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

Abstract

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.

Figure 1

Pedigrees of families included in this study.

Figure 2

Retinal imaging data for patients with IDH3A variants. (Wide-field) color fundus photographs, optical coherence tomography OCT and fundus autofluorescence (FAF) imaging with fundus-camera-based autofluorescence photography or confocal scanning laser ophthalmoscopy (cSLO). Patient A-II:1 at age 7 y, (A) pink optic discs, mildly attenuated blood vessels, RPE alterations in the fovea and periphery, (B) small central disruptions in the ellipsoid zone, (C) intact autofluorescence of the posterior pole. Patient A-II:2 at age 3 y, (D) distinct atrophy of the RPE and choriocapillaris in the macular region demarcated by a hyperpigmented ring, peripheral RPE alterations, (E) atrophy of the RPE, abnormal outer retinal layers. Patient B-II:1 at age 18 y, (F) mid-peripheral atrophy with bone spicule-like pigmentation nasal>temporal, OS>OD, (G) bilateral severe cystoid macular edema (RE>LE) with thickening of the retina and loss of normal foveal structure, thinning and loss of the photoreceptor nuclei layer (ONL) is evident in the para-macular regions of the scans, (H) hyper-autofluorescent ring around the fovea. Patient B-II:2 at age 15 y, (I) mid-peripheral atrophy with bone spicule-like pigmentation nasal>temporal, OS>OD, (J) presence of the photoreceptor nuclei layer in the fovea without edema, but marked thinning and loss of the ONL is evident in para-macular regions, (K) prominent hyper-autofluorescent ring surrounding the center of the macula. Patient C-II:1 at age 20 y, (L) pale aspect of the optic disc, attenuated blood vessels, RPE alterations from mid-periphery towards the far periphery, (M) extensive peripheral atrophy of the outer segments and distortion of the foveal architecture. Patient D-II:2 at age 26 y, (N) peripheral bone-spicule pigmentary changes, peripheral and mid-peripheral pigmentary retinopathy, macular pigmentation with severe pseudocoloboma-like atrophy, mild arteriolar narrowing and mild optic atrophy, (O) macular atrophy with lamellar disorganization, (P) strongly reduced autofluorescence within the macula, diffusely increasing in a broad ring around the macula, and fading towards the periphery.

Figure 3

Multiple sequence alignment of IDH3A orthologs around missense variant sites (highlighted in light blue) generated by NCBI HomoloGene. Amino acids highlighted in grey are not identical to the corresponding amino acid in the human ortholog.

Figure 4

3D structure of the IDH3 complex and the location of the missense variants. The IDH3 protein complex contains two alpha subunits (pink, yellow), one beta subunit (purple) and one gamma subunit (blue). Missense variants are indicated in red in only one of the two alpha subunits for clarity. In patients with compound heterozygous variants, the NAD-IDH complex may consist of two identical alpha subunits altered by the same variant or two different alpha subunits.