December 2023
Volume 64, Issue 15
Open Access
Retina  |   December 2023
Double Hyperautofluorescence Rings as a Sign of CFAP410-related Retinopathy
Author Affiliations & Notes
  • Xueqing Li
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
  • Yingwei Wang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
  • Junwen Wang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
  • Panfeng Wang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
  • Qingjiong Zhang
    State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China
  • Correspondence: Qingjiong Zhang, FARVO, Pediatric and Genetic Eye Clinic, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 7 Jinsui Road, Guangzhou 510623, China; [email protected] or [email protected]
  • Footnotes
     XL and YW contributed equally to this work.
Investigative Ophthalmology & Visual Science December 2023, Vol.64, 44. doi:https://doi.org/10.1167/iovs.64.15.44
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      Xueqing Li, Yingwei Wang, Junwen Wang, Panfeng Wang, Qingjiong Zhang; Double Hyperautofluorescence Rings as a Sign of CFAP410-related Retinopathy. Invest. Ophthalmol. Vis. Sci. 2023;64(15):44. https://doi.org/10.1167/iovs.64.15.44.

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Abstract

Purpose: Variants in CFAP410 have been reported to cause retinal dystrophy with or without systemic symptoms. This study was designed to characterize the fundus changes of patients with biallelic variants in CFAP410.

Methods: Variants in CFAP410 were identified through whole exome sequencing and targeted exome sequencing of 10,530 probands. Biallelic variants in CFAP410 were evaluated by comprehensive in silico analysis and confirmed by Sanger sequencing and segregation analysis. Ocular phenotypes including fundus photographs, scanning laser ophthalmoscopy, autofluorescence images, ERG, and optical coherence tomography were characterized.

Results: Nine patients from eight families were homozygotes or compound heterozygotes for a total of four variants in CFAP410, including c.144-6_159del (novel), c.340_351dup, c.347C>T, and c.545+1G>A. Three patients were diagnosed with cone–rod dystrophy, and the remaining six patients with RP. Among eight patients performed with ultra-wide scanning laser ophthalmoscopy, double hyperautofluorescence rings inside and outside of the macular vascular arcades were observed in six patients, and the remaining two older patients demonstrated single hyperautofluorescence ring surrounded by pigmentation. CFAP410-associated retinopathy in early stage was generally tapetoretinal degeneration without noticeable bone spicule pigmentation, with more severe degeneration in the inferior nasal retina. ERG recordings delineated a severely reduced cone response and mildly to severely reduced rod response. Posterior staphyloma was seen in seven patients who underwent optical coherence tomography examinations.

Conclusions: The present study demonstrates the fundus characteristics of patients with biallelic variants in CFAP410 and expands the genotype–phenotype spectrum of CFAP410-related retinal degeneration, in which posterior staphyloma together with double hyperautofluorescence rings might be common peculiar signs.

CFAP410 (MIM: 603191) on chromosome 21q22.3 is essential for ciliogenesis1 and functions in DNA repair.2 Mutations in CFAP410 have been reported to cause autosomal recessive retinal dystrophy with or without macular staphyloma.3,4 Localization of CFAP410 in the photoreceptor cilia of mammals suggests that CFAP410 plays an important role in maintaining the physiological function of photoreceptors.1 Photoreceptor sensory cilia, located in the outer segments of photoreceptors, have disc membranes on which light detection and phototransduction occur.5 Mutations in genes expressed in cilia, such as CEP290,6 lead to dysfunction of photoreceptors and can result in RP and Leber congenital amaurosis. Degeneration of photoreceptors is a hallmark of RP, which is also considered a common inherited eye disease with an incidence of 1 in 4000 people.7 Biallelic variants in CFAP410 have currently been reported to cause cone–rod dystrophy or RP with and without systemic signs.2,8 Fundus changes have been described individually for most patients with CFAP410 mutations, including vessel attenuation, mottled RPE layer,9,10 whereas ERG recordings usually demonstrate severe cone impairment with moderately to severely decreased rod responses.3,9 However, the genotype–phenotype correlations for biallelic CFAP410 variants, especially for fundus characteristics, need further characterization. 
In the current study, nine patients from eight unrelated families with biallelic pathogenic or likely pathogenic variants in CFAP410 were analyzed, and a detailed investigation of their ocular phenotypes was carried out. Double hyperautofluorescence rings inside and outside of the macular vascular arcades were observed in six of eight patients conducted with wide-filed autofluorescence fundus examination and thus are highly indicative of mutations in CFAP410
Methods
Subjects
Whole exome sequencing or targeted exome sequencing were performed on genomic DNA from peripheral venous blood samples of 10,530 probands with various eye conditions, as previously described in our studies.11,12 Written informed consent in accordance with the tenets of the Declaration of Helsinki was obtained from the patient or their guardians before the collection of clinical data and venous blood samples. This study was approved by the institutional review board of the Zhongshan Ophthalmic Center. 
Variant Assessment
For the genetic analysis, variants in CFAP410 were selected and evaluated by multiple computational analysis. The analysis steps were as follows: (1) variants with low confidence or with coverage less than 5× were excluded; (2) intronic variants, variants in untranslated regions, and synonymous variants without effect on splicing according the prediction by the Berkeley Drosophila Genome Project (BDGP, http://www.fruitfly.org/) were excluded; (3) variants with a minor allele frequency of greater than 0.05 based on the gnomAD database (https://gnomad.broadinstitute.org/) were excluded; and (4) homozygous or compound heterozygous in CFAP410 meeting the above criteria were selected. The variants that selected out by the above steps were further evaluated by American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines13 and confirmed by Sanger sequencing using protocols described previously.14 Additionally, cosegregation analysis was performed with available family members. The primers used for Sanger sequencing were designed via the Primer 3.0 website (http://primer3.ut.ee/). 
Collection of Clinical Data
The clinical data of patients with biallelic pathogenic or likely pathogenic variants in CFAP410 were collected in the Genetic Clinic of the Zhongshan Ophthalmic Center and included best-corrected visual acuity (BCVA), ophthalmoscopic examination, ultra-wide field optical coherence tomography (TowardPi, Beijing, China), regular optical coherence tomography (Cirrus HD-optical coherence tomography 5000 Carl Zeiss, Jena, Germany), regular fundus photography (Kowa nonmyd α-D III, Japan), scanning laser ophthalmoscopy (Daytona Optos, Dunfermline, Scotland, UK), and Humphrey visual field examination (Carl Zeiss Meditec, Inc., Dublin, CA, USA). In addition, radiographs of three patients from two unrelated families were also available. 
ERG testing was performed following the International Society for Clinical Electrophysiology of Vision standard testing criteria.15 ERGs were carried out with dilated pupils. After at least 20 minutes of dark adaption, dark-adapted ERG with flash strengths of 0.01, 3, and 10 phot cd·s·m–2 were recorded. This was followed by 10 min of light adaption, then the light-adapted ERG was recorded with a single flash with a strength of 3 phot cd·s·m–2 under a background luminance of 30 cd·m–2, as well as at a frequency of 30 Hz. One patient (F1-II2) came to the outpatient clinic at a young age, and ERG testing was performed using a RETeval (LKC Technologies, Gaithersburg, MD, USA).16 International Society for Clinical Electrophysiology of Vision standard flicker parameters were also followed.17 
Patients were predominantly diagnosed with cone–rod dystrophy according to the following criteria18 (1) The ERG shows a greater reduction in cone responses relative to rod responses. (2) The fundus shows macular dystrophy, pallor of the optic discs, or retinal dystrophy. 
Criteria for a predominant diagnosis of RP7 were listed. (1) The ERG showed essentially flat response of rod photoreceptors. Cone responses may also be reduced, but this reduction happened behind rod subnormal response. (2) The fundus examination showed waxy pallor of the optic discs, attenuation of the retinal vessels, retinal degeneration in the peripheral retina with or without pigmentation, and reduction in the peripheral visual fields. 
Because poor vision is the main complaint of patients in the present study, the symptom involving photophobia was helpful to make the predominant diagnosis as cone–rod dystrophy, whereas night blindness was helpful to make the predominant diagnosis as RP. 
Statistical Analysis
Statistical analysis was performed using IBM SPSS software ver26.0 (IBM Corp, Armonk, NY, USA). The comparison of patients with RP or cone–rod dystrophy in different ethnic groups was performed using the χ2 test, and the BCVA in patients with RP or cone–rod dystrophy were compared through a Mann–Whitney U test. A difference with a P value of less than 0.05 was considered significant. 
Results
A total of four pathogenic or likely pathogenic variants in CFAP410 in homozygous or compound heterozygous status were detected in nine patients from eight unrelated families, including one frameshift deletion (c.144-6_159del), one in-frame duplication (c.340_351dup/p.(Thr114_Arg117dup)), one missense variant (c.347C>T/p.(Pro116Leu)), and one splice donor site (c.545+1G>A), in which c.144-6_159del was novel. All the four CFAP410 variants were evaluated as pathogenic or likely pathogenic ones based on ACMG/AMP criteria. The minor allele frequencies of all four variants were less than 0.001 in gnomAD database. Interestingly, c.340_351dup was detected in all eight families, including five with a homozygous status and three with a compound heterozygous status. All variants were confirmed by Sanger sequencing and cosegregation analyses were performed in five families, including three with a homozygous (F1, F3, and F4) and two with a compound heterozygous status (F6 and F8) (Fig. 1A, online Supplementary Fig. S1). The distribution of the four pathogenic variants in CFAP410 from the present study and 15 variants described in previous studies is shown in Figure 1B. 
Figure 1.
 
The pedigrees, distribution of variants in CFAP410 and scattered graph of visual acuity and examination age. (A) The diagrams of the eight pedigrees with biallelic variants in CFAP410. The rectangular and circle represented male and female respectively. The filled rectangle and circle represent affected patients. The arrow labelled the proband. (B) Variants of CFAP410 in the present study were located superior of blue bar, which represented coding region of CFAP410. Although variants in CFAP410 from previous studies were located inferior of the bar. Lines with blue, green, and red meant missense variants, in-frame variants, and truncation variants, respectively. In addition, pink triangles meant patients with ocular signs only. (C) The proportion of patients with RP and cone–rod dystrophy in different populations. Numbers inside the circle meant families count. The same color represented the same population, partial circle without white solid line meant patients with RP and the other meant patients with cone–rod dystrophy. (D) The scatter of available BCVA of patients with various ages based on the present study and previous studies.
Figure 1.
 
The pedigrees, distribution of variants in CFAP410 and scattered graph of visual acuity and examination age. (A) The diagrams of the eight pedigrees with biallelic variants in CFAP410. The rectangular and circle represented male and female respectively. The filled rectangle and circle represent affected patients. The arrow labelled the proband. (B) Variants of CFAP410 in the present study were located superior of blue bar, which represented coding region of CFAP410. Although variants in CFAP410 from previous studies were located inferior of the bar. Lines with blue, green, and red meant missense variants, in-frame variants, and truncation variants, respectively. In addition, pink triangles meant patients with ocular signs only. (C) The proportion of patients with RP and cone–rod dystrophy in different populations. Numbers inside the circle meant families count. The same color represented the same population, partial circle without white solid line meant patients with RP and the other meant patients with cone–rod dystrophy. (D) The scatter of available BCVA of patients with various ages based on the present study and previous studies.
Three of the nine patients—F1-II1, F2-II1, and F3-II2—were diagnosed with cone–rod dystrophy because their ERG showed a more severely reduced cone response compared with mildly reduced rod response and F2-II1 manifested photophobia (Table). The average examination age was 15.0 ± 13.0 years old (range, 7–30 years). The other six patients were diagnosed with RP based on ERG recordings with severe reductions of both the cone and rod responses. Of the six, three complained of night blindness and the others of poor vision or nystagmus. The average examination age was 15.2 ± 9.2 years old (range, 4–26 years). There is no significant difference in the examination ages between patients with cone–rod dystrophy and RP (P = 0.42). The BCVA of patients with cone–rod dystrophy and RP were recorded each time they came to the clinic and ranged from 0.70 to 1.70. The distribution of BCVA in patients with cone–rod dystrophy and RP from the present study and previous studies is shown in Figure 1C. Overall, the BCVA in patients with RP (median, 0.81) was better than that of those with cone–rod dystrophy (median, 1.11) (P = 0.03). 
Table.
 
Clinical Data of 9 Patients With Biallelic Variants in CFAP410 in the Present Study
Table.
 
Clinical Data of 9 Patients With Biallelic Variants in CFAP410 in the Present Study
Ophthalmoscopic examination indicated pale optic discs, arteriolar attenuation, and significant tapetoretinal degeneration in proximity to the optic nerve and posterior vascular arcades in all nine patients (Fig. 2). Macular changes were more distinct in ultra-wide field scanning laser ophthalmoscopy under autofluorescence mode (Fig. 3). However, the distribution of tapetoretinal degeneration varied personally. Retinal dystrophy was more frequently seen in the inferior retina and especially the inferior-nasal quadrants in six patients (Figs. 3A–F), whereas it was relatively uniform in the superior and inferior the retinas of patients F7-II1 and F8-II1 (Fig. 2 and Figs. 3G, 3H). Various-shaped pigment deposits were observed in the midperipheral retina in two relatively older patients (F7-II1 and F8-II1) (Figs. 3G, 3H), but not in seven other patients. Fundus autofluorescence revealed unique double hyperautofluorescence rings encircling the central macula, as well as the vascular arcades in both eyes of six patients with ultra-wide filed autofluorescence. The other two patients displayed a single hyperautofluorescence ring surrounded by pigmentation. In addition, hypoautofluorescence signals in the central macula and inside the inner ring, as well as in the inferior-nasal retina between the two rings were observed (Fig. 3). Three patients—F1-II2, F2-II1, and F5-II1—displayed significant double hyperautofluorescence rings encircling the retinal vessels and fovea (Figs. 3B, 3C, 3F). Additional two older patients (F7-II1 and F8-II1) were examined at 26 years of age. Because of increased retinal pigmentation, the outer hyperautofluorescence ring were not obvious (Figs. 3G, 3H). Hyperautofluorescence was also observed in the midperipheral retina of the remaining three patients—F1-II1, F3-II2, and F4-II2—although there was no clear boundary to the outer ring (Figs. 3A, 3D, 3E). The outer hyperautofluorescence ring encircling the vascular arcade and optic disc was remarkable on scanning laser ophthalmoscopy, but hardly visible under conventional fundus imaging. Based on ultra-wide field-optical coherence tomography from five patients (Figs. 4I–N) and regular optical coherence tomography from two patients (Supplementary Fig. S3), posterior staphyloma was observed in all of the seven patients. Other findings included degenerative changes of the photoreceptor layer and RPE in the central macula and disappearance of the ellipsoid zone (Figs. 4I–N). Standard Humphrey perimetry with 30° test pattern and 60° test pattern was performed. The former covered 30° centrally and demonstrated various defects in quadrants that corresponded with retinopathy in the different retinal regions (Figs. 4A–C, 4F). The 60° test pattern represented peripheral visual filed which displayed diffused visual field defect (Figs. 4E, 4G, 4H), as well as defects in quadrants (Fig. 4D). ERG data were assessed in nine patients, in whom all showed severe reductions in cone response. Three patients with cone–rod dystrophy displayed mild to moderate reduction of rod response amplitudes, while the remaining six patients with RP showed moderate to severe reduction for rod responses (Table, Supplementary Fig. S2). In addition, chest and hand radiographs were available for three patients (F1-II1, F1-II2, and F2-II1), in which no abnormalities were observed on their hands or thorax (Supplementary Fig. S4). 
Figure 2.
 
Images of regular color fundus in eight patients with biallelic variants in CFAP410. Letters at the left corner are individual IDs, followed by ages. Retinal degeneration including optic disc pale, arterioles attenuation, tapetoretinal degeneration around the optic nerve and retinal vessels, and macular dystrophy were displayed in all patients. Symmetry retinal atrophy especially in the inferior-nasal retina were obvious in F1 to F5. Uniform retinal degeneration was shown in patients F7 and F8 with older age. F1-II1, F2-II1, and F3-II2 were diagnosed as cone–rod dystrophy and the others were patients with RP.
Figure 2.
 
Images of regular color fundus in eight patients with biallelic variants in CFAP410. Letters at the left corner are individual IDs, followed by ages. Retinal degeneration including optic disc pale, arterioles attenuation, tapetoretinal degeneration around the optic nerve and retinal vessels, and macular dystrophy were displayed in all patients. Symmetry retinal atrophy especially in the inferior-nasal retina were obvious in F1 to F5. Uniform retinal degeneration was shown in patients F7 and F8 with older age. F1-II1, F2-II1, and F3-II2 were diagnosed as cone–rod dystrophy and the others were patients with RP.
Figure 3.
 
Regular and fundus autofluorescence mode scanning laser ophthalmoscopy images in eight patients. Double hyperautofluorescence rings inside and outside the macular vascular arcades were captured and enhanced in scanning laser ophthalmoscopy image with fundus autofluorescence mode. Retinal degeneration around the retinal vessels and various degree of macular atrophy were the typical sign in all eight patients. Severe tapetoretinal degeneration in the inferior-nasal retina was observed (A–F). Retinal pigment deposits were also observed (G, H).
Figure 3.
 
Regular and fundus autofluorescence mode scanning laser ophthalmoscopy images in eight patients. Double hyperautofluorescence rings inside and outside the macular vascular arcades were captured and enhanced in scanning laser ophthalmoscopy image with fundus autofluorescence mode. Retinal degeneration around the retinal vessels and various degree of macular atrophy were the typical sign in all eight patients. Severe tapetoretinal degeneration in the inferior-nasal retina was observed (A–F). Retinal pigment deposits were also observed (G, H).
Figure 4.
 
Humphrey visual field examination and wide-field optical coherence tomography images. The left visual field image was captured from left eye of each person while the right one was right eye. The 30° tests were performed in four patients (AC, F). The 60° tests which indicated the visual function of peripheral retina, were performed in another four patients (D, E, G, H). (A) F1-II1 displayed upper visual field defect, which was consistent with inferior retinal dystrophy. (B) Diffused and severe visual field defect were observed in F1-II2. (C) For patient F2-II1, the visual field defect matched the region of inferior-nasal retinal tapetoretinal degeneration. (D) Relative severe inferior and nasal retinal degeneration was observed in F3-II2, which corresponded with the fundus photography in Figure 2 and Figure 3. (EH) Full-field visual impairments were displayed in four patients. (IN) The upper ultra-wide field optical coherence tomography image of each subject was OD and the lower one was OS. (IM) Posterior staphyloma was observed in five patients ultra-wide field optical coherence tomography images. Macular dystrophy, photoreceptor layer degeneration, and disruption of ellipsoid zones were also displayed through optical coherence tomography images. (N) The ultra-wide field optical coherence tomography images from normal control (NC).
Figure 4.
 
Humphrey visual field examination and wide-field optical coherence tomography images. The left visual field image was captured from left eye of each person while the right one was right eye. The 30° tests were performed in four patients (AC, F). The 60° tests which indicated the visual function of peripheral retina, were performed in another four patients (D, E, G, H). (A) F1-II1 displayed upper visual field defect, which was consistent with inferior retinal dystrophy. (B) Diffused and severe visual field defect were observed in F1-II2. (C) For patient F2-II1, the visual field defect matched the region of inferior-nasal retinal tapetoretinal degeneration. (D) Relative severe inferior and nasal retinal degeneration was observed in F3-II2, which corresponded with the fundus photography in Figure 2 and Figure 3. (EH) Full-field visual impairments were displayed in four patients. (IN) The upper ultra-wide field optical coherence tomography image of each subject was OD and the lower one was OS. (IM) Posterior staphyloma was observed in five patients ultra-wide field optical coherence tomography images. Macular dystrophy, photoreceptor layer degeneration, and disruption of ellipsoid zones were also displayed through optical coherence tomography images. (N) The ultra-wide field optical coherence tomography images from normal control (NC).
Combining results from the present study with previous studies yields 16 variants in CFAP410 in 35 patients from 27 unrelated families with retinal disease with or without systematic abnormalities3,4,19,20 (Supplementary Table S1). All 16 variants are distributed in the coding region of CFAP410 (Fig. 1B), in which the c.340_351dup/p.(Thr114_Arg117dup) was the most frequent variant reported so far, especially in East Asians. All of these variants had a minor allele frequency of less than 0.001 in the gnomAD database. Of the patients from the 27 reported families, those from 16 families were diagnosed with RP, including 9 East Asian, 3 South Asian, 1 European, 1 Ashkenazi Jewish, 1 African American, and 1 Australian. The other 11 families were reported with cone–rod dystrophy, including 6 East Asian, 4 South Asian and 1 European (Fig. 1C). East Asians showed the highest incidence of CFAP410-related retinopathy, although the proportion of patients with RP and cone–rod dystrophy were not significantly different among the different populations (Fig. 1C). 
Discussion
A total of four pathogenic or likely pathogenic variants in CFAP410, including one novel, were detected in nine patients from eight families reported in the present study. The c.340_351dup variant was the most frequent one in East Asian patients. A unique fundus sign, double hyperautofluorescence rings encircling the macula and tapetoretinal degeneration around the vascular arcades are seen in most of our patients, in addition to posterior staphyloma. Bone spicule pigmentations were not observed in most of our patients at younger age, but did present in two of nine patients at the age of 26 years. 
An additional proband (SF1-II1) presented to our clinic with a complaint of night blindness. Whole exome sequencing and Sanger sequencing confirmed that variant c.340_351dup and c.347C>T in CFAP410 were present in SF1-II1 (Supplementary Fig. S5). Segregation analysis was conducted in family F6, and c.347C>T was evaluated as a likely pathogenic variant based on ACMG/AMP criteria. Unfortunately, DNA samples from the parents of SF1-II1 were not available for study. Thus, family SF1 is presented in the Supplementary materials and not included in the Results. However, there is significant evidence supporting the pathogenicity of c.347C>T. (1) The allele frequency based on gnomAD database is rare (6.04E-05) and no homozygotes are listed. (2) Variant c.347C>T in CFAP410 was detected in two families (F6 and SF1) in compound heterozygous form in our cohort, but was not detected in subjects with other inherited eye diseases. (3) Multiple in silico tools including SIFT, Polyphen2, and PROVEAN predict that this variant is damaging. (4) The fundus photographs of SF1 are similar to other patients with RP in the present study. All of these factors support the c.347C>T change as causative in patient SF1. 
When compared with classic RP, generally defined by pigment deposits in the mid periphery along with retinal atrophy, the fundi of patients with biallelic variants in CFAP410 most often show double hyperautofluorescence rings, as well as degeneration concentrated in the vascular arcades. Unlike concentric RP,21 which tends to show better BCVA and photoreceptor responses in the ERG than typical RP, patients with biallelic variants in CFAP410 show a worse BCVA and associated macular atrophy. The ellipsoid zone in patients with CFAP410 mutations needs further quantitative study to confirm whether there is a difference among concentric RP, typical RP, and CFAP410-related RP. In addition, hyperautofluorescence rings inside the macular vascular arcades are common in Stargardt disease, and double concentric autofluorescence rings including a perimacular ring and another ring within the vascular arcades have been described in patients with NR2E3-associated RP.22 Thus, double autofluorescence rings inside and outside of the vascular arcades might be considered as a peculiar sign of CFAP410-related retinopathy, as shown in the present study, especially combined with posterior staphyloma. Additionally, the outer hyperfluorescence ring was invisible in two older patients at 26 years of age. Double hyperautofluorescence rings could be seen in the early stage of CFAP410 related retinal disorder in the younger patients from our cohort. It was suspicious that the fundus changes of single of hyperautofluorescence ring are characteristic of progressive stage of the disease and changes of hyperautofluorescence rings were followed at patients in who were their 40s or older. Gene-specific fundus changes have been reported for other genes, such as nummular pigment deposits for CRB1,23 diffuse mottled hypopigmentation for SPATA7,24 more severe atrophy of the parafovea than the fovea region for RDH12,25 and discontinuous pigment deposits from macular and peripheral retina for PROM1.26 As the genes expressed in the cilia of photoreceptors, CFAP410-associated retinopathy shared some similarity with those caused by other genes, like IQCB1 and CEP290,2729 such as tapetoretinal degeneration without obvious pigmentation in most cases. In addition, other key ciliopathy-associated proteins, including SPATA7, RPGRIP1, and NEK1, might interact with CFAP410. Clinically, biallelic variants in SPATA7 cause RP, with well-preserved macular and yellowish–white frosted retinal degeneration concentrated in the midperiphery.24 Patients with variants in RPGRIP1 share similar fundus changes with CFAP410, including varying macular atrophy, mottled pigmentary changes, and quadrant aggravated retinal degeneration.30 Previous studies have also shown an interaction between SPATA7 and RPGRIP1.31,32 In patients with variants in NEK1, a mottled ellipsoid band on optical coherence tomography images corresponds with the ring of hyperautofluorescence on fundus autofluorescence images.33 The correlation about the retinal degeneration edge and fundus autofluorescence double hyperautofluorescence rings needs further clarification based on the known association between NEK1 and CFAP410.34 However, skeletal manifestations, including a narrowed thorax, pectus carinatum, and shortening of the metacarpal, have also been described in patients with CFAP410 mutations in previous studies,3,4,20 but rarely were seen in our patients. The pathogenic mechanisms responsible for the ocular degeneration and skeletal dysplasia also needs to be clarified. 
In summary, specific fundus changes that might be gene specific were identified in Chinese patients with biallelic CFAP410 variants based on clinical and genetic analysis of nine patients from eight families. Gene-specific fundus signs might be not only of value in the diagnosis and differential diagnosis as well as evaluation of prognosis and intervention effectiveness, but also serve as a potential clue into the molecular pathophysiology of retinal degeneration. 
Acknowledgments
The authors really appreciate James Fielding Hejtmancik's assistance in language editing. Xueqing Li is currently in Hejtmancik's lab at the NEI, NIH. The authors are grateful to the patients for their participation. 
Supported by the grants from the National Natural Science Foundation of China (81970837) and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology. 
Disclosure: X. Li, None; Y. Wang, None; J. Wang, None; P. Wang, None; Q. Zhang, None 
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Figure 1.
 
The pedigrees, distribution of variants in CFAP410 and scattered graph of visual acuity and examination age. (A) The diagrams of the eight pedigrees with biallelic variants in CFAP410. The rectangular and circle represented male and female respectively. The filled rectangle and circle represent affected patients. The arrow labelled the proband. (B) Variants of CFAP410 in the present study were located superior of blue bar, which represented coding region of CFAP410. Although variants in CFAP410 from previous studies were located inferior of the bar. Lines with blue, green, and red meant missense variants, in-frame variants, and truncation variants, respectively. In addition, pink triangles meant patients with ocular signs only. (C) The proportion of patients with RP and cone–rod dystrophy in different populations. Numbers inside the circle meant families count. The same color represented the same population, partial circle without white solid line meant patients with RP and the other meant patients with cone–rod dystrophy. (D) The scatter of available BCVA of patients with various ages based on the present study and previous studies.
Figure 1.
 
The pedigrees, distribution of variants in CFAP410 and scattered graph of visual acuity and examination age. (A) The diagrams of the eight pedigrees with biallelic variants in CFAP410. The rectangular and circle represented male and female respectively. The filled rectangle and circle represent affected patients. The arrow labelled the proband. (B) Variants of CFAP410 in the present study were located superior of blue bar, which represented coding region of CFAP410. Although variants in CFAP410 from previous studies were located inferior of the bar. Lines with blue, green, and red meant missense variants, in-frame variants, and truncation variants, respectively. In addition, pink triangles meant patients with ocular signs only. (C) The proportion of patients with RP and cone–rod dystrophy in different populations. Numbers inside the circle meant families count. The same color represented the same population, partial circle without white solid line meant patients with RP and the other meant patients with cone–rod dystrophy. (D) The scatter of available BCVA of patients with various ages based on the present study and previous studies.
Figure 2.
 
Images of regular color fundus in eight patients with biallelic variants in CFAP410. Letters at the left corner are individual IDs, followed by ages. Retinal degeneration including optic disc pale, arterioles attenuation, tapetoretinal degeneration around the optic nerve and retinal vessels, and macular dystrophy were displayed in all patients. Symmetry retinal atrophy especially in the inferior-nasal retina were obvious in F1 to F5. Uniform retinal degeneration was shown in patients F7 and F8 with older age. F1-II1, F2-II1, and F3-II2 were diagnosed as cone–rod dystrophy and the others were patients with RP.
Figure 2.
 
Images of regular color fundus in eight patients with biallelic variants in CFAP410. Letters at the left corner are individual IDs, followed by ages. Retinal degeneration including optic disc pale, arterioles attenuation, tapetoretinal degeneration around the optic nerve and retinal vessels, and macular dystrophy were displayed in all patients. Symmetry retinal atrophy especially in the inferior-nasal retina were obvious in F1 to F5. Uniform retinal degeneration was shown in patients F7 and F8 with older age. F1-II1, F2-II1, and F3-II2 were diagnosed as cone–rod dystrophy and the others were patients with RP.
Figure 3.
 
Regular and fundus autofluorescence mode scanning laser ophthalmoscopy images in eight patients. Double hyperautofluorescence rings inside and outside the macular vascular arcades were captured and enhanced in scanning laser ophthalmoscopy image with fundus autofluorescence mode. Retinal degeneration around the retinal vessels and various degree of macular atrophy were the typical sign in all eight patients. Severe tapetoretinal degeneration in the inferior-nasal retina was observed (A–F). Retinal pigment deposits were also observed (G, H).
Figure 3.
 
Regular and fundus autofluorescence mode scanning laser ophthalmoscopy images in eight patients. Double hyperautofluorescence rings inside and outside the macular vascular arcades were captured and enhanced in scanning laser ophthalmoscopy image with fundus autofluorescence mode. Retinal degeneration around the retinal vessels and various degree of macular atrophy were the typical sign in all eight patients. Severe tapetoretinal degeneration in the inferior-nasal retina was observed (A–F). Retinal pigment deposits were also observed (G, H).
Figure 4.
 
Humphrey visual field examination and wide-field optical coherence tomography images. The left visual field image was captured from left eye of each person while the right one was right eye. The 30° tests were performed in four patients (AC, F). The 60° tests which indicated the visual function of peripheral retina, were performed in another four patients (D, E, G, H). (A) F1-II1 displayed upper visual field defect, which was consistent with inferior retinal dystrophy. (B) Diffused and severe visual field defect were observed in F1-II2. (C) For patient F2-II1, the visual field defect matched the region of inferior-nasal retinal tapetoretinal degeneration. (D) Relative severe inferior and nasal retinal degeneration was observed in F3-II2, which corresponded with the fundus photography in Figure 2 and Figure 3. (EH) Full-field visual impairments were displayed in four patients. (IN) The upper ultra-wide field optical coherence tomography image of each subject was OD and the lower one was OS. (IM) Posterior staphyloma was observed in five patients ultra-wide field optical coherence tomography images. Macular dystrophy, photoreceptor layer degeneration, and disruption of ellipsoid zones were also displayed through optical coherence tomography images. (N) The ultra-wide field optical coherence tomography images from normal control (NC).
Figure 4.
 
Humphrey visual field examination and wide-field optical coherence tomography images. The left visual field image was captured from left eye of each person while the right one was right eye. The 30° tests were performed in four patients (AC, F). The 60° tests which indicated the visual function of peripheral retina, were performed in another four patients (D, E, G, H). (A) F1-II1 displayed upper visual field defect, which was consistent with inferior retinal dystrophy. (B) Diffused and severe visual field defect were observed in F1-II2. (C) For patient F2-II1, the visual field defect matched the region of inferior-nasal retinal tapetoretinal degeneration. (D) Relative severe inferior and nasal retinal degeneration was observed in F3-II2, which corresponded with the fundus photography in Figure 2 and Figure 3. (EH) Full-field visual impairments were displayed in four patients. (IN) The upper ultra-wide field optical coherence tomography image of each subject was OD and the lower one was OS. (IM) Posterior staphyloma was observed in five patients ultra-wide field optical coherence tomography images. Macular dystrophy, photoreceptor layer degeneration, and disruption of ellipsoid zones were also displayed through optical coherence tomography images. (N) The ultra-wide field optical coherence tomography images from normal control (NC).
Table.
 
Clinical Data of 9 Patients With Biallelic Variants in CFAP410 in the Present Study
Table.
 
Clinical Data of 9 Patients With Biallelic Variants in CFAP410 in the Present Study
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