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 Table of Contents  
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 302-304

Prenatal diagnosis for isolated aniridia: A case report and simplified diagnostic approach for ophthalmologists

1 Suchak Hospital, Thane, Maharashtra, India
2 MIRA Hospital and IVF Centre, Bhayendar, Thane, Maharashtra, India
3 Jyotirmay Eye Clinic, Thane, Maharashtra, India

Date of Submission09-Jul-2020
Date of Acceptance10-Dec-2020
Date of Web Publication01-Apr-2021

Correspondence Address:
Dr. Shruti Bajaj
403- Mickey's Paradize, Opposite Orlem Garden, Tank Road, Orlem, Malad (West), Mumbai - 400 064, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijo.IJO_2208_20

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Approximately 60%–90% of the isolated aniridia (IA) in India is reported to be sporadic (simplex) in nature, with much lesser contribution by autosomal dominant inheritance. The Indian genomic profile for IA indicates the commonest mutations to be single nucleotide variations in PAX6, whereas copy number variants, especially deletions, are rare. Deletions involving PAX6 along with another gene are even rarer. Our paper highlights an unreported Indian scenario of prenatal genetic counseling for sporadic IA due to PAX6 and ELP4 exon deletions and expands the mutation spectrum associated with IA in India.

Keywords: Congenital aniridia, next-generation sequencing, PAX6 protein, prenatal genetic counseling

How to cite this article:
Bajaj S, Koradia DR, Kothari M. Prenatal diagnosis for isolated aniridia: A case report and simplified diagnostic approach for ophthalmologists. Indian J Ophthalmol Case Rep 2021;1:302-4

How to cite this URL:
Bajaj S, Koradia DR, Kothari M. Prenatal diagnosis for isolated aniridia: A case report and simplified diagnostic approach for ophthalmologists. Indian J Ophthalmol Case Rep [serial online] 2021 [cited 2021 Aug 3];1:302-4. Available from: https://www.ijoreports.in/text.asp?2021/1/2/302/312362

Aniridia is a congenital panocular disorder presenting in isolation or as a syndrome, inherited either as an autosomal-dominant trait or occurring sporadically.[1] If the specific mutation in the proband is known, preimplantation-genetic-diagnosis (PGD) or prenatal diagnosis (PND) can be offered.[1]

  Case Report Top

A nonconsanguineous couple presented in the ninth week of pregnancy desiring prenatal genetic counseling. Their 6-year-old daughter had isolated aniridia (IA) (bilateral complete aniridia, nystagmus, and nonprogressive cataracts), without evidence of glaucoma or keratopathy. She had mild scholastic difficulties too. The parents' ophthalmic evaluation was normal. The couple had reservations about bearing another affected child. Despite outlining a <1% risk of recurrence for sporadic IA,[1],[2] normal lifespan and relative lack of morbidity even if born affected; the couple was determined to prevent a recurrence of IA.

Proband's old records revealed normal karyotype and negative multiplex-ligation-probe-dependent-amplification for PAX6-WT1-deletion. Next-generation sequencing (NGS)-based clinical-exome sequencing (CES) was ordered in the proband. It revealed large heterozygous- pathogenic deletions in PAX6 (exons 12-14) and ELP4 (exons 8-12); confirmed by quantitative-PCR (qPCR) (Supplemental Files 1 and 2)[Additional file 1][Additional file 2]. Testing the parents for the above family-specific mutation and germline mosaicism was declined stating financial restraints. Although the parents were clinically normal and the pedigree was unremarkable [Figure 1], the proband's IA was most-probably sporadic. The couple conveyed their decision to discontinue the pregnancy if the subsequent prenatal test results returned unfavorably. Amniocentesis and fetal-DNA testing by qPCR for the above specific deletions returned negative, indicating an unaffected fetus. The couple delivered a healthy girl at term.
Figure 1: Pedigree chart of the proband. Note the index case was the only affected case in the family

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The genomic diagnosis had collateral benefits for the proband. Her six-monthly renal sonograms were discontinued since the deletions spared WT1-region. PAX6-ELP4 involvement prompted brainstem-evoked-response audiometry (BERA) to rule out auditory-processing-defects, which returned normal. Importance of early detection for any underlying auditory deficits, especially in the setting of preexisting visual impairment and learning difficulties, was highlighted. The need for annual hearing and ophthalmic assessment was reiterated.

  Discussion Top

Mutation in PAX6, a crucial gene for ocular morphogenesis, is responsible for 90% of the cases of congenital aniridia.[1] Other candidate genes include PITX2, PITX3, FOXC1, ELP4; some yet unidentified.[1] Indian studies have shown sporadic IA to be commoner (60-90%) than the inherited type.[3],[4] The commonest IA mutations in India involve single nucleotide variants (SNV) of PAX6 followed by copy number variants (CNV) in PAX6; deletions being rarer than duplications.[3],[4] Deletion of PAX6 and ELP4 in the same patient, as described here, is the first to be reported in an Indian patient.

ELP4 has crucial regulatory action on PAX6.[1] Disruption of ELP4 alone can induce classical aniridia, even in absence of PAX6-mutation.[1] The traditional use of specific genetic tests targeting only PAX6 (deletion studies, Sanger-sequencing) could be responsible for under-reporting of ELP4 in IA. Use of chromosomal-microarray (CMA), NGS-based testing options, and targeted tools to detect ELP4-deletions could increase our knowledge about ELP4 involvement in IA.[1] Incomplete genomic diagnosis can especially have an impact on prenatal counseling.

With an expansive understanding of genetics, ophthalmologists would be increasingly expected to incorporate these principles in practice.[5],[6] The newer genetic tests; CMA, Sanger-sequencing, and NGS-based options (CES, whole-exome-sequencing, panels, whole-genome-sequencing) cost in the range of 10,000.00₹–1,50,000.00₹. The onus of choosing the most appropriate test rests on the ordering physician. Ordering the correct test has an impact in terms of the expenses incurred by patient as well as time taken to reach the correct diagnosis. Lack of information about these newer genetic tests,[7] prohibitive costs and accessibility could be some of the factors resulting in an underutilization of genomics in Indian ophthalmology, with the exception of premier teaching institutes. We suggest a simplified approach toward genetic diagnosis of IA [Figure 2].[1],[5]
Figure 2: Flowchart for the genetic approach to a case with aniridia

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Precise molecular diagnosis in cases of congenital aniridia has many benefits: a) Diagnosis confirmation b) Curates ongoing surveillance c) Enables testing other at-risk individuals, offering timely surveillance for visual and systemic complications d) Opens avenues to prenatal and preconception reproductive counseling e) With the usher of gene-therapy, genome-editing, CRISPR-CAS9; precise genomic diagnosis can be potentially helpful, most of the futuristic therapies being genotype-specific.[5] For example, ataluren, a drug under-trial phase, is known to improve vision in aniridia, specifically for the types with nonsense-mutations in PAX6.[1]

In our case, the parents' outlook toward the recurrence of aniridia and the value of PND can be considered with differing medical perspectives. Given the relative lack of morbidity and normal lifespan; pregnancy-termination in IA is not the obvious medical advice.[1] The purpose of seeking PND could sometimes be to prepare oneself, mentally and financially, for a child needing special care.[8] Amanda et al. highlight such a family of father-son duo affected with IA. Even though PND detected the next pregnancy to be affected with IA, the couple gave birth to the baby.[8] PGD, a technique which aids the prospective parents to select the healthy embryo pre-implantation, is an option for those who wish to have an unaffected child, and yet avoid invasive tests and the 'emotional labour' of terminating an affected pregnancy.[9] Literature documents two families who availed of PGD for IA. However, the challenges of in-vitro-fertilization and costs involved in PGD may be unacceptable to some families. Sometimes, severity of the proband's illness, unpredictability of the phenotype of the affected fetus,[1] inaccessibility of visual-rehabilitation services, out-of-pocket expenses,[10] challenged socio-educational background, and perception of parents' own quality of life due to visual-impairment in their child,[11] may make them consider discontinuing a pregnancy with unfavorable PND results.[9] It is thus recommended to follow nondirective genetic counseling that allows couples to take their own informed decision in such grey-zones.[1],[7]

  Conclusion Top

We intend to highlight the benefits of timely and appropriate prenatal genetic counseling while underlining its 'nondirective' nature, and report the first Indian IA with PAX6 and ELP4 deletion.


We would like to thank the parents of the child for their approval and kind support toward publishing this case.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Moosajee M, Hingorani M, Moore AT. PAX6-Related Aniridia. 2003 May 20 [Updated 2018 Oct 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1360/ [Last accessed on 2020 Jul 01].  Back to cited text no. 1
Campbell IM, Stewart JR, James RA, Lupski JR, Stankiewicz P, Olofsson P, et al. Parent of origin, mosaicism, and recurrence risk: Probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet 2014;95:345-59.  Back to cited text no. 2
Singh B, Mohamed A, Chaurasia S, Ramappa M, Mandal AK, Jalali S, et al. Clinical manifestations of congenital aniridia. J Pediatr Ophthalmol Strabismus 2014;51:59-62.  Back to cited text no. 3
Dubey SK, Mahalaxmi N, Vijayalakshmi P, Sundaresan P. Mutational analysis and genotype-phenotype correlations in southern Indian patients with sporadic and familial aniridia. Mol Vis 2015;21:88-97.  Back to cited text no. 4
Verma IC, Paliwal P, Singh K. Genetic testing in pediatric ophthalmology. Indian J Pediatr 2018;85:228-36.  Back to cited text no. 5
Stone EM, Aldave AV, Drack AV, Maccumber MW, Sheffield VC, Traboulsi E, et al. Recommendations for genetic testing of inherited eye diseases: A report of the American Academy of Ophthalmology task force on genetic testing. Ophthalmology 2012;119:2408-10.  Back to cited text no. 6
Drack AV, Miraldi Utz V, Wang K, Alcorn DM, Brooks BP, Costakos DM, et al. Survey of practice patterns for the management of ophthalmic genetic disorders among AAPOS members: Report by the AAPOS genetic eye disease task force. J AAPOS 2019;23:226-8.e1.  Back to cited text no. 7
Churchill AJ, Hanson IM, Markham AF. Prenatal diagnosis of aniridia. Ophthalmology 2000;107:1153-6.  Back to cited text no. 8
Yahalom C, Macarov M, Lazer-Derbeko G, Altarescu G, Imbar T, Hyman JH, et al. Preimplantation genetic diagnosis as a strategy to prevent having a child born with an heritable eye disease. Ophthalmic Genet 2018;39:450-6.  Back to cited text no. 9
Muranjan M, Vijayalakshmi P. The unforeseen toll of birth defects and their economic burden at a tertiary care public institute in Mumbai. Indian J Pediatr 2014;81:1005-9.  Back to cited text no. 10
Lupon M, Armayones M, Cardona G. Quality of life among parents of children with visual impairment: A literature review. Res Dev Disabil 2018;83:120-31.  Back to cited text no. 11


  [Figure 1], [Figure 2]


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