular clinical manifestations in 56 patients. Am J Med Genet A 158A:1909–1917

    Article  PubMed  Google Scholar 

  14. 14.

    Meindl A, Berger W, Meitinger T et al (1992) Norrie disease is caused by mutations in an extracellular protein resembling C-terminal globular domain of mucins. Nat Genet 2:139–143

    Article  PubMed  CAS  Google Scholar 

  15. 15.

    Ye X, Wang Y, Cahill H et al (2009) Norrin, frizzled-4, and Lrp5 signaling in endothelial cells controls a genetic program for retinal vascularization. Cell 139:285–298

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  16. 16.

    Hutcheson KA, Paluru PC, Bernstein SL et al (2005) Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis 11:501–508

    PubMed  CAS  Google Scholar 

  17. 17.

    Dong B, Chen J, Zhang X et al (2013) Two novel PRPF31 premessenger ribonucleic acid processing factor 31 homolog mutations including a complex insertion-deletion identified in Chinese families with retinitis pigmentosa. Mol Vis 19:2426–2435

    PubMed  PubMed Central  CAS  Google Scholar 

  18. 18.

    D’haene B, Vandesompele J, Hellemans J (2010) Accurate and objective copy number profiling using real-time quantitative PCR. Methods 50(4):262–270

    Article  PubMed  CAS  Google Scholar 

  19. 19.

    Sudha D, Patric IRP, Ganapathy A et al (2016) Genetic studies in an X-linked retinoschisis patient coexisting with developmental delay and sensorineural hearing loss. Opthalmic Genet. doi:10.1080/13816810.2016.1214972

    Article  Google Scholar 

  20. 20.

    Rodriguez-Revenga L, Madrigal I, Alkhalidi LS et al (2007) Contiguous deletion of the NDP, MAOA, MAOB, and EFHC2 genes in a patient with Norrie disease, severe psychomotor retardation and myoclonic epilepsy. Am J Med Genet A 143A(9):916–920

    Article  PubMed  CAS  Google Scholar 

  21. 21.

    Schuback DE, Chen ZY, Craig IW et al (1995) Mutations in the Norrie Disease Gene. Hum Mutat 5:285–292

    Article  PubMed  CAS  Google Scholar 

  22. 22.

    Okumura A, Arai E, Kitamura Y et al (2015) Epilepsy phenotypes in siblings with Norrie disease. Brain Dev 37(10):978–982

    Article  PubMed  Google Scholar 

  23. 23.

    Staropoli JF, Xin W, Sims KB (2010) Co-segregation of Norrie disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region at Xp11.3-p11.4. J Med Genet 47(11):786–790

    Article  PubMed  CAS  Google Scholar 

  24. 24.

    Whibley A, Urquhart J, Dore J et al (2010) Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements. Eur J Hum Genet 18:1095–1099

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gu W, Sander T, Heils A et al (2005) A new EF-hand containing gene EFHC2 on Xp11.4: tentative evidence for association with juvenile myoclonic epilepsy. Epilepsy Res 66(1–3):91–98

    Article  PubMed  CAS  Google Scholar 

  26. 26.

    Dreyer B, Brox V, Tranebjaerg L et al (2008) Spectrum of USH2A mutations in Scandinavian patients with Usher syndrome type II. Hum Mutat 29(3):451

    Article  PubMed  Google Scholar 

  27. 27.

    Oshima A, Jaijo T, Aller E et al (2008) Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I. Hum Mutat 29(6):E37–E46

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. 28.

    Marshall JD, Hinman EG, Collin GB et al (2007) Spectrum of ALMS1 variants and evaluation of genotype-phenotype correlations in Alström syndrome. Hum Mutat 28(11):1114–1123

    Article  PubMed  CAS  Google Scholar 

  29. 29.

    Gilmour DF (2015) Familial exudative vitreoretinopathy and related retinopathies. Eye 29:1–14

    Article  PubMed  CAS  Google Scholar 

Download references


The authors thank the patients and family members for their cooperation and participation in the study. The authors would like to acknowledge Vision Research Foundation (Ref No. 202-2009-P) and the Department of Biotechnology, Government of India (RGYI scheme; BT/PR15111/GBD/27/322/2011) for funding the study and Mr. Manoj Prabhakar for his contribution toward PCR standardization.


This study was funded by Vision Research Foundation (Ref No. 202-2009-P) and the Department of Biotechnology, Government of India (RGYI scheme; BT/PR15111/GBD/27/322/2011).

Author information



Corresponding author

Correspondence to Jayamuruga Pandian Arunachalam.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Vision Research Foundation (Ref No. 202-2009-P)) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.”

Informed consent

Informed consent was obtained from all the patients/family members who participated in the study.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 18 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Sudha, D., Ganapathy, A., Mohan, P. et al. Clinical and genetic analysis of Indian patients with NDP-related retinopathies. Int Ophthalmol 38, 1251–1260 (2018).

Download citation


  • NDP-related retinopathies
  • Norrie disease
  • FEVR
  • NDP gene
  • Mutation