To describe the ocular and systemic phenotype in IQCB1-related disease.
Four cases (3 males, 1 female) with molecularly confirmed IQCB1-related disease underwent ophthalmological examination including best-corrected visual acuity (BCVA) measurement, fundus evaluation, electroretinography (ERG), and spectral-domain optical coherence tomography (SD-OCT). Systemic evaluation including abdominal ultrasound was performed in all cases.
BCVA ranged from perception of light (Case-2; 1 year) to 20/125 (Case-1; 9 years). Fundus evaluation showed whitish or silvery reflex outside the vascular arcades in all cases; the reflex was circumferential, irregular and covered at-least 6 clock hours at younger ages (3 cases; 1–4 years). The reflex was less conspicuous with increasing age (Case-1 (9 years) and Case-4 (20 years)). The peripheral retinal SD-OCT scans showed evidence of extensive deposition at the level of retinal pigment epithelium with complete absence of overlying photoreceptor outer segments and myoid zone. The ERG was non-detectable in all cases. All cases harbored biallelic nonsense (p.R364*, p. R455*) or frameshifting (p.M370Yfs*49, p.C253Afs*9) mutations in IQCB1. Case-1 additionally had developmental delay, hemi-hyperplasia, toe syndactyly, and kidney cysts.
IQCB1-related syndromic or non-syndromic Leber congenital amaurosis (LCA) carries unique retinal characteristics which helps differentiate IQCB1-retinopathy from other genetic forms of LCA in childhood.
Primary cilia are non-motile sensory organelles that perform critical and diverse cell-specific functions in multiple mammalian cells during development and after birth.1, 2 In the retina, ciliary proteins modulate photoreceptor cilia length, and facilitate transport of membrane and soluble proteins along the cilium.2, 3 Mutations involving ciliary proteins commonly cause complex multi-system disorders broadly referred to as ciliopathies, a group of overlapping disorders that commonly manifest with retinal dystrophy, renal cysts, cardiac defects, digit anomalies, and cerebellar developmental defects.2 Senior-Loken syndrome (SLSN) is a rare, genetically heterogeneous, autosomal recessive ciliopathy that manifests with nephronophthisis (NPHP) and Leber Congenital Amaurosis (LCA).3, 4 Biallelic mutations in IQCB1 (NPHP5) cause SLSN and non-syndromic LCA.5, 6, 7
In this study, we report four cases harboring biallelic mutations in IQCB1 and describe the specific retinal phenotype best seen in childhood in this disorder; associated novel spectral-domain optical coherence tomography (SD-OCT) features are also documented.
A male child of South-Asian descent was born (full-term) with right sided hemi-hypertrophy and bilateral toe syndactyly. His milestones were delayed, and the child developed nystagmus and symptoms of nyctalopia in infancy. At 4 years, best-corrected-distance-visual-acuity (BCVA) was 20/200 in either eye (Refraction: +5.25/+1.25 × 130° and +6.25 in the right and left eyes, respectively). Fundus examination showed a 270° ring of silvery white reflex in the periphery (Figure 1a, d, f, and h). Whitish dots were noted along the posterior edge of the reflex in some areas (Figure 1a, d, and f); lobular retinal pigment epithelial (RPE) changes were seen scattered anteriorly (Figure 1h). The SD-OCT showed relative preservation of the ellipsoid zone (EZ) in the central macula. The peripheral scans showed thick contiguous hyper-reflective deposition at the RPE corresponding to the areas of reflex; the photoreceptor outer structures [outer segments (OS), EZ and myoid zone] were absent in these regions, but the retina appeared thicker compared to adjacent regions (Figure 1b, c, e, and g). Full-field electroretinogram (ERG) showed non-detectable rod and cone responses. Ultrasound examination at 2 years of age showed bilateral renal parenchymal hyper-echogenicity. At 4 years, a cortical cyst was noted in the right kidney. The serum creatinine levels progressively worsened from 5 years of age; persistent hematuria was noted since 6 years of age. The child developed end-stage kidney disease that required renal transplant at 8 years.
At 9 years, the child developed photophobia; BCVA was 20/125 (Refraction: +2.00/+2.25 × 90° (either eye)). Fundus showed features of early retinitis pigmentosa (Figure 1i, m); the whitish reflex was scantily visible. The central sub-foveal thickness was 223 and 225 μm in the right and left eyes, respectively (Figure 1l, q); the peripheral scans failed to detect deposition from previously tested areas (Figure 1j, n, and o). Fundus auto-fluorescence (FAF) testing showed a peri-foveal ring of hyper-AF (Figure 1k, p). A homozygous stop mutation (c.1363C>T/p.R455*) was identified in IQCB1.7 Investigations for Beckwith Wiedemann related hemi-hypertrophy syndromes (methylation abnormalities of 11p15) were negative.
A 1-year-old female child of Chinese descent presented with nystagmus, oculo-digital reflex and history of staring towards bright light. Visual acuity was perception of light (Refraction: +5.00 (either eye)). Retinal examination showed a peripheral band (300°) of whitish deep retinal reflex (Figure 2a, d, f, and h). The SD-OCT showed residual preservation of EZ in the central macula (Figure 2c). The peripheral scans showed thick, contiguous deposition at the RPE corresponding to the whitish reflex, and photoreceptor OS and myoid zone were absent (Figure 2b, e, g, and i). The ERG was non-detectable to all tested stimuli. Detailed renal function tests and kidney ultrasound were normal. A homozygous null mutation (c.1060C>T/p.R364*) was identified in IQCB1.8, 9
A 1-year-old male child of Lebanese descent presented with history of nystagmus, oculo-digital reflex and staring at bright light. Visual acuity was perception of light (Refraction: +10.00; both eyes). Retinal evaluation showed greyish-white deep retinal reflex in the mid-periphery involving superior and temporal quadrants (Figure 2j, l, n, and p). The SD-OCT showed residual preservation of EZ in the central macula (Figure 2k, o). The peripheral scans showed thick, contiguous deposition at the RPE; photoreceptor OS and myoid zone were absent in these regions (Figure 2m, q). The ERG was non-detectable to all stimuli. Renal function tests and ultrasound were normal. A novel homozygous frameshifting insertion (c.1107dupT/p.M370Yfs*49) was identified in IQCB1.
A 20-year-old male of Filipino descent presented with history of infantile onset nystagmus, photophobia and poor vision. The patient had nyctalopia since childhood. BCVA was 20/500 in either eye. Retinal examination showed a para-foveal annular yellowish reflex (2r); mid-peripheral retina showed patchy retinal silvery reflex with patchy lobular architecture (2v). The macular OCT showed disruption of EZ and OS in the sub-foveal region (2s). Some macular line scans showed localized evidence of RPE deposition (Figure 2s); peripheral scans showed absence of photoreceptor OS and myoid zone, and there was no evidence of RPE deposition (Figure 2t, u). FAF showed foveal hyper-autofluorescence surrounded by a ring of hypo-autofluorescence (Figure 2w). The ERG was non-detectable to all stimuli. Renal function tests and abdominal ultrasound were normal. Compound heterozygous mutations (c.1060C>T/p.R364*; c.757delT/p.C253Afs*9) were identified in IQCB1; the frame shifting variant is novel.
This report highlights the fundus and peripheral SD-OCT features in IQCB1-related retinopathy. The whitish/silvery deep retinal reflex was observed in all cases; however, it was more conspicuous in the peripheral retina of young affected individuals. A previously described lobular aspect to the retinal changes was observed in patches in two of our cases (Case-1 at 4 years; Case-4 at 20 years).6 The peripheral OCT findings are novel and suggest the origins of the fundus reflex to be consequent upon the extensive deposition at the level of the RPE. There is absence of photoreceptor OS and myoid zone overlying the deposition, and in the peripheral retina. The central macula showed preservation of EZ in younger affected individuals as reported previously.10, 11
Mice knock out models of Nphp5−/− demonstrated absence of development of rod OS and axoneme with ensuing nuclear degeneration.12 A spontaneously occurring dog model of Nphp5 showed 90% of cones to have abnormal OS development, but there was some preservation of OS in the cone-rich visual streak.10 Hence, the widespread absence of OS in the peripheral retina along with residual preservation of foveal cones in humans shows some similarity to both mice and dog models, respectively.10, 12 The peripheral retinal deposition may represent abnormally developed photoreceptor OS; however, no deposition was observed in animal models.10, 12 Secondary changes likely explain the paucity of retinal deposition in older patients (Case-1 at 9 years and Case-4 at 20 years).
Hyperopic refractive error and the classical triad of LCA (nystagmus, poor vision and non-detectable ERG) seen in this series were common amongst previously reported IQCB1 cases.6, 7 The p.R455* variant manifesting as SLSN in the present study, has previously been associated with non-syndromic LCA (6 years).7 The p.R364* variant manifesting as non-syndromic LCA in this study (1 year and 20 years, respectively), has been previously associated with LCA (28 years) and SLSN (16 years and 12 years).8, 9 Hence, there are likely genetic or environmental modifiers that influence IQCB1-phenotype. Syndactyly and developmental delay commonly seen in Bardet–Biedl syndrome was observed in one of our cases, and is consistent with the phenotypic overlap described in ciliopathies.13, 14 Hemi-hypertrophy seen in one case in the present study has not been associated with ciliopathy; whether this is specific to IQCB1 needs further evidence.
Multimodal phenotyping of retinal dystrophies, even at a young age, guide genetic diagnosis and shed light on underlying pathology. This report identifies a whitish peripheral retinal reflex due to deep retinal deposition as a phenotypic marker for IQCB1-retinopathy.
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The authors declare no conflict of interest.
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Vincent, A., AlAli, A., MacDonald, H. et al. Specific retinal phenotype in early IQCB1-related disease. Eye 32, 646–651 (2018). https://doi.org/10.1038/eye.2017.283