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Mutation spectrum of NDP, FZD4 and TSPAN12 genes in Indian patients with retinopathy of prematurity
  1. Sonika Rathi1,
  2. Subhadra Jalali2,
  3. Ganeswara Rao Musada1,
  4. Satish Patnaik1,
  5. Divya Balakrishnan2,
  6. Anjli Hussain2,
  7. Inderjeet Kaur1
  1. 1 Kallam Anji Reddy Molecular Genetics Laboratory, Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad, India
  2. 2 Smt Kanuri Santhamma Centre for Vitreo Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India
  1. Correspondence to Dr Inderjeet Kaur, Kallam Anji Reddy Molecular Genetics Laboratory, Prof Brien Holden Eye Research Centre, L V Prasad Eye Institute, Hyderabad 500034, India; inderjeet{at}


Aim Retinopathy of prematurity (ROP) is a vasoproliferative eye disease in preterm infants. Based on its phenotypic similarities with familial exudative vitreo retinopathy (FEVR), the present study was conducted to screen the Norrin signalling pathway genes (already been implicated in FEVR) for understanding their involvement among Indian patients with ROP.

Methods The study cohort consisted of patients with ROP (n=246) and controls (n=300) that included full term (n=110) and preterm babies devoid of ROP (n=190). Screening of the NDP, FZD4, TSPAN12 genes were accomplished by resequencing the entire coding and untranslated regions (UTR). The genotype data of the patients with ROP were analysed in the background of their clinical manifestations and further analysed in conjunction with other available data on these genes worldwide.

Results Two novel variants in intron 1 (IVS1 +16A>G) and 3′UTR (c.5 22T>C) along with a previously reported change in the 5′UTR (c.395_409del14bp) were observed in the NDP gene in three patients with ROP. Screening of the FZD4 revealed four heterozygous variants, p.(Pro33Ser), p.(Pro168Ser), p.(Ile192Ile) and p.(Ile360Val), a compound heterozygous (p.(Pro33Ser)/p.(Pro168Ser)) and a 3′UTR (c*G>T) variants in the study cohort. Variants p.(Pro33Ser) and p.(Pro168Ser) were found to be significantly associated with ROP. A heterozygous variant p.(Leu119Arg) in TSPAN12 gene was observed in a patient with threshold ROP. However, a formal genotype–phenotype correlation could not be established due to the low frequencies of the variant alleles in these genes.

Conclusions This is a first study that revealed association of few variants in Norrin signalling genes among Indian patients with ROP that warrants further detailed investigation worldwide.

  • ROP
  • Premature births
  • DNA
  • genetics

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  • Contributors Inderjeet Kaur and Subhadra Jalali conceived the idea and wrote the protocol; Inderjeet Kaur served as principal investigator; Subhadra Jalali, Divya Balakrishnan and Anjli Hussain were coinvestigators, performed clinical examinations and graded the fundus images and surgeries for the preterm; Sonika Rathi, Satish Patnaik and Ganeswara Rao Musada collected blood samples and family history of the probands; Sonika Rathi performed most of the molecular biology-based analysis of blood; Satish Patnaik and Ganeswara Rao Musada performed a part of molecular screening; Sonika Rathi and Inderjeet Kaur analysed the data and wrote the manuscript; and all authors revised the paper and approved the submitted version.

  • Funding This work was supported in parts by a grant from the Program Support grant by Department of Biotechnology (BT/01/COE/06/02/10 and BT/PR3992/MED/97/31/2011) and Champaulimaud Foundation grant Portugal to Inderjeet Kaur and Indian Council of Medical Research fellowship to Sonika Rathi.

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval The study protocol was approved by the Institutional Review Board (LEC029149029) of the L.V. Prasad Eye Institute (LVPEI).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement Study data is available for research use from the corresponding author and principal investigator of the study upon request.

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