Elsevier

Ophthalmology

Volume 124, Issue 7, July 2017, Pages 992-1003
Ophthalmology

Original article
Whole-Exome Sequencing Identifies Biallelic IDH3A Variants as a Cause of Retinitis Pigmentosa Accompanied by Pseudocoloboma

https://doi.org/10.1016/j.ophtha.2017.03.010Get rights and content

Purpose

To identify the genetic cause of and describe the phenotype in 4 families with autosomal recessive retinitis pigmentosa (arRP) that can be associated with pseudocoloboma.

Design

Case series.

Participants

Seven patients from 4 unrelated families with arRP, among whom 3 patients had bilateral early-onset macular pseudocoloboma.

Methods

We performed homozygosity mapping and whole-exome sequencing in 5 probands and 2 unaffected family members from 4 unrelated families. Subsequently, Sanger sequencing and segregation analysis were performed in additional family members. We reviewed the medical history of individuals carrying IDH3A variants and performed additional ophthalmic examinations, including full-field electroretinography, fundus photography, fundus autofluorescence imaging, and optical coherence tomography.

Main Outcome Measures

IDH3A variants, age at diagnosis, visual acuity, fundus appearance, visual field, and full-field electroretinography, fundus autofluorescence, and optical coherence tomography findings.

Results

We identified 7 different variants in IDH3A in 4 unrelated families, that is, 5 missense, 1 nonsense, and 1 frameshift variant. All participants showed symptoms early in life, ranging from night blindness to decreased visual acuity, and were diagnosed between the ages of 1 and 11 years. Four participants with biallelic IDH3A variants displayed a typical arRP phenotype and 3 participants were diagnosed with arRP and pseudocoloboma of the macula.

Conclusions

IDH3A variants were identified as a novel cause of typical arRP in some individuals associated with macular pseudocoloboma. We observed both phenotypes in 2 siblings carrying the same compound heterozygous variants, which could be explained by variable disease expression and warrants caution when making assertions about genotype–phenotype correlations.

Section snippets

Participants and Clinical Evaluation

The study protocol adhered to the tenets of the Declaration of Helsinki and received approval from the respective local ethics committees. Written informed consent was obtained from all participants or parents of children before their inclusion in this study. Patients were ascertained in the Rotterdam Eye Hospital (Rotterdam, The Netherlands), Hadassah-Hebrew University Medical Center (Jerusalem, Israel), or Leiden University Medical Center (Leiden, The Netherlands), or were recruited from the

Clinical Findings

We ascertained 7 patients from 4 families between the ages of 3 and 26 years. Their clinical characteristics are summarized in Table 1, and the family pedigrees are shown in Figure 1. All patients had early-onset night blindness and were diagnosed between 1 and 11 years of age. Visual acuity (VA) was available for all patients and ranged from 20/20 to counting fingers at 1 m.

The youngest patient (patient A-II:2) of a Dutch family was diagnosed with a macular pseudocoloboma at the age of 1 year

Discussion

In this study, we identified novel variants in IDH3A in 4 patients with typical arRP and 3 patients with arRP and macular pseudocoloboma from 4 unrelated families. These families originated from The Netherlands, Israel, and South Africa. All patients showed visual symptoms early in life, ranging from night blindness to severe visual impairment. In patients with RP and macular pseudocoloboma (patients A-II:2, D-II:2, and D-II:3), the visual impairment was more severe than in patients with

Acknowledgments

The authors thank the patients and their family members for their participation.

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    Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

    Supported by the Foundation Combined Ophthalmic Research Rotterdam (CORR), Rotterdam, The Netherlands (to L.H.M.P); the Directorate General for Higher Education (DIKTI) of the Ministry for National Education of Indonesia and the Radboud University Medical Center, Nijmegen, The Netherlands (to G.D.N.A.); Retina South Africa, South Africa; the South African Medical Research Council, Cape Town, South Africa; the National Research Foundation of South Africa, Pretoria, South Africa; the United States–Israel Binational Science Foundation, Jerusalem, Israel (grant no.: 2011202 [to D.S., A.S.]); Foundation Fighting Blindness, Columbia, Maryland (grant no.: BR-GE-0214-0639 [to D.S., E.M.H.F.B.]); a Yedidut Research Grant, Mexico City, Mexico, [to E.M.F.H.B.]; and the Intramural Research Program of the National Eye Institute, National Institutes of Health, Bethesda, Maryland (grant no.: EY000546).

    Author Contributions:

    Conception and design: Ramesar, Swaroop, Sharon, Cremers

    Analysis and interpretation: Pierrache, Kimchi, Ratnapriya, Roberts, Astuti, Beryozkin, Bongers, Ramesar, Swaroop, van den Born, Sharon, Cremers

    Data collection: Pierrache, Kimchi, Ratnapriya, Roberts, Astuti, Obolensky, Tjon-Fo-Sang, Schuil, Beryozkin, Klaver, Bongers, Haer-Wigman, Schalij, Breuning, Fischer, Banin, van den Born

    Obtained funding: none

    Overall responsibility: Pierrache, Kimchi, Ratnapriya, Roberts, Astuti, Obolensky, Tjon-Fo-Sang, Schuil, Beryozkin, Klaver, Bongers, Haer-Wigman, Schalij, Breuning, Fischer, Banin, Ramesar, Swaroop, van den Born, Sharon, Cremers

    Laurence H.M. Pierrache, MD, MSc, Adva Kimchi, MSc, Rinki Ratnapriya, PhD, and Lisa Roberts, MSc contributed equally as first authors.

    Eyal Banin, MD, PhD, Raj S. Ramesar, PhD, MSc, Anand Swaroop, PhD, L. Ingeborgh van den Born, MD, PhD, Dror Sharon, PhD, and Frans P.M. Cremers, PhD share senior authorship.

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