Molecular Vision 2020; 26:588-602 <http://www.molvis.org/molvis/v26/588>
Received 26 July 2019 | Accepted 20 August 2020 | Published 22 August 2020

This Article

Download PDF

Citation (for Endnote)

Google Scholar

Articles by the Authors

Genotypes and phenotypes of genes associated with achromatopsia: A reference for clinical genetic testing

Wenmin Sun, Shiqiang Li, Xueshan Xiao, Panfeng Wang, Qingjiong Zhang

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China

Correspondence to: Qingjiong Zhang, Pediatric and Genetic Eye Clinic, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou 510060, China; Phone: (+86)-20-66677083; FAX: (+86)-20-66686996; email: zhangqji@mail.sysu.edu.cn or zhangqingjiong@gzzoc.com

Abstract

Purpose: Achromatopsia is a congenital autosomal recessive cone disorder, and it has been found to be associated with six genes. However, pathogenic variants in these six genes have been identified in patients with various retinal dystrophies with the exception of achromatopsia. Thus, this study aims to investigate the contribution of these genes in hereditary retinal diseases and the potential genotype–phenotype correlations.

Methods: Biallelic variants in six achromatopsia-related genes, namely, CNGA3, CNGB3, GNAT2, ATF6, PDE6C, and PDE6H, were analyzed based on data obtained from 7,195 probands with different eye conditions. A systematic genotype–phenotype analysis of these genes was performed based on these data, along with the data reported in the literature.

Results: Biallelic potential pathogenic variants (PPVs) in five of the six genes were identified in 119 probands with genetic eye diseases. The variants in CNGA3 were the most common and accounted for 81.5% (97/119). Of the 119 probands, 62.2% (74/119) have cone-rod dystrophy, whereas only 25.2% (30/119) have achromatopsia. No biallelic pathogenic variants in these genes were identified in patients with rod-dominant degeneration. A systematic review of genotypes and phenotypes revealed certain characteristics of each of the six genes, providing clues for the pathogenicity evaluation of the variants of the genes.

Conclusions: PPVs in the six genes were identified in various inherited retinal degeneration diseases, most of which are cone-dominant diseases but no rod-dominant diseases based on the data from a cohort of 7,195 probands with different eye conditions. The systematic genotype–phenotype analysis of these genes will be useful in drafting guidelines for the clinical genetic diagnostic application for the investigated genes.

Introduction

Achromatopsia (ACHM, OMIM 216900) is a rare congenital autosomal recessive cone disorder with a prevalence of less than 1 in 30,000 [1]. However, the prevalence of ACHM could be as high as 4–10% in certain regions where consanguinity is common [2]. The clinical features of ACHM include congenital nystagmus, photophobia, reduced visual acuity (VA), color blindness, and severely reduced to nonrecordable cone response but with a normal rod response [1]. Some patients also develop macular dystrophy. ACHM was previously considered a stationary disorder, but follow-up studies have shown that ACHM is characterized by progressive loss of photoreceptor cells [3-5].

Potential pathogenic variants (PPVs) in six genes have been identified in patients with ACHM, including CNGA3 (OMIM 600053), CNGB3 (OMIM 605080), GNAT2 (OMIM 139340), ATF6 (OMIM 605537), PDE6C (OMIM 600827), and PDE6H (OMIM 601190). ATF6 encodes a widely expressed endoplasmic reticulum stress response element-binding protein. The five other genes encode cone-specific expression and function in the G-protein cascade of phototransduction. CNGA3 and CNGB3 encode the α- and β-subunits of the cGMP-gated channel, respectively [6]. GNAT2 encodes the α2-subunit for the G-protein transduction [7]. PDE6C and PDE6H encode the catalytic subunit and the γ-subunit of cGMP phosphodiesterase, respectively [8,9]. PPVs in these five cone-specific genes (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) have been identified in patients with various retinal dystrophies, including ACHM, cone-rod dystrophy (CORD), and Leber congenital amaurosis (LCA) [10-16]. Studies have also identified PPVs in CNGA3 in patients with retinitis pigmentosa (RP) [10,14] and congenital stationary night blindness (CSNB) [17]. However, there are several concerns regarding these PPVs in CNGA3. First, several of these PPVs have been identified in only a few cases with RP or CSNB, leading to the following question: What are the characteristics of these PPVs and of the rare phenotypes in these few cases? Second, most PPVs in the genes above were identified based on a cohort of patients with a single disease (especially ACHM). Thus, the following questions arise: Are there additional PPVs in the other five genes in patients with rod-dominant degeneration? What is the contribution of the PPVs in these six genes in all inherited retinal dystrophies (IRDs) as well as in different groups? Third, the potential genotype–phenotype correlation has yet to be investigated.

With the use of whole-exome sequencing and targeted exome sequencing for genetic analysis, variants in a panel of genes can be obtained from individuals with different diseases. These tools are useful in genotype-guided organization of the phenotypic spectrum and in the pathogenicity evaluation of the variants of a single gene. In this study, we systematically analyzed the frequencies, spectra, and phenotypes associated with the PPVs in six genes (ATF6, CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) based on exome sequencing data from 7,195 probands with different eye conditions. We performed a systematic genotype–phenotype analysis of the six genes based on the present data, along with the data reported in the literature. The results will be useful in establishing guidelines for genetic diagnostic application of the investigated genes.

Methods

Subjects

As part of an ongoing study of the genetic basis of inherited eye diseases, this research involved 7,195 families with different eye conditions recruited at the Pediatric and Genetic Eye Clinic of the Zhongshan Ophthalmic Center. Of the 7,195 families, 5,063 were new participants, and 2,132 families had been previously investigated [11,18-25]. The peripheral blood and clinical data of these families were collected after written informed consent was obtained from the participants or from their guardians in accordance with the tenets of the Declaration of Helsinki. Genomic DNA was prepared from leukocytes of the peripheral blood. Diagnoses were made based on their symptoms and ophthalmic examinations, including a VA test, a slit-lamp examination, and ophthalmoscopy, along with other required examinations, such as electroretinogram (ERG), optical coherence tomography (OCT), and fundus fluorescein angiography [26]. This study was approved by the institutional review board of the Zhongshan Ophthalmic Center.

Whole-exome sequencing

Whole-exome sequencing (WES) was performed on genomic DNA obtained from 5,280 unrelated individuals. Of these individuals, 3,735 were newly enrolled, whereas 1,545 had been previously subjected to a systematic variant analysis of a panel of genes, including the ACHM-associated genes above [18-23]. We described the WES process in a previous study [27].

Targeted exome sequencing

Targeted exome sequencing (TES) was performed on genomic DNA obtained from 1,896 probands exhibiting different eye diseases. Of these probands, 1,328 were newly enrolled, and 568 probands had been previously analyzed [24]. The TES was performed as described previously [24].

Evaluation and verification of the variants obtained through WES and TES

The variants of the six ACHM-associated genes were selected from the exome sequencing data of 7,176 probands; the data included the WES data from 5,280 probands and the TES data from 1,896 probands. After the low-certainty variants with coverage of fewer than ten were excluded, the variants detected in the investigated genes were filtered through multistep bioinformatics analyses, as follows: 1) exclusion of variants with minor allelic frequencies (MAFs) of less than 0.01 according to the 1000 Genomes and the Exome Aggregation Consortium (ExAC), 2) exclusion of variants at the noncoding region and of synonymous variants that did not affect the splice sites, 3) exclusion of missense variants that were predicted to be benign by SIFT and PolyPhen-2, and 4) exclusion of single heterozygous variants. The remaining candidate variants were verified in the probands and in the available family members through Sanger sequencing. A variant was excluded if it did not segregate with the disease in the family. In addition, PPVs in CNGA3, CNGB3, and PDE6C were identified in 19 additional probands by using Sanger sequencing as we described in a previous study [11].

Systematic review of the genotypes and phenotypes of the six genes based on the present data combined with the data reported in the literature

The present data and the data on the available PPVs and clinical diagnoses obtained from the Human Gene Mutation Database and through a search in PubMed were combined. A total of 169 CNGA3 PPVs in 409 families [2,4-6,10,11,13-18,28-70], 119 CNGB3 PPVs in 829 families [5,6,12,15,16,18,30-32,34,38,39,43,45,49-52,57,62,63,67,71-89], 61 PDE6C PPVs in 53 families [8,14,15,18,58,62,79,86,89-94], 17 GNAT2 PPVs in 17 families [7,12,15,31,50,63,95-99], 16 ATF6 PPVs in 17 families [15,100-105], and one PDE6H PPV in three families [106-108] were identified. The genotypes (including the frequencies, types, and locations) and the phenotypes (including congenital nystagmus, photophobia, impaired color vision, VA, refractive error, and ERG) of the PPVs in the six genes were summarized and serve as a reference in the application of clinical genetic testing.

Results

Mutational frequencies in the six genes in 7,195 Chinese probands with various genetic eye diseases

In total, 92 PPVs in five of the six genes were identified in 119 of the 7,195 probands; these 92 PPVs comprise 33 novel and 59 reported PPVs (Appendix 1) [18]. Moreover, the 92 PPVs comprise 63 variants in CNGA3, 16 in PDE6C, eight in CNGB3, three in ATF6, and two in GNAT2. For the PPVs in CNGA3, the missense and truncation variants accounted for 65.1% (41/63) and 31.7% (20/63), respectively, while the remaining two PPVs were non-frameshift variants. For CNGB3 and PDE6C, the missense and truncation variants accounted for about half of the total, respectively. The three ATF6 PPVs included one splicing and two missense variants, whereas the two GNAT2 PPVs were missense variants. Of the 119 probands with PPVs in the five genes, 51 were newly recruited (Appendix 2), and the remaining 68 probands were included in our previous studies (Appendix 3) [11,18,21,24]. Segregation analysis in available family members of 38 families suggested that the PPVs cosegregated with disease in these families (Appendix 4). The clinical data of the 51 new probands are described in Appendix 2. The PPVs in CNGA3 were the most common and were identified in 81.5% (97/119) of the probands, whereas the PPVs in GNAT2, ATF6, CNGB3, and PDE6C were detected in one, two, 7, and 12 probands, respectively. No biallelic PPVs were identified in PDE6H in the 7,195 probands (Appendix 2, Appendix 3).

Phenotypic spectrum of the 119 Chinese probands with PPVs in five of the investigated ACHM-associated genes

Of the 119 probands with PPVs in five of the investigated genes, 74 were diagnosed with CORD, 30 with ACHM, one with LCA, one with early-onset high myopia (eoHM), three with macular dystrophy (MD), and ten with unclassified IRD (Appendix 2, Appendix 3). ERG recordings were available for 40 of the 51 newly recruited probands, and all had severely reduced or even extinguished cone responses with different rod responses (Appendix 2, Figure 1). The available OCT results from ten newly recruited probands showed different patterns, including normal, irregular or disruption ellipsoid zone, foveal hypoplasia, macular atrophy, and thinning retina (Appendix 2, Appendix 5). No biallelic PPVs in the six genes were identified in patients with rod-dominant retinopathy, such as RP and CSNB. Biallelic PPVs in CNGA3 had the highest frequency; it was found in 81.1% (60/74) of the probands with CORD and in 86.7% (26/30) of those with ACHM.

Genotypes of the investigated genes

Currently, 321 PPVs in the six genes have been reported in previous literature except the 62 PPVs from the present cohort (Appendix 6). The total 383 PPVs included 169 CNGA3 PPVs from 409 families, 119 CNGB3 PPVs from 829 families, 61 PDE6C PPVs from 53 families, 17 GNAT2 PPVs from 17 families, 16 ATF PPVs from 17 families, and one PDE6H PPV from three families. Regarding the variant types of the six investigated genes, the PPVs in CNGA3 were predominately missense, accounting for 69.8% (118/169), whereas the PPVs in CNGB3, GNAT2, and ATF6 were predominately truncation variants (frameshift, nonsense, splicing change, start loss, and gross deletion/insertion; Figure 2). Missense and truncation PPVs accounted for half of the variants in PDE6C (Figure 2), and the lone PPV in PDE6H was a truncation variant. The PPVs in the six genes were identified in 1,328 families. In these families, the biallelic PPVs in CNGB3 were the most common, and they were found in 62.4% (829/1,328) of the families, while the PPVs in CNGA3 were found in 30.8% (409/1,328) of the families. The PPVs in PDE6C, GNAT2, ATF6, and PDE6H were detected in 4.0% (53/1,328), 1.3% (17/1,328), 1.3% (17/1,328), and 0.2% (3/1,328) of the investigated families, respectively.

The functional domains in the investigated genes, except in GNAT2, were studied. CNGA3 and CNGB3 have six similar transmembrane domains, four loops, one pore region, and one cGMP-binding domain (Figure 3A,D). Most of the missense PPVs in CNGA3 are located at the regions that encode functional domains, and the four hotspots are as follows: p.Arg277, p.Arg283, p.Val529, and p.Phe547. Among them, p.Arg277 and p.Arg283 are located at the S4 transmembrane domain, whereas p.Val529 and p.Phe547 are located at the cGMP-binding domain. None of the PPVs are located at exon 4 of CNGA3 that is exclusively present in transcript isoform 1 (NM_001298.2) and is absent in isoform 2 (NM_001079878.1), whereas one splicing variant is located in the upstream region of exon 4. In addition, all but one of the nine PPVs in the first four coding exons and their adjacent intronic regions in CNGA3 are truncation variants (Figure 3A). The remaining missense variant c.284C>T (p.Pro95Leu) was predicted to be tolerated by SIFT and PolyPhen-2 (Appendix 6). The CNGB3 gene has five mutation hotspots: p.Arg274Valfs*, c.991–3T>G, p.Glu336*, p.Thr383Ilefs*, and c.1578+1G>A. These five hotspots, as well as most truncation variants in CNGA3 and CNGB3, are located before the regions that encode the last functional domain (cGMP-binding domain). This pattern indicates that these truncation PPVs could affect at least one functional domain (Figure 3A,D). In addition, the PPVs in the three other genes (PDE6C, ATF6, and PDE6H) have similar locations, and all their truncation variants affect at least one functional domain (Appendix 7).

The combined number of PPVs in the literature and identified in the present data is 383, and four of these PPVs showed an MAF higher than 0.1% according to the ExAC database. These PPVs are as follows: c.682G>A (p.Glu228Lys) and c.1618G>A (p.Val540Ile) in CNGA3 and c.1148del (p.Thr383Ilefs*) and c.1208G>A (p.Arg403Gln) in CNGB3. The MAFs of the other PPVs were all lower than 0.1%. The allele frequencies of the reported PPVs in the general population based on ExAC are shown in Appendix 6. Two of the four PPVs, namely, c.1148del (p.Thr383Ilefs*) and c.1208G>A (p.Arg403Gln) in CNGB3, showed an allele frequency of 224/120,952 and 618/120,874 in ExAC, respectively. However, these allele frequencies were statistically significantly higher than the controls based on ExAC (p<0.01), whereas the allele frequencies for the other two variants did not differ statistically significantly from the controls (Appendix 8). Additionally, all three missense PPVs were predicted by SIFT and PolyPhen-2 to be damaging (Appendix 6).

Diseases associated with PPVs in the investigated genes

Of the 1,328 families with PPVs in the investigated genes (Appendix 9), 85.8% (1139/1,328) had ACHM, and 9.3% (124/1,328) had CORD (Figure 4A). The highest percentage of ACHM in all cases with PPVs in the six genes was caused by biallelic PPVs in CNGB3 (Figure 4B). The PPVs in CNGA3 were most common in Asian patients with ACHM and CORD, whereas the PPVs in CNGB3 were mostly identified in Caucasian patients with ACHM. Thus, the phenotypic spectrum and the distribution of the CNGA3 and CNGB3 PPVs differed between Asian and Caucasian patients (Figure 5).

The patients carrying the PPVs in the six genes displayed the ACHM-associated phenotypes, including congenital nystagmus, photophobia, color blindness, and extinguished or severely reduced cone response but with normal rod response by ERG. Moreover, some cases showed refractive error, abnormal OCT results, and fundus changes in MD [52].

The VA of patients with PPVs in CNGA3, CNGB3, GNAT2, PDE6C, and ATF6 mostly ranged from 0.05 to 0.20 (Figure 6) and did not show progression with age, whereas the VA of the five patients with PPVs in PDE6H ranged from 0.1 to 0.4. The presence of nystagmus, photophobia, impaired color vision, and cone response by ERG in patients with PPVs in the six genes are summarized in Table 1. A distinguished or severely reduced cone response by ERG was seen in 98.1% (205/209) of the patients with PPVs in CNGA3 and in all of the patients with PPVs in the five other genes (Table 1). A mild to moderate reduced cone response by ERG was seen in four of the 209 patients with PPVs in CNGA3. Furthermore, a mild to moderate reduced rod response by ERG was seen in nine of the 42 patients with PPVs in CNGA3 whose rod response descriptions were available; the other 33 patients showed a normal rod response. Additionally, refractive error was observed in patients carrying the PPVs in the six genes. Hyperopia and myopia were present in patients with PPVs in CNGA3, CNGB3, PDE6C, and ATF6, whereas myopia alone was present in patients age 5 years and older with PPVs in GNAT2 and PDE6H (Appendix 10).

Genotype–phenotype correlations

The various biallelic variant types of the six genes in patients exhibiting different diseases are summarized in Appendix 11. The biallelic variant types of CNGA3 differed between families with ACHM and families with CORD (Appendix 12), and the PPVs in CNGA3 were rare in patients with other diseases. For families with PPVs in CNGB3, the biallelic truncation PPVs were the most common in families with all diseases and did not show differences among different diseases. Therefore, the genotype–phenotype correlation of the six genes remains unclear.

Discussion

In this study, a systematic analysis of the variants and the phenotypes of the six ACHM-associated genes was performed based on variants identified from 7,195 probands with different eye conditions. A total of 92 PPVs were identified in 119 probands exhibiting different genetic eye diseases, including CORD, ACHM, LCA, MD, eoHM, and unclassified IRD, whereas no biallelic PPVs were identified in patients with rod-dominant diseases.

The review of genotypes and phenotypes of the six genes based on previous literature and the present data revealed several characteristics of variants in the investigated genes. First, the truncation variants and the missense variants that could affect the functional domains are evidence of the pathogenicity of these variants. Therefore, a missense variant might be tolerated when it is located outside the functional domains of the genes; examples include any of the first four exons of CNGA3 or any of the five exons of CNGB3 (e.g., c.284C>T, p.Pro95Leu in CNGA3) [43]. Second, different mutation hot spots were identified in Asian and Caucasian patients. The missense variants affecting p.Arg277, p.Arg283, and p.Phe547 were common among Caucasians, whereas those affecting p.Val529 were common among Asians. Five mutational hot spots in CNGB3 were found in Caucasians, and the hot spots were all truncations; none were identified in Asians. All of the reported PPVs in the six genes were rare in the general population with an MAF of less than 1%, mostly less than 0.1%. Thus, it is difficult to set a cut-off allele frequency in control populations to evaluate the pathogenicity of a variant in the six genes. However, an MAF that is significantly higher in patients than in the controls would strongly indicate the pathogenicity of a variant, as is the case for the most common c.1148del variant in CNGB3.

The PPVs in the six genes were all initially identified in patients with ACHM and subsequently identified in patients with other autosomal recessive IRDs, most of which were related to cone-predominant dystrophy, including ACHM and CORD. For phenotypic characteristics, congenital nystagmus or photophobia or both were common symptoms among patients with PPVs in the six genes. Congenital nystagmus or photophobia or both with a normal-like fundus would suggest pathogenic mutations in the six genes. The ERG test is strongly suggested for the function evaluation of cones and rods. Additionally, extinguished or severely reduced cone response with or without mild to moderate reduced rod response would additionally indicate the pathogenicity of the variants in the investigated genes.

Several PPVs in these genes were reported to cause LCA or MD, apart from ACHM and CORD, which are common diseases; in some rare cases, PPVs even caused rod-predominant diseases, including RP and CSNB [17,60]. RP and CSNB were identified in several patients with PPVs in CNGA3, and LCA was identified in patients with PPVs in CNGA3 and CNGB3 [13,15,62]. Seven PPVs in CNGA3 and four PPVs in CNGB3 were identified in families with LCA. All of the 11 known PPVs in the two genes are pathogenic because of truncation variants, at functional domains, or with significantly higher frequencies in patients than in the controls. Additionally, there were two PPVs identified in PDE6C for patients with LCA: One was a truncation variant, and the other was a missense, which was located outside any functional domains but still predicted to be damaging. Five PPVs in CNGA3 were identified in patients with RP. Among these PPVs, three were likely pathogenic, whereas the other two located outside the functional domains were identified only in patients with RP and not in patients with ACHM or CORD. However, the pathogenicity of these variants could not be excluded due to their low frequencies in the controls, and because the variants were predicted to be damaging. Two PPVs in CNGA3 were identified in patients with CSNB: One was a truncation variant, and the other was located at the cGMP-binding domain [17]. In the present data, one missense variant in PDE6C was identified in a proband with eoHM. The proband with eoHM was identified to have biallelic missense PPVs in PDE6C and showed a bilateral corrected VA of 0.2 at the age of 5 years [21]. Unfortunately, the patient’s ERG examination was unavailable. This variant was not identified in previous studies and was located at the functional domain of PDE6C.

In all the families affected by rare diseases, the clinical phenotype of only one patient with LCA was described. This patient, with a homozygous c.1579C>A (p.Leu 527Met) variant, exhibited congenital nystagmus and no visual responses with nonrecordable ERG together which indicated LCA [13]. A similar condition was observed in the proband with LCA from the present cohort. Unfortunately, the clinical descriptions of the five patients with RP or CSNB were not mentioned, except the clinical diagnoses. However, none of the biallelic PPVs in the six genes were identified in probands with RP or CSNB based on the present data from 7,195 probands with different eye conditions.

In summary, a systematic genotype–phenotype analysis of the six genes associated with ACHM was performed based on the present data from 7,195 probands with different eye conditions, along with data reported in the literature. The PPVs in the six genes were identified in various IRDs, most of which are cone-dominant diseases. Clear genotype–phenotype correlations have yet to be established in these genes although the truncation variants of CNGA3 were initially found to be considerably more common in patients with CORD than in patients with ACHM. These results will be valuable for clinical genetic testing involving the investigated genes.

Appendix 1. Rare variants in biallelic status in five of the six genes detected in the 119 probands with genetic eye diseases.

Appendix 2. Clinical information of 51 new probands with pathogenic variants in ACHM-associated genes.

Appendix 3. The 68 reported probands with potential pathogenic variants in three of the six genes.

Appendix 4. Pedigrees of 51 new families with PPVs in the ACHM-associated genes.

Appendix 5. The transfoveal OCT image of seven newly recruited probands.

Appendix 6. Pathogenic variants in the six genes from previous literature except our cohort.

Appendix 7. Variant locations in PDE6C and ATF6.

Appendix 8. Comparison offrequencies between patients and controls from ExAC

Appendix 9. Biallelic pathogenic variants in the six genes and their associated phenotypes reported so far.

Appendix 10. Distribution of the available refractive error in relation to age in patients with PPVs in the investigated genes.

Appendix 11. Variant types of genes in families with different diseases.

Appendix 12. Biallelic variant types in CNGA3 in patients with ACHM and CORD.

Acknowledgments

We thank the patients for their participation. This study is supported by grants from the National Natural Science Foundation of China (81770965, 30971588, 81600768), the Science and Technology Planning Projects of Guangzhou (201607020013), the Natural Science Foundation of Guangdong Province (2015A030310453), and the Fundamental Research Funds of the State Key Laboratory of Ophthalmology.

References

  1. Aboshiha J, Dubis AM, Carroll J, Hardcastle AJ, Michaelides M. The cone dysfunction syndromes. Br J Ophthalmol. 2016; 100:115-21. [PMID: 25770143]
  2. Genead MA, Fishman GA, Rha J, Dubis AM, Bonci DM, Dubra A, Stone EM, Neitz M, Carroll J. Photoreceptor structure and function in patients with congenital achromatopsia. Invest Ophthalmol Vis Sci. 2011; 52:7298-308. [PMID: 21778272]
  3. Eksandh L, Kohl S, Wissinger B. Clinical features of achromatopsia in Swedish patients with defined genotypes. Ophthalmic Genet. 2002; 23:109-20. [PMID: 12187429]
  4. Fahim AT, Khan NW, Zahid S, Schachar IH, Branham K, Kohl S, Wissinger B, Elner VM, Heckenlively JR, Jayasundera T. Diagnostic fundus autofluorescence patterns in achromatopsia. Am J Ophthalmol. 2013; 156:1211-9.
  5. Thiadens AA, Somervuo V, van den Born LI, Roosing S, van Schooneveld MJ, Kuijpers RW, van Moll-Ramirez N, Cremers FP, Hoyng CB, Klaver CC. Progressive loss of cones in achromatopsia: an imaging study using spectral-domain optical coherence tomography. Invest Ophthalmol Vis Sci. 2010; 51:5952-7. [PMID: 20574029]
  6. Nishiguchi KM, Sandberg MA, Gorji N, Berson EL, Dryja TP. Cone cGMP-gated channel mutations and clinical findings in patients with achromatopsia, macular degeneration, and other hereditary cone diseases. Hum Mutat. 2005; 25:248-58. [PMID: 15712225]
  7. Kohl S, Baumann B, Rosenberg T, Kellner U, Lorenz B, Vadala M, Jacobson SG, Wissinger B. Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. Am J Hum Genet. 2002; 71:422-5. [PMID: 12077706]
  8. Thiadens AA, den Hollander AI, Roosing S, Nabuurs SB, Zekveld-Vroon RC, Collin RW, De Baere E, Koenekoop RK, van Schooneveld MJ, Strom TM, van Lith-Verhoeven JJ, Lotery AJ, van Moll-Ramirez N, Leroy BP, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Homozygosity mapping reveals PDE6C mutations in patients with early-onset cone photoreceptor disorders. Am J Hum Genet. 2009; 85:240-7. [PMID: 19615668]
  9. Piri N, Gao YQ, Danciger M, Mendoza E, Fishman GA, Farber DB. A substitution of G to C in the cone cGMP-phosphodiesterase gamma subunit gene found in a distinctive form of cone dystrophy. Ophthalmology. 2005; 112:159-66. [PMID: 15629837]
  10. Ellingford JM, Barton S, Bhaskar S, O’Sullivan J, Williams SG, Lamb JA, Panda B, Sergouniotis PI, Gillespie RL, Daiger SP, Hall G, Gale T, Lloyd IC, Bishop PN, Ramsden SC, Black GCM. Molecular findings from 537 individuals with inherited retinal disease. J Med Genet. 2016; 53:761-7. [PMID: 27208204]
  11. Li S, Huang L, Xiao X, Jia X, Guo X, Zhang Q. Identification of CNGA3 mutations in 46 families: common cause of achromatopsia and cone-rod dystrophies in Chinese patients. JAMA Ophthalmol. 2014; 132:1076-83. [PMID: 24903488]
  12. Bryant L, Lozynska O, Maguire AM, Aleman TS, Bennett J. Prescreening whole exome sequencing results from patients with retinal degeneration for variants in genes associated with retinal degeneration. Clin Ophthalmol. 2017; 12:49-63. [PMID: 29343940]
  13. Wang X, Wang H, Cao M, Li Z, Chen X, Patenia C, Gore A, Abboud EB, Al-Rajhi AA, Lewis RA, Lupski JR, Mardon G, Zhang K, Muzny D, Gibbs RA, Chen R. Whole-exome sequencing identifies ALMS1, IQCB1, CNGA3, and MYO7A mutations in patients with Leber congenital amaurosis. Hum Mutat. 2011; 32:1450-9. [PMID: 21901789]
  14. Patel N, Aldahmesh MA, Alkuraya H, Anazi S, Alsharif H, Khan AO, Sunker A, Al-Mohsen S, Abboud EB, Nowilaty SR, Alowain M, Al-Zaidan H, Al-Saud B, Alasmari A, Abdel-Salam GM, Abouelhoda M, Abdulwahab FM, Ibrahim N, Naim E, Al-Younes B. A E A, AlIssa A, Hashem M, Buzovetsky O, Xiong Y, Monies D, Altassan N, Shaheen R, Al-Hazzaa S A, Alkuraya F S. Expanding the clinical, allelic, and locus heterogeneity of retinal dystrophies. Genet Med. 2016; 18:554-62. [PMID: 26355662]
  15. Carss KJ, Arno G, Erwood M, Stephens J, Sanchis-Juan A, Hull S, Megy K, Grozeva D, Dewhurst E, Malka S, Plagnol V, Penkett C, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, Carmichael J, Chitre M, Henderson RHH, Hurst J, MacLaren RE, Murphy E, Paterson J, Rosser E, Thompson DA, Wakeling E, Ouwehand WH, Michaelides M, Moore AT. Consortium N I-B R D, Webster A R, Raymond F L. Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease. Am J Hum Genet. 2017; 100:75-90. [PMID: 28041643]
  16. Di Iorio V, Karali M, Brunetti-Pierri R, Filippelli M, Di Fruscio G, Pizzo M, Mutarelli M, Nigro V, Testa F, Banfi S, Simonelli F. Clinical and Genetic Evaluation of a Cohort of Pediatric Patients with Severe Inherited Retinal Dystrophies. Genes (Basel). 2017; 8:280
  17. Carrigan M, Duignan E, Malone CP, Stephenson K, Saad T, McDermott C, Green A, Keegan D, Humphries P, Kenna PF, Farrar GJ. Panel-Based Population Next-Generation Sequencing for Inherited Retinal Degenerations. Sci Rep. 2016; 6:33248 [PMID: 27624628]
  18. Huang L, Xiao X, Li S, Jia X, Wang P, Sun W, Xu Y, Xin W, Guo X, Zhang Q. Molecular genetics of cone-rod dystrophy in Chinese patients: New data from 61 probands and mutation overview of 163 probands. Exp Eye Res. 2016; 146:252-8. [PMID: 26992781]
  19. Xu Y, Xiao X, Li S, Jia X, Xin W, Wang P, Sun W, Huang L, Guo X, Zhang Q. Molecular genetics of Leber congenital amaurosis in Chinese: New data from 66 probands and mutation overview of 159 probands. Exp Eye Res. 2016; 149:93-9. [PMID: 27375279]
  20. Xu Y, Guan L, Xiao X, Zhang J, Li S, Jiang H, Jia X, Yang J, Guo X, Yin Y, Wang J, Zhang Q. Mutation analysis in 129 genes associated with other forms of retinal dystrophy in 157 families with retinitis pigmentosa based on exome sequencing. Mol Vis. 2015; 21:477-86. [PMID: 25999675]
  21. Sun W, Huang L, Xu Y, Xiao X, Li S, Jia X, Gao B, Wang P, Guo X, Zhang Q. Exome Sequencing on 298 Probands With Early-Onset High Myopia: Approximately One-Fourth Show Potential Pathogenic Mutations in RetNet Genes. Invest Ophthalmol Vis Sci. 2015; 56:8365-72. [PMID: 26747767]
  22. Zhou L, Xiao X, Li S, Jia X, Zhang Q. Frequent mutations of RetNet genes in eoHM: Further confirmation in 325 probands and comparison with late-onset high myopia based on exome sequencing. Exp Eye Res. 2018; 171:76-91. [PMID: 29453956]
  23. Sun W, Xiao X, Li S, Ouyang J, Li X, Jia X, Liu X, Zhang Q. Rare variants in novel and known genes associated with primary angle closure glaucoma based on whole exome sequencing of 549 probands. J Genet Genomics. 2019; 46:353-7. [PMID: 31377238]
  24. Wang P, Li S, Sun W, Xiao X, Jia X, Liu M, Xu L, Long Y, Zhang Q. An Ophthalmic Targeted Exome Sequencing Panel as a Powerful Tool to Identify Causative Mutations in Patients Suspected of Hereditary Eye Diseases. Transl Vis Sci Technol. 2019; 8:21 [PMID: 31106028]
  25. Huang L, Li S, Xiao X, Jia X, Wang P, Guo X, Zhang Q. Screening for variants in 20 genes in 130 unrelated patients with cone-rod dystrophy. Mol Med Rep. 2013; 7:1779-85. [PMID: 23563732]
  26. Sun W, Zhang Q. Diseases associated with mutations in CNGA3: Genotype-phenotype correlation and diagnostic guideline. Prog Mol Biol Transl Sci. 2019; 161:1-27.
  27. Li S, Xiao X, Yi Z, Sun W, Wang P, Zhang Q. RPE65 mutation frequency and phenotypic variation according to exome sequencing in a tertiary centre for genetic eye diseases in China. Acta Ophthalmol. 2020; 98:e181-90. [PMID: 31273949]
  28. Kohl S, Marx T, Giddings I, Jagle H, Jacobson SG, Apfelstedt-Sylla E, Zrenner E, Sharpe LT, Wissinger B. Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nat Genet. 1998; 19:257-9. [PMID: 9662398]
  29. Wissinger B, Gamer D, Jagle H, Giorda R, Marx T, Mayer S, Tippmann S, Broghammer M, Jurklies B, Rosenberg T, Jacobson SG, Sener EC, Tatlipinar S, Hoyng CB, Castellan C, Bitoun P, Andreasson S, Rudolph G, Kellner U, Lorenz B, Wolff G, Verellen-Dumoulin C, Schwartz M, Cremers FP, Apfelstedt-Sylla E, Zrenner E, Salati R, Sharpe LT, Kohl S. CNGA3 mutations in hereditary cone photoreceptor disorders. Am J Hum Genet. 2001; 69:722-37. [PMID: 11536077]
  30. Johnson S, Michaelides M, Aligianis IA, Ainsworth JR, Mollon JD, Maher ER, Moore AT, Hunt DM. Achromatopsia caused by novel mutations in both CNGA3 and CNGB3. J Med Genet. 2004; 41:e20 [PMID: 14757870]
  31. Kellner U, Wissinger B, Kohl S, Kraus H, Foerster MH. Molecular genetic findings in patients with congenital cone dysfunction. Mutations in the CNGA3, CNGB3, or GNAT2 genes Ophthalmologe. 2004; 101:830-5. [PMID: 15459792]
  32. Varsanyi B, Wissinger B, Kohl S, Koeppen K, Farkas A. Clinical and genetic features of Hungarian achromatopsia patients. Mol Vis. 2005; 11:996-1001. [PMID: 16319819]
  33. Goto-Omoto S, Hayashi T, Gekka T, Kubo A, Takeuchi T, Kitahara K. Compound heterozygous CNGA3 mutations (R436W, L633P) in a Japanese patient with congenital achromatopsia. Vis Neurosci. 2006; 23:395-402. [PMID: 16961972]
  34. Wiszniewski W, Lewis RA, Lupski JR. Achromatopsia: the CNGB3 p.T383fsX mutation results from a founder effect and is responsible for the visual phenotype in the original report of uniparental disomy 14. Hum Genet. 2007; 121:433-9. [PMID: 17265047]
  35. Ahuja Y, Kohl S, Traboulsi EI. CNGA3 mutations in two United Arab Emirates families with achromatopsia. Mol Vis. 2008; 14:1293-7. [PMID: 18636117]
  36. Koeppen K, Reuter P, Kohl S, Baumann B, Ladewig T, Wissinger B. Functional analysis of human CNGA3 mutations associated with colour blindness suggests impaired surface expression of channel mutants A3(R427C) and A3(R563C). Eur J Neurosci. 2008; 27:2391-401. [PMID: 18445228]
  37. Reuter P, Koeppen K, Ladewig T, Kohl S, Baumann B, Wissinger B. Achromatopsia Clinical Study G. Mutations in CNGA3 impair trafficking or function of cone cyclic nucleotide-gated channels, resulting in achromatopsia. Hum Mutat. 2008; 29:1228-36. [PMID: 18521937]
  38. Thiadens AA, Slingerland NW, Roosing S, van Schooneveld MJ, van Lith-Verhoeven JJ, van Moll-Ramirez N, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Genetic etiology and clinical consequences of complete and incomplete achromatopsia. Ophthalmology. 2009; 116:1984-9.
  39. Azam M, Collin RW, Shah ST, Shah AA, Khan MI, Hussain A, Sadeque A, Strom TM, Thiadens AA, Roosing S, den Hollander AI, Cremers FP, Qamar R. Novel CNGA3 and CNGB3 mutations in two Pakistani families with achromatopsia. Mol Vis. 2010; 16:774-81. [PMID: 20454696]
  40. Ding XQ, Fitzgerald JB, Quiambao AB, Harry CS, Malykhina AP. Molecular pathogenesis of achromatopsia associated with mutations in the cone cyclic nucleotide-gated channel CNGA3 subunit. Adv Exp Med Biol. 2010; 664:245-53. [PMID: 20238023]
  41. Koeppen K, Reuter P, Ladewig T, Kohl S, Baumann B, Jacobson SG, Plomp AS, Hamel CP, Janecke AR, Wissinger B. Dissecting the pathogenic mechanisms of mutations in the pore region of the human cone photoreceptor cyclic nucleotide-gated channel. Hum Mutat. 2010; 31:830-9. [PMID: 20506298]
  42. Reicher S, Seroussi E, Gootwine E. A mutation in gene CNGA3 is associated with day blindness in sheep. Genomics. 2010; 95:101-4. [PMID: 19874885]
  43. Thiadens AA, Roosing S, Collin RW, van Moll-Ramirez N, van Lith-Verhoeven JJ, van Schooneveld MJ, den Hollander AI, van den Born LI, Hoyng CB, Cremers FP, Klaver CC. Comprehensive analysis of the achromatopsia genes CNGA3 and CNGB3 in progressive cone dystrophy. Ophthalmology. 2010; 117:825-30.
  44. Zelinger L, Greenberg A, Kohl S, Banin E, Sharon D. An ancient autosomal haplotype bearing a rare achromatopsia-causing founder mutation is shared among Arab Muslims and Oriental Jews. Hum Genet. 2010; 128:261-7. [PMID: 20549516]
  45. Azam M, Collin RW, Malik A, Khan MI, Shah ST, Shah AA, Hussain A, Sadeque A, Arimadyo K, Ajmal M, Azam A, Qureshi N, Bokhari H, Strom TM, Cremers FP, Qamar R, den Hollander AI. Identification of novel mutations in Pakistani families with autosomal recessive retinitis pigmentosa. Arch Ophthalmol. 2011; 129:1377-8. [PMID: 21987686]
  46. Lam K, Guo H, Wilson GA, Kohl S, Wong F. Identification of variants in CNGA3 as cause for achromatopsia by exome sequencing of a single patient. Arch Ophthalmol. 2011; 129:1212-7. [PMID: 21911670]
  47. Saqib MA, Awan BM, Sarfraz M, Khan MN, Rashid S, Ansar M. Genetic analysis of four Pakistani families with achromatopsia and a novel S4 motif mutation of CNGA3. Jpn J Ophthalmol. 2011; 55:676-80. [PMID: 21912902]
  48. Vincent A, Wright T, Billingsley G, Westall C, Heon E. Oligocone trichromacy is part of the spectrum of CNGA3-related cone system disorders. Ophthalmic Genet. 2011; 32:107-13. [PMID: 21268679]
  49. Doucette L, Green J, Black C, Schwartzentruber J, Johnson GJ, Galutira D, Young TL. Molecular genetics of achromatopsia in Newfoundland reveal genetic heterogeneity, founder effects and the first cases of Jalili syndrome in North America. Ophthalmic Genet. 2013; 34:119-29. [PMID: 23362848]
  50. Dubis AM, Cooper RF, Aboshiha J, Langlo CS, Sundaram V, Liu B, Collison F, Fishman GA, Moore AT, Webster AR, Dubra A, Carroll J, Michaelides M. Genotype-dependent variability in residual cone structure in achromatopsia: toward developing metrics for assessing cone health. Invest Ophthalmol Vis Sci. 2014; 55:7303-11. [PMID: 25277229]
  51. Greenberg JP, Sherman J, Zweifel SA, Chen RW, Duncker T, Kohl S, Baumann B, Wissinger B, Yannuzzi LA, Tsang SH. Spectral-domain optical coherence tomography staging and autofluorescence imaging in achromatopsia. JAMA Ophthalmol. 2014; 132:437-45. [PMID: 24504161]
  52. Yang P, Michaels KV, Courtney RJ, Wen Y, Greninger DA, Reznick L, Karr DJ, Wilson LB, Weleber RG, Pennesi ME. Retinal morphology of patients with achromatopsia during early childhood: implications for gene therapy. JAMA Ophthalmol. 2014; 132:823-31. [PMID: 24676353]
  53. Chen XT, Huang H, Chen YH, Dong LJ, Li XR, Zhang XM. Achromatopsia caused by novel missense mutations in the CNGA3 gene. Int J Ophthalmol. 2015; 8:910-5. [PMID: 26558200]
  54. Liang X, Dong F, Li H, Li H, Yang L, Sui R. Novel CNGA3 mutations in Chinese patients with achromatopsia. Br J Ophthalmol. 2015; 99:571-6. [PMID: 25637600]
  55. Saqib MA, Nikopoulos K, Ullah E, Sher Khan F, Iqbal J, Bibi R, Jarral A, Sajid S, Nishiguchi KM, Venturini G, Ansar M, Rivolta C. Homozygosity mapping reveals novel and known mutations in Pakistani families with inherited retinal dystrophies. Sci Rep. 2015; 5:9965 [PMID: 25943428]
  56. Shaikh RS, Reuter P, Sisk RA, Kausar T, Shahzad M, Maqsood MI, Yousif A, Ali M, Riazuddin S, Wissinger B, Ahmed ZM. Homozygous missense variant in the human CNGA3 channel causes cone-rod dystrophy. Eur J Hum Genet. 2015; 23:473-80. [PMID: 25052312]
  57. Zelinger L, Cideciyan AV, Kohl S, Schwartz SB, Rosenmann A, Eli D, Sumaroka A, Roman AJ, Luo X, Brown C, Rosin B, Blumenfeld A, Wissinger B, Jacobson SG, Banin E, Sharon D. Genetics and Disease Expression in the CNGA3 Form of Achromatopsia: Steps on the Path to Gene Therapy. Ophthalmology. 2015; 122:997-1007. [PMID: 25616768]
  58. Abouelhoda M, Sobahy T, El-Kalioby M, Patel N, Shamseldin H, Monies D, Al-Tassan N, Ramzan K, Imtiaz F, Shaheen R, Alkuraya FS. Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden. Genet Med. 2016; 18:1244-9. [PMID: 27124789]
  59. Kuniyoshi K, Muraki-Oda S, Ueyama H, Toyoda F, Sakuramoto H, Ogita H, Irifune M, Yamamoto S, Nakao A, Tsunoda K, Iwata T, Ohji M, Shimomura Y. Novel mutations in the gene for alpha-subunit of retinal cone cyclic nucleotide-gated channels in a Japanese patient with congenital achromatopsia. Jpn J Ophthalmol. 2016; 60:187-97. [PMID: 27040408]
  60. Li L, Chen Y, Jiao X, Jin C, Jiang D, Tanwar M, Ma Z, Huang L, Ma X, Sun W, Chen J, Ma Y, M’Hamdi O, Govindarajan G, Cabrera PE, Li J, Gupta N, Naeem MA, Khan SN, Riazuddin S, Akram J, Ayyagari R, Sieving PA, Riazuddin SA, Hejtmancik JF. Homozygosity Mapping and Genetic Analysis of Autosomal Recessive Retinal Dystrophies in 144 Consanguineous Pakistani Families. Invest Ophthalmol Vis Sci. 2017; 58:2218-38. [PMID: 28418496]
  61. Lisowska J, Lisowski L, Kelbsch C, Maeda F, Richter P, Kohl S, Zobor D, Strasser T, Stingl K, Zrenner E, Peters T, Wilhelm H, Fischer MD, Wilhelm B. Consortium R-C. Development of a Chromatic Pupillography Protocol for the First Gene Therapy Trial in Patients With CNGA3-Linked Achromatopsia. Invest Ophthalmol Vis Sci. 2017; 58:1274-82. [PMID: 28241315]
  62. Riera M, Navarro R, Ruiz-Nogales S, Mendez P, Bures-Jelstrup A, Corcostegui B, Pomares E. Whole exome sequencing using Ion Proton system enables reliable genetic diagnosis of inherited retinal dystrophies. Sci Rep. 2017; 7:42078 [PMID: 28181551]
  63. Taylor RL, Parry NRA, Barton SJ, Campbell C, Delaney CM, Ellingford JM, Hall G, Hardcastle C, Morarji J, Nichol EJ, Williams LC, Douzgou S, Clayton-Smith J, Ramsden SC, Sharma V, Biswas S, Lloyd IC, Ashworth JL, Black GC, Sergouniotis PI. Panel-Based Clinical Genetic Testing in 85 Children with Inherited Retinal Disease. Ophthalmology. 2017; 124:985-91. [PMID: 28341476]
  64. Zobor D, Werner A, Stanzial F, Benedicenti F, Rudolph G, Kellner U, Hamel C, Andreasson S, Zobor G, Strasser T, Wissinger B, Kohl S, Zrenner E. Consortium R-C. The Clinical Phenotype of CNGA3-Related Achromatopsia: Pretreatment Characterization in Preparation of a Gene Replacement Therapy Trial. Invest Ophthalmol Vis Sci. 2017; 58:821-32. [PMID: 28159970]
  65. Abdelkader E, Brandau O, Bergmann C, AlSalamah N, Nowilaty S, Schatz P. Novel causative variants in patients with achromatopsia. Ophthalmic Genet. 2018; 39:678-83. [PMID: 30289319]
  66. Burkard M, Kohl S, Kratzig T, Tanimoto N, Brennenstuhl C, Bausch AE, Junger K, Reuter P, Sothilingam V, Beck SC, Huber G, Ding XQ, Mayer AK, Baumann B, Weisschuh N, Zobor D, Hahn GA, Kellner U, Venturelli S, Becirovic E, Charbel Issa P, Koenekoop RK, Rudolph G, Heckenlively J, Sieving P, Weleber RG, Hamel C, Zong X, Biel M, Lukowski R, Seeliger MW, Michalakis S, Wissinger B, Ruth P. Accessory heterozygous mutations in cone photoreceptor CNGA3 exacerbate CNG channel-associated retinopathy. J Clin Invest. 2018; 128:5663-75. [PMID: 30418171]
  67. Matet A, Kohl S, Baumann B, Antonio A, Mohand-Said S, Sahel JA, Audo I. Multimodal imaging including semiquantitative short-wavelength and near-infrared autofluorescence in achromatopsia. Sci Rep. 2018; 8:5665 [PMID: 29618791]
  68. Mejecase C, Hummel A, Mohand-Said S, Andrieu C, El Shamieh S, Antonio A, Condroyer C, Boyard F, Foussard M, Blanchard S, Letexier M, Saraiva JP, Sahel JA, Zeitz C, Audo I. Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone dystrophy. Clin Genet. 2019; 95:329-333. [PMID: 30267408]
  69. Schallhorn CS, Granet DB, Ferreyra HA. Electronegative Electroretinogram in Achromatopsia. Retin Cases Brief Rep. 2018; 12:143-8. [PMID: 27820752]
  70. Tager J, Kohl S, Birch DG, Wheaton DKH, Wissinger B, Reuter P. An early nonsense mutation facilitates the expression of a short isoform of CNGA3 by alternative translation initiation. Exp Eye Res. 2018; 171:48-53. [PMID: 29499183]
  71. Kohl S, Baumann B, Broghammer M, Jagle H, Sieving P, Kellner U, Spegal R, Anastasi M, Zrenner E, Sharpe LT, Wissinger B. Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Hum Mol Genet. 2000; 9:2107-16. [PMID: 10958649]
  72. Sundin OH, Yang JM, Li Y, Zhu D, Hurd JN, Mitchell TN, Silva ED, Maumenee IH. Genetic basis of total colourblindness among the Pingelapese islanders. Nat Genet. 2000; 25:289-93. [PMID: 10888875]
  73. Rojas CV, Maria LS, Santos JL, Cortes F, Alliende MA. A frameshift insertion in the cone cyclic nucleotide gated cation channel causes complete achromatopsia in a consanguineous family from a rural isolate. Eur J Hum Genet. 2002; 10:638-42. [PMID: 12357335]
  74. Peng C, Rich ED, Varnum MD. Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels. J Biol Chem. 2003; 278:34533-40. [PMID: 12815043]
  75. Michaelides M, Aligianis IA, Ainsworth JR, Good P, Mollon JD, Maher ER, Moore AT, Hunt DM. Progressive cone dystrophy associated with mutation in CNGB3. Invest Ophthalmol Vis Sci. 2004; 45:1975-82. [PMID: 15161866]
  76. Okada A, Ueyama H, Toyoda F, Oda S, Ding WG, Tanabe S, Yamade S, Matsuura H, Ohkubo I, Kani K. Functional role of hCngb3 in regulation of human cone cng channel: effect of rod monochromacy-associated mutations in hCNGB3 on channel function. Invest Ophthalmol Vis Sci. 2004; 45:2324-32. [PMID: 15223812]
  77. Kohl S, Varsanyi B, Antunes GA, Baumann B, Hoyng CB, Jagle H, Rosenberg T, Kellner U, Lorenz B, Salati R, Jurklies B, Farkas A, Andreasson S, Weleber RG, Jacobson SG, Rudolph G, Castellan C, Dollfus H, Legius E, Anastasi M, Bitoun P, Lev D, Sieving PA, Munier FL, Zrenner E, Sharpe LT, Cremers FP, Wissinger B. CNGB3 mutations account for 50% of all cases with autosomal recessive achromatopsia. Eur J Hum Genet. 2005; 13:302-8. [PMID: 15657609]
  78. Khan NW, Wissinger B, Kohl S, Sieving PA. CNGB3 achromatopsia with progressive loss of residual cone function and impaired rod-mediated function. Invest Ophthalmol Vis Sci. 2007; 48:3864-71. [PMID: 17652762]
  79. Andersen MK, Christoffersen NL, Sander B, Edmund C, Larsen M, Grau T, Wissinger B, Kohl S, Rosenberg T. Oligocone trichromacy: clinical and molecular genetic investigations. Invest Ophthalmol Vis Sci. 2010; 51:89-95. [PMID: 19797231]
  80. Thiadens AA, Phan TM, Zekveld-Vroon RC, Leroy BP, van den Born LI, Hoyng CB, Klaver CC. Writing Committee for the Cone Disorders Study Group C, Roosing S, Pott J W, van Schooneveld M J, van Moll-Ramirez N, van Genderen M M, Boon C J, den Hollander A I, Bergen A A, De Baere E, Cremers F P, Lotery A J. Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy. Ophthalmology. 2012; 119:819-26. [PMID: 22264887]
  81. Corton M, Nishiguchi KM, Avila-Fernandez A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, Ayuso C, Rivolta C. Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS One. 2013; 8:e65574 [PMID: 23940504]
  82. Huang L, Zhang Q, Li S, Guan L, Xiao X, Zhang J, Jia X, Sun W, Zhu Z, Gao Y, Yin Y, Wang P, Guo X, Wang J, Zhang Q. Exome sequencing of 47 chinese families with cone-rod dystrophy: mutations in 25 known causative genes. PLoS One. 2013; 8:e65546 [PMID: 23776498]
  83. Wawrocka A, Kohl S, Baumann B, Walczak-Sztulpa J, Wicher K, Skorczyk-Werner A, Krawczynski MR. Five novel CNGB3 gene mutations in Polish patients with achromatopsia. Mol Vis. 2014; 20:1732-9. [PMID: 25558176]
  84. Habibi I, Chebil A, Falfoul Y, Allaman-Pillet N, Kort F, Schorderet DF, El Matri L. Identifying mutations in Tunisian families with retinal dystrophy. Sci Rep. 2016; 6:37455
  85. Langlo CS, Patterson EJ, Higgins BP, Summerfelt P, Razeen MM, Erker LR, Parker M, Collison FT, Fishman GA, Kay CN, Zhang J, Weleber RG, Yang P, Wilson DJ, Pennesi ME, Lam BL, Chiang J, Chulay JD, Dubra A, Hauswirth WW, Carroll J. Group A-S. Residual Foveal Cone Structure in CNGB3-Associated Achromatopsia. Invest Ophthalmol Vis Sci. 2016; 57:3984-95. [PMID: 27479814]
  86. Weisschuh N, Mayer AK, Strom TM, Kohl S, Glockle N, Schubach M, Andreasson S, Bernd A, Birch DG, Hamel CP, Heckenlively JR, Jacobson SG, Kamme C, Kellner U, Kunstmann E, Maffei P, Reiff CM, Rohrschneider K, Rosenberg T, Rudolph G, Vamos R, Varsanyi B, Weleber RG, Wissinger B. Mutation Detection in Patients with Retinal Dystrophies Using Targeted Next Generation Sequencing. PLoS One. 2016; 11:e0145951 [PMID: 26766544]
  87. Ellingford JM, Campbell C, Barton S, Bhaskar S, Gupta S, Taylor RL, Sergouniotis PI, Horn B, Lamb JA, Michaelides M, Webster AR, Newman WG, Panda B, Ramsden SC, Black GC. Validation of copy number variation analysis for next-generation sequencing diagnostics. Eur J Hum Genet. 2017; 25:719-24. [PMID: 28378820]
  88. Mayer AK, Van Cauwenbergh C, Rother C, Baumann B, Reuter P, De Baere E, Wissinger B, Kohl S, Group AS. CNGB3 mutation spectrum including copy number variations in 552 achromatopsia patients. Hum Mutat. 2017; 38:1579-91. [PMID: 28795510]
  89. Dedania VS, Liu JY, Schlegel D, Andrews CA, Branham K, Khan NW, Musch DC, Heckenlively JR, Jayasundera KT. Reliability of kinetic visual field testing in children with mutation-proven retinal dystrophies: Implications for therapeutic clinical trials. Ophthalmic Genet. 2018; 39:22-8. [PMID: 28704108]
  90. Chang B, Grau T, Dangel S, Hurd R, Jurklies B, Sener EC, Andreasson S, Dollfus H, Baumann B, Bolz S, Artemyev N, Kohl S, Heckenlively J, Wissinger B. A homologous genetic basis of the murine cpfl1 mutant and human achromatopsia linked to mutations in the PDE6C gene. Proc Natl Acad Sci USA. 2009; 106:19581-6. [PMID: 19887631]
  91. Grau T, Artemyev NO, Rosenberg T, Dollfus H, Haugen OH, Cumhur Sener E, Jurklies B, Andreasson S, Kernstock C, Larsen M, Zrenner E, Wissinger B, Kohl S. Decreased catalytic activity and altered activation properties of PDE6C mutants associated with autosomal recessive achromatopsia. Hum Mol Genet. 2011; 20:719-30. [PMID: 21127010]
  92. Boulanger-Scemama E, El Shamieh S, Demontant V, Condroyer C, Antonio A, Michiels C, Boyard F, Saraiva JP, Letexier M, Souied E, Mohand-Said S, Sahel JA, Zeitz C, Audo I. Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation. Orphanet J Rare Dis. 2015; 10:85 [PMID: 26103963]
  93. Porto FBO, Jones EM, Branch J, Soens ZT, Maia IM, Sena I F G, Sampaio S A M, Simoes RT, Chen R. Molecular Screening of 43 Brazilian Families Diagnosed with Leber Congenital Amaurosis or Early-Onset Severe Retinal Dystrophy. Genes (Basel). 2017; 8:355 [PMID: 29186038]
  94. Weisschuh N, Stingl K, Audo I, Biskup S, Bocquet B, Branham K, Burstedt MS, De Baere E, De Vries MJ, Golovleva I, Green A, Heckenlively J, Leroy BP, Meunier I, Traboulsi E, Wissinger B, Kohl S. Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia. Hum Mutat. 2018; 39:1366-71. [PMID: 30080950]
  95. Aligianis IA, Forshew T, Johnson S, Michaelides M, Johnson CA, Trembath RC, Hunt DM, Moore AT, Maher ER. Mapping of a novel locus for achromatopsia (ACHM4) to 1p and identification of a germline mutation in the alpha subunit of cone transducin (GNAT2). J Med Genet. 2002; 39:656-60. [PMID: 12205108]
  96. Pina AL, Baumert U, Loyer M, Koenekoop RK. A three base pair deletion encoding the amino acid (lysine-270) in the alpha-cone transducin gene. Mol Vis. 2004; 10:265-71. [PMID: 15094710]
  97. Rosenberg T, Baumann B, Kohl S, Zrenner E, Jorgensen AL, Wissinger B. Variant phenotypes of incomplete achromatopsia in two cousins with GNAT2 gene mutations. Invest Ophthalmol Vis Sci. 2004; 45:4256-62. [PMID: 15557429]
  98. Ouechtati F, Merdassi A, Bouyacoub Y, Largueche L, Derouiche K, Ouragini H, Nouira S, Tiab L, Baklouti K, Rebai A, Schorderet DF, Munier FL, Zografos L, Abdelhak S, El Matri L. Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene. J Hum Genet. 2011; 56:22-8. [PMID: 21107338]
  99. Ueno S, Nakanishi A, Kominami T, Ito Y, Hayashi T, Yoshitake K, Kawamura Y, Tsunoda K, Iwata T, Terasaki H. In vivo imaging of a cone mosaic in a patient with achromatopsia associated with a GNAT2 variant. Jpn J Ophthalmol. 2017; 61:92-8. [PMID: 27718025]
  100. Thuerauf DJ, Marcinko M, Belmont PJ, Glembotski CC. Effects of the isoform-specific characteristics of ATF6 alpha and ATF6 beta on endoplasmic reticulum stress response gene expression and cell viability. J Biol Chem. 2007; 282:22865-78. [PMID: 17522056]
  101. Ansar M, Santos-Cortez RL, Saqib MA, Zulfiqar F, Lee K, Ashraf NM, Ullah E, Wang X, Sajid S, Khan FS. Amin-ud-Din M, University of Washington Center for Mendelian G, Smith J D, Shendure J, Bamshad M J, Nickerson D A, Hameed A, Riazuddin S, Ahmed Z M, Ahmad W, Leal S M. Mutation of ATF6 causes autosomal recessive achromatopsia. Hum Genet. 2015; 134:941-50. [PMID: 26063662]
  102. Kohl S, Zobor D, Chiang WC, Weisschuh N, Staller J, Gonzalez Menendez I, Chang S, Beck SC, Garcia Garrido M, Sothilingam V, Seeliger MW, Stanzial F, Benedicenti F, Inzana F, Heon E, Vincent A, Beis J, Strom TM, Rudolph G, Roosing S, Hollander AI, Cremers FP, Lopez I, Ren H, Moore AT, Webster AR, Michaelides M, Koenekoop RK, Zrenner E, Kaufman RJ, Tsang SH, Wissinger B, Lin JH. Mutations in the unfolded protein response regulator ATF6 cause the cone dysfunction disorder achromatopsia. Nat Genet. 2015; 47:757-65. [PMID: 26029869]
  103. Xu M, Gelowani V, Eblimit A, Wang F, Young MP, Sawyer BL, Zhao L, Jenkins G, Creel DJ, Wang K, Ge Z, Wang H, Li Y, Hartnett ME, Chen R. ATF6 Is Mutated in Early Onset Photoreceptor Degeneration With Macular Involvement. Invest Ophthalmol Vis Sci. 2015; 56:3889-95. [PMID: 26070061]
  104. Sieber J, Hauer C, Bhuvanagiri M, Leicht S, Krijgsveld J, Neu-Yilik G, Hentze MW, Kulozik AE. Proteomic Analysis Reveals Branch-specific Regulation of the Unfolded Protein Response by Nonsense-mediated mRNA Decay. Mol Cell Proteomics. 2016; 15:1584-97. [PMID: 26896796]
  105. Skorczyk-Werner A, Chiang WC, Wawrocka A, Wicher K, Jarmuz-Szymczak M, Kostrzewska-Poczekaj M, Jamsheer A, Ploski R, Rydzanicz M, Pojda-Wilczek D, Weisschuh N, Wissinger B, Kohl S, Lin JH, Krawczynski MR. Autosomal recessive cone-rod dystrophy can be caused by mutations in the ATF6 gene. Eur J Hum Genet. 2017; 25:1210-6. [PMID: 28812650]
  106. Kohl S, Coppieters F, Meire F, Schaich S, Roosing S, Brennenstuhl C, Bolz S, van Genderen MM, Riemslag FC. European Retinal Disease C, Lukowski R, den Hollander A I, Cremers F P, De Baere E, Hoyng C B, Wissinger B. A nonsense mutation in PDE6H causes autosomal-recessive incomplete achromatopsia. Am J Hum Genet. 2012; 91:527-32. [PMID: 22901948]
  107. Pedurupillay CR, Landsend EC, Vigeland MD, Ansar M, Frengen E, Misceo D, Stromme P. Segregation of Incomplete Achromatopsia and Alopecia Due to PDE6H and LPAR6 Variants in a Consanguineous Family from Pakistan. Genes (Basel). 2016; 7:41 [PMID: 27472364]
  108. Abouelhoda M, Faquih T, El-Kalioby M, Alkuraya FS. Revisiting the morbid genome of Mendelian disorders. Genome Biol. 2016; 17:235 [PMID: 27884173]