Cone and Cone–Rod Dystrophies

Non-syndromic progressive cone dystrophy (COD) and cone–rod dystrophy (CORD), with the subtypes by gene (ABCA4, GUCY2D, CRX, GUCA1A, PRPH2, PROM1, RPGR, KCNV2, ADAM9, CDHR1, CERKL, RAB28, POC1B, TTLL5 and others), the syndromic forms with CORD (Alström, Jalili, spondylometaphyseal dysplasia with CORD, CORD with short stature) and, as differential diagnoses, achromatopsia and blue cone monochromatism.

Literature and regulatory information updated: 10 October 2026.

0. Initial Reference Table

The following table brings together the entities within scope, with the MANE Select (Matched Annotation from NCBI and EMBL-EBI) reference transcript when it was confirmed in VariantValidator and the GeneGuidance RefSeq in the other cases [22, 23].

1. Introduction

1.1. Definition and place among inherited retinal dystrophies

The outer retina has two types of photoreceptors with complementary functions. Cones function in bright illumination and sustain fine visual acuity and colour discrimination; rods function at low luminance and serve the peripheral visual field and motion detection. Inherited photoreceptor dystrophies are classified by the cell population predominantly affected (rods, cones or both) and by the presence of macular involvement; by 2017 more than 200 genes associated with this group were known [69]. Pure cone or rod dystrophies are rare, and most diseases involve both photoreceptors with predominance of one of them [69].

Cone–rod dystrophy (CORD, also abbreviated CRD) is an isolated inherited retinal disease characterised by primary degeneration of the cones, with significant secondary involvement of the rods and a variable fundus appearance. The typical presentation includes reduced visual acuity, central scotoma, photophobia and altered colour vision, followed by night blindness and loss of the peripheral field [1]. Hamel described CORD as belonging to the pigmentary retinopathies, with the reverse sequence of retinitis pigmentosa (RP): the cones are affected first, or cones and rods simultaneously, reduced acuity is the earliest symptom and nyctalopia appears later and is never as prominent as in RP [10]. For this reason CORD has also been called «inverse» or «central» RP [4]. In RP, or rod–cone dystrophy, early loss is of the rods (nyctalopia and mid-peripheral field loss) and the foveal cones are affected late; in the end stage the two diseases may become clinically indistinguishable [10, 70].

Progressive cone dystrophy (COD) is the form in which cone dysfunction dominates the presentation, with photophobia, progressive loss of visual acuity, central visual field changes, abnormal colour vision and psychophysical and electrophysiological evidence of cone dysfunction; it usually presents in childhood or early adulthood, with a tendency to develop rod dysfunction later [2]. In a cohort of 98 probands with COD followed for a mean of 19 years, 37% developed rod involvement on the electroretinogram, which shows that the boundary between COD and CORD is partly a question of stage [13].

1.2. Electrophysiological classification

The operational classification rests on the full-field electroretinogram (ffERG). In macular dystrophy the ffERG is normal and the dysfunction is confined to the macula; in cone dystrophy only the photopic responses are reduced; in CORD both photopic and scotopic responses are reduced [16, 70]. The classification of the same patient may change from macular dystrophy to COD or CORD as the disease progresses [16]. The AAO groups cone–rod degenerations in its category 2 and places «cone degeneration» among the dystrophies with macular involvement of category 4, with common assessment protocols [14].

Cone diseases are also divided into stationary and progressive. Cone dysfunction syndromes (complete and incomplete achromatopsia, blue cone monochromatism, Bornholm eye disease, oligocone trichromacy and bradyopsia) have congenital or early childhood onset, pure cone dysfunction and a stable course in most patients; progressive cone dystrophies begin later and generally progress with rod involvement [9, 11]. Overlap exists in both directions: a minority of patients with achromatopsia have limited progression, and blue cone monochromatism, generally stationary, may progress [9].

The 2021 French national diagnosis and care protocol (PNDS) of the Haute Autorité de Santé (HAS) for genetic maculopathies places pure cone dystrophy at the boundary between the maculopathies and the mixed dystrophies: it shares with the former the reduced vision, central scotoma and dyschromatopsia, but the genes are the same as in CORD, and the separation between pure cone dystrophy and CORD is, according to the document, clinical and not genetic, reflecting the severity of the variants and not the gene [19]. For this reason, the maculopathy PNDS covers COD/CORD only as a differential diagnosis and announces a dedicated protocol for these dystrophies [19].

1.3. Historical overview and molecular discovery

Before the molecular era, CORD was mapped to numbered loci. In 2007, Hamel counted 13 genes or loci (10 cloned and 3 only mapped), including CORD1 in a Danish family with intellectual disability, CORD4 in a Canadian family with neurofibromatosis, CORD8 in a Pakistani family, a CORD9 locus in a Brazilian family and CORDX2 at Xq27 [10]. The sequence of gene discoveries allows the pathophysiology of the disease to be read.

In 1989, Nathans and colleagues showed that blue cone monochromatism results from alterations of the red and green opsin gene cluster at Xq28, including deletions of a 579 bp upstream region (the locus control region) essential for expression of both genes [67]. In 1997, Freund and colleagues identified the photoreceptor-specific homeobox gene CRX at the CORD2 locus (19q13), with a missense variant E80A and a 1 bp deletion that truncates the 132 C-terminal residues; this was the founding article of CORD2 and showed that CRX is required for photoreceptor maintenance [27]. In 1998, Kelsell and colleagues mapped CORD6 to 17p12-p13 and found dominant variants in the retinal guanylate cyclase gene GUCY2D (RETGC-1), until then linked to recessive Leber congenital amaurosis (LCA) [71]. In the same year, Payne and colleagues described the p.(Tyr99Cys) variant of GUCA1A, which encodes guanylate cyclase-activating protein 1 (GCAP1), in a British family with AD cone dystrophy linked to 6p21.1 [72], and Cremers and colleagues demonstrated that the Stargardt disease gene (ABCR, now ABCA4) causes AR CORD and RP in a consanguineous family with pseudodominance, establishing the model in which severity follows the loss of residual function (Stargardt less severe than CORD, and the latter less severe than RP) [73].

In 2002, Demirci and colleagues reassigned X-linked CORD from the COD1 locus to RPGR exon ORF15 [33]. There followed KCNV2 in «cone dystrophy with supernormal rod ERG» (Wu 2006) [35], ADAM9 in four consanguineous families with early-onset AR CORD (Parry 2009) [37], CNNM4 in Jalili syndrome (Parry 2009; Polok 2009) [74, 75], PCDH21, now CDHR1 (Henderson 2010; Ostergaard 2010) [39, 76], RAB28 (Roosing 2013) [77], POC1B (Roosing 2014; Durlu 2014) [45, 78], TTLL5 (Sergouniotis 2014) [79] and PCYT1A in spondylometaphyseal dysplasia with CORD (Hoover-Fong 2014; Yamamoto 2014) [80, 81]. In 2019, the review by Gill and colleagues counted at least 30 COD/CORD genes [9].

1.4. Reclassifications and nomenclature

Two examples show why historical nomenclature cannot be read as current practice. CORD7, attributed since 2003 to the RIMS1 p.(Arg820His) variant in a four-generation British family, was reassessed by genome sequencing: the nine affected individuals carried the PROM1 c.1117C>T p.(Arg373Cys) variant, one affected individual with macular dystrophy did not have the RIMS1 variant, and the latter had a carrier frequency above 1/5000 in Europeans; the family's disease is fully explained by PROM1 [31]. Reference books that list RIMS1 among CORD genes, and the Gill 2019 review itself, reflect the earlier attribution [9, 69, 82]. Likewise, the GUCA1A p.(Pro50Leu) variant, presented as a cause of CORD, was reclassified as likely benign after a pathogenic variant in RPGR was found in the original family [11].

Several genes have changed name: RDS became PRPH2, ABCR became ABCA4, PCDH21 became CDHR1, C8orf37 became CFAP418 and C21orf2 became CFAP410 [4, 9, 76]. The designation «cone dystrophy with supernormal rod response» is retained by tradition, although rod function is not psychophysically enhanced [9, 11]. CRB1, often included in inherited retinal dystrophy gene lists, does not appear in the Orphanet list of CORD genes or in the Gill 2019 table of COD/CORD genes; the sources consulted associate it with LCA, early-onset retinal dystrophy, RP with or without Coats-like vasculopathy and maculopathy, and the only observation in a cohort of macular and cone dystrophies was a homozygous patient with late-onset macular dystrophy at 49 years [1, 9, 11, 16]. For this reason, CRB1 is treated in this article as a differential diagnosis and not as an established CORD gene.

1.5. Scope of the article

This article covers non-syndromic COD and CORD and their subtypes by gene, including KCNV2-associated cone dystrophy, GUCA1A-associated COD/CORD and PROM1 bull's-eye maculopathy. The syndromic forms in which CORD is the ocular manifestation (Alström, Jalili and Bardet-Biedl syndromes, spondylometaphyseal dysplasia with CORD and CORD with short stature) are described insofar as they bear on recognition and differential diagnosis. ABCA4-associated retinopathy, LCA and early-onset dystrophies, RP and Best disease, as well as achromatopsia and blue cone monochromatism, enter as differential diagnoses.

2. Molecular Genetics and Pathophysiology

2.1. Cellular pathways affected

COD/CORD genes encode proteins of at least six cellular processes, and the location of the lesion explains part of the differences between phenotypes. The first is phototransduction and its recovery. Absorption of a photon converts 11-cis-retinal into all-trans-retinal; the activated opsin activates transducin, whose α subunit activates phosphodiesterase 6 (PDE6) by removing the inhibitory γ subunits; hydrolysis of cyclic guanosine monophosphate (cGMP) closes the cyclic nucleotide-gated (CNG) cation channels and hyperpolarises the cell [5, 9]. In cones, these steps depend on cone transducin α (GNAT2), the α' and γ subunits of cone PDE6 (PDE6C and PDE6H) and the CNG channel formed by three CNGA3 subunits and one CNGB3 [5]. Recovery requires regeneration of cGMP by retinal guanylate cyclase 1 (RetGC1, encoded by GUCY2D), under the control of calcium-sensitive activating proteins (GCAP), of which GCAP1 is encoded by GUCA1A [9]. Gain-of-function variants in these two genes produce excess cGMP in the dark, sustained opening of CNG channels, calcium overload and death of the cones and, later, of the rods [9, 28].

The second process is morphogenesis and renewal of the outer segment discs: peripherin-2 (PRPH2) forms, with ROM1, the disc rim structure; prominin-1 (PROM1) and the cadherin CDHR1 regulate evagination and the formation of new discs; the ABCA4 transporter removes N-retinylidene-phosphatidylethanolamine from the discs, and its loss leads to accumulation of bisretinoids such as A2E in the lipofuscin of the retinal pigment epithelium (RPE) [9, 24, 30, 38]. The third is ciliary transport: RPGR is located in the photoreceptor connecting cilium and depends on RPGRIP1 as a scaffold and on polyglutamylation by TTLL5; POC1B is a basal body protein and RAB28 is required for shedding and phagocytosis of cone discs [32, 44, 46, 48, 83]. The fourth is the interface between the outer segments and the RPE, where the metalloprotease ADAM9 cleaves membrane proteins; in the Adam9−/− mouse the apical processes of the RPE are disorganised at 12 months, before any photoreceptor change, and degeneration appears only at 20 months [36, 37]. The fifth is transcriptional regulation, with the homeodomain factor CRX, which transactivates opsin promoters and cooperates with NRL, RORB and RAX2 [26, 49]. The sixth is synaptic transmission and the ionic physiology of the inner segment, represented by the Cav1.4 calcium channel (CACNA1F), the α2δ4 subunit (CACNA2D4) and the silent modulatory subunit Kv8.2 (KCNV2), which forms heterotetramers with Kv2.1 and modulates the inner segment potassium current [9, 11, 35].

Hamel proposed that, in several of these diseases, photoreceptors die by apoptosis with an approximately constant probability throughout life («one-hit model»), which has implications for the therapeutic intervention window [10].

2.2. Genetic distribution by mode of inheritance

The most widely used estimate of the contribution of each gene comes from the aggregation, by Gill and colleagues, of unrelated probands with COD/CORD published up to November 2018. The gene was identified in 56.3% of patients; among solved cases, ABCA4 explained 62.2% of AR cases, GUCY2D 34.6% of AD cases and RPGR 73.0% of XL cases, and more than 75% of AD cases were attributed to GUCY2D, PRPH2, CRX and GUCA1A; 10 AD, 18 AR and 4 XL genes were counted [9]. These proportions describe published cohorts, not the population distribution. Hamel had estimated, in 2007, that ABCA4 explained 30–60% of AR CORD and CRX 5–10% of dominant CORD [10]. Georgiou and colleagues attribute about 30% of AD COD/CORD to GUCY2D, about 20% to PRPH2 and about 15% to GUCA1A, which together explain 65–70% of AD forms, and about 70% of XL forms to RPGR [11].

Consecutive clinical cohorts give a complementary picture. In 251 consecutive patients with macular dystrophy, COD or CORD from Bonn (Germany, 2012–2015), the most frequent genes were ABCA4 (94 patients, 37%), PRPH2 (29, 12%) and BEST1 (19, 8%), which together explained 57% of all patients and 77% of solved cases; they were followed by CDHR1, GUCY2D and PROM1 (six patients each), CRX (four) and GUCA1A (three) [16]. In the Thiadens cohort, ABCA4 explained 9% of AR COD and 26% of AR CORD, CNGB3 3%, KCNV2 4% and PDE6C 1% of AR COD, and RPGR both XL COD and 4 of 5 XL CORD [13]. In Spain, in cone-dominant phenotypes, ABCA4 explained 82.7% of solved AR cases and PRPH2 42.2% of AD cases [12]. The differences between cohorts reflect inclusion criteria (some include macular dystrophies), referral bias towards centres with an interest in ABCA4 and founder populations [12, 16].

2.3. Autosomal dominant genes

GUCY2D (CORD6). GUCY2D (17p13.1) encodes RetGC1, which synthesises cGMP in the outer segments of rods and cones and allows recovery of phototransduction [23]. The gene causes two non-overlapping conditions. Biallelic loss-of-function variants cause LCA1 (10–20% of non-syndromic LCA) and, rarely, congenital stationary night blindness 1I [6, 23]. Dominant heterozygous variants cause CORD6 and are concentrated in exon 13, which encodes the dimerisation domain (amphipathic helix) of the enzyme [10, 84]. Codon 838 is the hotspot: NM_000180.4:c.2512C>T p.(Arg838Cys) and c.2513G>A p.(Arg838His) [22, 25]. The original CORD6 family had p.(Glu837Asp), and three other families with AD CORD had p.(Arg838Cys) [71]. Tucker and colleagues showed in vitro that p.(Arg838Cys) reduces overall catalytic activity and stimulation by GCAP2, but increases the apparent affinity for GCAP1 and shifts calcium sensitivity, so that the enzyme remains stimulated at calcium concentrations at which it should be inhibited; the result is a dominant gain of function, with abnormal cGMP synthesis in dark-adapted photoreceptors [84]. Rod involvement is milder in families with a single variant than in those with complex alleles [9]. This mechanism has therapeutic consequences: adding a normal copy of the gene, effective in principle in LCA1, does not correct a dominant gain-of-function disease [11, 85].

GUCA1A (COD3/CORD14). GUCA1A (6p21.1) has four exons and encodes GCAP1, with three «EF-hand» calcium-binding motifs [9]. Pathogenic variants, such as p.(Tyr99Cys) in EF-hand 3, p.(Glu155Gly) and p.(Asp100Gly), prevent GCAP1 from switching off RetGC1 when calcium rises, which maintains cGMP synthesis and opening of CNG channels; this is a gain of function [9, 28, 72]. The founder variant p.(Tyr99Cys) corresponds to NM_001384910.1:c.296A>G; the older literature uses transcript NM_000409.x, with identical c. numbering for this variant [22]. In a four-generation British family with p.(Tyr99Cys), different relatives had COD, CORD and isolated macular dysfunction [86]. The p.(Arg120Leu) variant was described in a Chinese family with heterogeneous macular dystrophy [9]. The p.(Pro50Leu) variant (NM_001384910.1:c.149C>T), previously associated with CORD, has been reclassified as likely benign [11, 22]. GUCA1A is frequent in European cohorts and rare in Japan (3 of 1192 families with inherited retinal dystrophy, 0.25%) [28, 87].

CRX (CORD2). CRX (19q13.33) encodes a homeodomain transcription factor that transactivates the TAATC[CA] element upstream of the opsin genes [26]. Heterozygous variants cause a spectrum ranging from LCA and early-onset retinal dystrophy to CORD2, AD macular dystrophy and AD RP (about 1% of AD RP), sometimes within the same pedigree [26, 88, 89]. Freund and colleagues proposed, in the founding article, haploinsufficiency or a dominant negative effect [27]; truncating or frameshift variants that remove the activation domain and preserve DNA binding are associated with an antimorphic effect and more severe disease, and de novo variants are frequent in severe presentations [26, 90]. The variant of the original CORD2 family, E80A, corresponds to NM_000554.6:c.239A>C p.(Glu80Ala) [22, 27]. There are no extraocular manifestations; keratoconus and lens opacities appear as late changes [26].

PRPH2. PRPH2 (6p21.1; formerly RDS) has five exons and encodes peripherin-2, a tetraspanin of the outer segment disc rim [9, 29]. Variants associated with CORD are concentrated in the second, cysteine-rich intradiscal loop: p.(Asn244His), p.(Val200Glu) and p.(Arg172Trp) [9]. p.(Arg172Trp) (NM_000322.5:c.514C>T) has extreme expressivity, ranging from non-penetrance to severe CORD, with RP, macular dystrophy, central areolar choroidal dystrophy and LCA/early-onset dystrophy; it is associated with faster loss of acuity than p.(Arg172Gln) [9, 11, 22]. The p.(Asn244His) and p.(Val200Glu) variants produce early central RPE atrophy with peripheral progression and little intrafamilial variability, and p.(Gly167Asp) is associated with AD RP and butterfly-shaped dystrophy [11]. Intrafamilial variability has been documented since 1993 in a family with deletion of codon 153 or 154, with RP, pattern dystrophy and fundus flavimaculatus [91, 92]. Digenic inheritance of PRPH2 c.554T>C p.(Leu185Pro) with a ROM1 variant causes RP and not CORD [4, 93]. In a large French cohort of cone and cone–rod dystrophies, PRPH2 explained 3.4% of all cases and 11.8% of AD cases [16].

Dominant PROM1. The recurrent variant PROM1 NM_006017.3:c.1117C>T p.(Arg373Cys) causes AD bull's-eye maculopathy, associated with rod, rod–cone or macular dystrophy. The notation c.1118C>T that appears in recent articles does not match the reference sequence (nucleotide 1118 is G); the correct notation, confirmed in VariantValidator and ClinVar (VCV 5610), is c.1117C>T [11, 22, 31]. The mechanism of the AD forms is an effect of the mutant protein on disc morphogenesis and not haploinsufficiency [30]. In five unrelated families, onset ranged from 9 to 58 years, with RPE mottling in young people, bull's-eye maculopathy and later macular atrophy; electrophysiology ranged from isolated maculopathy with normal generalised function to severe rod and cone dysfunction indistinguishable from RP [30, 94]. The OMIM labels for PROM1 (Stargardt 4, retinal macular dystrophy 2, CORD12 and RP41) correspond to points on a continuum [30].

Other AD genes. RAX2 causes AD CORD11 in a family of six members with a heterozygous frameshift variant with a dominant negative effect, with central scotomas, waxy disc pallor, yellow macular deposits and an electronegative bright-flash scotopic ERG; biallelic variants cause AR RP95 [49, 50, 95]. UNC119 (CORD24) has scant evidence: a 57-year-old woman with late-onset CORD and a heterozygous nonsense variant, a transgenic mouse with degeneration and eight Mexican patients with macular or cone-dominant dystrophy [96]. AIPL1 appears in AD CORD gene lists, but ClinGen classified the AD relationship with retinal dystrophy as disputed (April 2025), and an isolated heterozygous variant should not be taken as causal; the well-established disease is AR LCA4 [9, 97]. PITPNM3 is part of the Gill 2019 list of AD genes, without additional clinical data in the sources consulted [9].

2.4. Autosomal recessive genes

ABCA4 (CORD3). ABCA4 (1p22.1; 50 exons) is the most frequent gene in AR CORD. The associated disease forms a continuum determined by residual function: mild alleles, often missense, give late-onset Stargardt disease with foveal sparing; more severe combinations give classical childhood-onset Stargardt; near-complete loss of function gives CORD (CORD3) or RP (RP19) with a severely reduced ERG [9, 24]. More than 1000 causal variants have been described; biallelic null variants are associated with severe, early CORD, and homozygous p.(Gly1961Glu) (NM_000350.3:c.5882G>A) with mild disease [9, 22]. Hamel noted that truncating variants, often biallelic, are associated with CORD and missense variants with Stargardt disease [10]. In Spain, the c.3386G>T p.(Arg1129Leu) variant is the most frequent in cone-dominant phenotypes and is almost exclusive to the Spanish population, accounting for 19.4% of alleles in the Basque Country [12, 22]. The heterozygote frequency, estimated at about 0.02 since 1998, explains pseudodominance [73]. ABCA4-associated retinopathy has its own genetics, natural history and therapeutic trials.

KCNV2. KCNV2 (9p24.2) encodes the Kv8.2 subunit, which does not form functional channels on its own and modulates the activation of Kv2.1 channels in the inner segment of cones and rods [11, 34]. The disease is AR and KCNV2 is the only gene of the entity «cone dystrophy with supernormal rod response» [34]. Wu and colleagues identified the gene by homozygosity mapping in a consanguineous family and found variants on 17 alleles in 10 other families [35]. In the international report of 117 patients, 75 variants were described on 230 alleles, 28 of them novel; patients with missense variants had better acuity and retinal structure [11, 98].

ADAM9 (CORD9). Biallelic null variants of ADAM9 (8p11.22) cause early-onset, progressive AR CORD [36, 37]. ClinGen classified the ADAM9–AR retinopathy relationship as definitive (September 2022) [36]. In a consanguineous Egyptian family, severe CORD was associated with cataract and, in one son, a coloboma-like macular lesion [99]. The proportion of AR CORD explained by ADAM9 has not been determined, and ClinVar records 269 variants of uncertain significance, a reflection of the gene's inclusion in panels [36].

CDHR1 (CORD15). CDHR1 (10q23.1; formerly PCDH21) encodes a photoreceptor-specific cadherin required for disc morphogenesis [38]. The first families had homozygous deletions with nyctalopia in late adolescence, good central vision until the late 30s and circular RPE atrophy in the macula and periphery [76]. In the Faroe Islands, the duplication NM_033100.4:c.524dup p.(Asn176GlufsTer48) (described in the original article as «c.524dupA p.Q175QfsX47») explains practically all pathogenic alleles, with a carrier frequency of 1/53 [22, 38, 39]. Hypomorphic variants give RP with relative cone preservation or late-onset macular dystrophy, which may mimic geographic atrophy of age-related macular degeneration [38, 100, 101].

CERKL. CERKL (2q31.3) encodes a protein without ceramide kinase activity, involved in protection against oxidative stress, autophagy and mitochondrial homeostasis [40, 102]. OMIM classifies the disease as RP26 [103], but the phenotype frequently includes early macular involvement and CORD. The nomenclature requires attention to the transcript: the MANE Select is NM_201548.5, and the Iberian founder variant «R257X» corresponds to NM_201548.5:c.769C>T p.(Arg257Ter), equivalent to NM_001030311.3:c.847C>T p.(Arg283Ter) in the long isoform used in the Brazilian cohort; c.847C>T on the MANE transcript would be a different variant, p.(Leu283Phe) [22, 41]. Other founder variants are c.238+1G>A in Yemenite Jews and c.375C>G p.(Cys125Trp) in Finland (both on NM_201548.5) [22, 40, 104].

RAB28 (CORD18). RAB28 encodes a small farnesylated GTPase located in the cone cilium, the ciliary rootlet and the RPE, required for disc shedding and phagocytosis; variants impair GTPase activity, with accumulation of membranous material that explains foveal hyperautofluorescence [77, 83]. p.(Thr26Asn) locks the protein in the inactive GDP-bound form [42]. The NM_001017979.3:c.68C>T p.(Ser23Phe) variant was described in the homozygous state in a Korean patient and a Haitian patient, and in apparent hemizygosity due to a de novo deletion of the maternal allele in a Korean child [22, 83, 105]. In Portugal, homozygous p.(His144Tyr) is a probable founder variant [43].

POC1B (CORD20) and TTLL5 (CORD19). POC1B encodes a basal body protein; the variants NP_758440.1:p.(Arg106Pro) and p.(Gln67del) (published protein designations, concordant with the MANE transcript NM_172240.3) lose basal body localisation and interaction with FAM161A [45]. An Iraqi family with LCA, Joubert syndrome and polycystic kidneys is a single observation [44]. TTLL5 encodes a tubulin glutamylase that polyglutamylates the glutamate- and glycine-rich region of RPGR-ORF15, placing the disease in the same ciliary pathway as RPGR [79, 106]. Men with biallelic truncating variants may have severely reduced sperm motility and infertility, unlike carriers of missense variants [46, 47]. Multiexon deletions are a mechanism in TTLL5, which makes copy number variation analysis mandatory when sequencing finds one or no variant [46].

RPGRIP1 (CORD13). RPGRIP1 encodes the connecting cilium scaffold that positions RPGR and causes LCA6 and CORD13 in a single spectrum [48]. In the largest series (18 patients from 17 families), 76% of families were double-null, with earlier onset and worse vision, and almost half of the gene's variants in ClinVar are of uncertain significance [48, 107].

SEMA4A (CORD10). The evidence comes from a Pakistani cohort of 190 patients (135 with RP, 25 with CORD and 30 with LCA), in which NP_071762.2:p.(Asp345His) and p.(Phe350Cys) (published protein designations, concordant with the MANE transcript NM_022367.4) were found only in affected individuals [52]; only p.(Phe350Cys) caused degeneration in a knock-in mouse, and p.(Arg713Gln) was found in unaffected homozygous relatives and is probably non-pathogenic [51]. A heterozygous frameshift variant was found in a 48-year-old patient with an atrophic macular lesion in the Bonn cohort [16]. Inheritance remains uncertain (AR according to OMIM, AD according to Orphanet) [51].

Genes allelic with achromatopsia. PDE6C causes complete achromatopsia and early-onset AR COD (COD4); Thiadens and colleagues identified it by homozygosity mapping in siblings with early COD and others with incomplete achromatopsia, and concluded that the two entities overlap genetically and clinically [108]. PDE6C explains about 1.4% of families with achromatopsia (15 of 1074) [109]. CNGA3, CNGB3 and GNAT2 cause, in addition to achromatopsia, AR progressive cone dystrophy, often distinguishable from achromatopsia only by documented progression [5]. The CNGB3 variant p.(Arg403Gln) in compound heterozygosity with p.(Thr383IlefsTer13) (NM_019098.5:c.1148del, the most common achromatopsia allele) is associated with progressive cone dystrophy, and digenic or triallelic inheritance with p.(Arg403Gln) has been described [11, 22]. ATF6, a transcription factor of the unfolded protein response, causes achromatopsia 7 and also AR CORD and macular dystrophy, by a mechanism of cone selectivity that is still unknown [5, 55].

Recessive PROM1 and other AR genes. Biallelic null variants of PROM1 cause panretinal CORD with early macular involvement and severe loss of acuity, generally by 20 years of age, in a two-centre series of 19 consecutive patients [110]; the first families had severe early-onset retinal degeneration and AR RP with early macular atrophy due to a frameshift subject to nonsense-mediated decay (NMD) [111, 112]. CFAP418 (C8orf37) causes CORD16 with polydactyly and is allelic with Bardet-Biedl syndrome 21 [8]. CEP78 and CFAP410 (C21orf2) are ciliogenesis genes on the Gill 2019 list [9]. DRAM2 caused CORD in two Portuguese sisters homozygous for c.517+5C>A (NM_001349884.2), with onset at 30 years and absence of normal transcript in leucocyte RNA [43].

2.5. X-linked genes

RPGR (CORDX1). RPGR (Xp11.4) has 19 exons; the ORF15 isoform, formed by exons 1 to 14 and part of intron 15, is the most highly expressed in the retina and contains the mutational hotspot responsible for most XL COD/CORD [9]. Exon ORF15 is repetitive and purine-rich, which makes it difficult to sequence by next-generation sequencing (NGS) and to cover in panels [4, 32]. Variants causing COD/CORD are concentrated at the 3' end of ORF15; the same variant may cause RP and CORD within a family [9, 11]. Demirci and colleagues found, in the COD1 locus families, 2-nucleotide deletions in ORF15 with frameshift and premature termination, and an in-frame 12-nucleotide deletion that did not segregate with the disease and was polymorphic [33]. In Bonn, two in-frame variants in ORF15 (c.2203_2226del and c.2919_2939dup) were not considered causal because they occur in the normal population [16]. The lesson is that an in-frame variant in ORF15 requires segregation and carrier studies before being considered pathogenic. The MANE Select for RPGR is the ORF15 isoform, NM_001034853.2 [22]; the nomenclature of older articles, such as c.2847_2848delinsCT «p.(E950*)» of Gill 2019, uses other numberings and should not be converted by hand [9]. The mechanism is loss of RPGR function in the connecting cilium, with failure of RAB8A- and RAB37-dependent ciliary trafficking [32]. RPGR is also one of the genes of X-linked primary ciliary dyskinesia, with RP associated with sinorespiratory infections and deafness [32, 113].

CACNA1F (CORDX3). CACNA1F (Xp11.23) encodes the α1F subunit of the Cav1.4 calcium channel of the photoreceptor synapse. The main disease is XL incomplete congenital stationary night blindness (CSNB2A); CORDX3, described in a Finnish family, shares features of CSNB2A with modestly progressive photoreceptor dysfunction, constricted fields, central scotomas and red–green defects [10, 53]. Heterozygous women are generally unaffected [53].

OPN1LW and OPN1MW. The genes for the L (red) and M (green) cone opsins form a tandem cluster at Xq28, of which only the first two genes are expressed; unequal recombination produces hybrid genes and deletions [114, 115]. These genes appear in the list of XL COD genes because of blue cone monochromatism and Bornholm eye disease, which are usually stationary and are covered in the differential diagnosis [9, 11].

2.6. RIMS1 and the refutation of CORD7

RIMS1 encodes an active zone protein of the synapse and is one of the genes of neurodevelopmental SNAREopathies [82]. AD CORD7 was mapped to 6q in a four-generation British family and attributed to the variant NM_014989.7:c.2459G>A p.(Arg820His) (p.Arg844His in another transcript) [22, 116]. Martin-Gutierrez and colleagues found that this variant has a carrier frequency above 1/5000 in Europeans (10 alleles in gnomAD) and is absent in other patients with CORD; genome sequencing of four members revealed PROM1 c.1117C>T p.(Arg373Cys) in the nine affected individuals, and one affected individual with macular dystrophy did not have the RIMS1 variant. The phenotype matched that of 27 individuals with the same PROM1 variant, and the conclusion was that the family's disease is fully explained by PROM1 [31]. ClinGen has no assertion for the gene, GenCC classifications range from disputed to limited, and OMIM records no phenotype for RIMS1 [56]. In practice, a heterozygous RIMS1 variant, including p.(Arg820His), should not be reported as a cause of CORD, and the patient should be studied for PROM1 and the remaining genes. The report of enhanced cognitive abilities in the CORD7 family inherits the same problem [56].

2.7. Nomenclature of reference variants

The following variants were normalised in VariantValidator (GRCh38, MANE Select transcripts) and, where indicated, confirmed in ClinVar on 10 October 2026 [22]. Variants from older articles that were not normalised (for example, the CDHR1 deletions of Henderson 2010) remain in the nomenclature of the articles.

2.8. Genotype–phenotype correlations, penetrance and modifiers

The most consistent rule is that of ABCA4: the lower the residual function, the earlier and more diffuse the disease, so that CORD occupies the intermediate position between Stargardt disease and RP [9, 73]. In GUCY2D the rule is that of mechanism: biallelic loss of function gives LCA and heterozygous gain of function in the dimerisation domain gives CORD, with no difference in course between p.(Arg838Cys) and p.(Arg838His) [10, 25]. In KCNV2, RPGRIP1 and CERKL, double-null genotypes are associated with earlier onset and worse vision [11, 107, 117]. In RPGR, the position of the variant within ORF15 guides the phenotype, and high myopia predicts faster decline [9, 11].

Variable expressivity is the rule in dominant forms. GUCA1A p.(Tyr99Cys) gives COD, CORD and isolated macular dysfunction in the same family [86]; CRX produces LCA, CORD and late-onset macular degeneration in the same pedigree [26, 88]; PRPH2 p.(Arg172Trp) ranges from non-penetrance to severe CORD [9]. Reduced penetrance in some AD families and ABCA4 pseudodominance complicate the reading of pedigrees [16, 69]. In female carriers of RPGR variants, severity follows X-chromosome inactivation: in a cohort of 77 carriers from 41 pedigrees, 57% of those with extreme skewing (≥80:20) were severely affected, versus 8% of the others [118].

2.9. Genes of the syndromic forms with CORD

ALMS1 (2p13.1) causes Alström syndrome, a ciliopathy in which CORD is present in all patients [59, 60]. CNNM4 (2q11.2) encodes a basolateral magnesium transporter and causes Jalili syndrome, with CORD and amelogenesis imperfecta [57, 74, 75]; one case resulted from paternal uniparental isodisomy of chromosome 2 [57]. PCYT1A (3q29) encodes CTP:phosphocholine cytidylyltransferase α (CCTα), the rate-limiting enzyme of phosphatidylcholine synthesis, and causes three AR phenotypes: spondylometaphyseal dysplasia with CORD, isolated retinal dystrophy and congenital generalised lipodystrophy type 5 (OMIM 620680) without retinal or skeletal involvement [62, 80, 119, 120]. CFAP410 causes CORD with short stature [63]. Among ciliopathy genes, IQCB1 causes LCA, early-onset dystrophy and CORD with nephronophthisis (Senior-Løken) [6], and CFAP418 is allelic with Bardet-Biedl syndrome, in which the retinal dystrophy is primarily a CORD [8]. MFSD8 (CLN7), whose adult form presents as macular or cone–rod dystrophy, appears in the Orphanet list of CORD genes; CLN3 has a protracted form with adult CORD [1, 102]. ABHD12 causes PHARC syndrome (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract), with cone–rod dysfunction in the 2nd–3rd decade [120]. Spinocerebellar ataxia type 7 (polyglutamine expansion of ataxin-7) may begin as isolated retinal dystrophy [10].

3. Clinical Spectrum and Manifestations by System

3.1. Symptoms and order of appearance

Cone dysfunction produces reduced central vision, photophobia and altered colour vision; patients often function better in dim light and experience discomfort and intense glare in normal lighting [69]. Rod dysfunction manifests as poor vision in dim light (nyctalopia) and loss of peripheral field [69, 70]. In COD, the presentation is loss of central vision, photophobia and dyschromatopsia; as cone function is usually normal early in life, nystagmus is usually absent, and the absence of early nyctalopia distinguishes COD from CORD [9]. Dyschromatopsia generally affects all three colour axes, with described exceptions of preferential degeneration of L cones (protan defect) or S cones (tritan defect) [9].

Hamel described two stages in CORD. In the first, reduced acuity is usually discovered at school, in the first decade, and does not improve significantly with glasses; patients shift their gaze to project the image onto less damaged parafoveal regions (eccentric fixation), have intense photophobia and variable dyschromatopsia, and nyctalopia is absent or not prominent; visual fields show central scotomas with sparing of the periphery, without mobility difficulties [10]. In the second stage, nyctalopia becomes apparent, peripheral field loss progresses and hampers independent mobility, acuity falls until reading becomes impossible and nystagmus is frequent; patients reach legal blindness (acuity below 1/20 in the definition used by Hamel) even with much of the peripheral field preserved [10]. Many patients are severely disabled or legally blind by the end of the second decade [10]. This 2007 description, focused on early-onset patients, should be read together with more recent cohorts, which show highly variable ages at onset and at visual loss.

3.2. Fundus and imaging

In COD, the fundus classically shows bull's-eye maculopathy, but more often a bilateral and relatively symmetric RPE change or atrophy, with progression; the periphery is normal while the rods are preserved [9]. In advanced CORD, peripheral RPE atrophy and bone-spicule pigment appear [9]. Hamel described, at the outset, a normal macula or subtle lesions with optic disc pallor, mainly temporal (papillomacular bundle), and later predominantly macular pigment deposits, vascular attenuation, waxy disc pallor and variable atrophy [10]. Other findings are white flecks at the level of the RPE (which herald later rod dysfunction), a dark choroid sign on fluorescein angiography and a tapetal-like reflex in XL CORD [9].

Wide-field fundus autofluorescence (FAF) shows an extent of abnormal autofluorescence that correlates with severity and duration of symptoms [9]. Spectral-domain optical coherence tomography (SD-OCT) shows first loss of the interdigitation zone, then disruption and loss of the ellipsoid zone (EZ, the line corresponding to the inner segment ellipsoids) and, in the advanced phase, atrophy of the outer retina and RPE [9]. Adaptive optics scanning laser ophthalmoscopy (AOSLO) revealed, in GUCY2D CORD, residual cone inner segments in the fovea that other modalities did not show, and in ABCA4 retinopathy cone mosaic anomalies precede psychophysical and FAF changes [9, 11].

3.3. Natural history in cohorts

The cohort of Thiadens and colleagues is the main source of general natural history. It included consecutive probands from the Netherlands, Belgium and the United Kingdom (98 with COD and 83 with CORD, plus 41 and 17 affected relatives), with a mean follow-up of 19 years [13]. The mean age at onset was 16 years (standard deviation 11) in COD and 12 years (standard deviation 11) in CORD (p=0.02). Ten years after diagnosis, bull's-eye maculopathy was present in 35% of COD and 51% of CORD, 70% of CORD had absolute peripheral field defects and 37% of COD had developed rod involvement on the ERG. The mean age at legal blindness was 48 years (standard error 3.1) in COD and 35 years (standard error 1.1) in CORD (p<0.001). ABCA4 and onset before 20 years were independently associated with faster progression to legal blindness [13]. The Gill 2019 review, summarising the same authors, states that more than half of patients with CORD reached legal blindness by 23 years, versus 48 years in COD; this value does not match the mean age of 35 years published in the abstract of the primary study, which is the value adopted in this article [9, 13]. Gill adds that many patients with CORD retain peripheral vision at the outset and develop a peripheral scotoma up to 10 years later, and that COD/CORD leads to marked visual loss earlier than RP [9]. Inheritance, inferred from family history, was AR in 92% of COD and 90% of CORD, but AD forms were not genotyped [13]. None of these data describes treated disease, because there is no disease-modifying treatment.

3.4. Phenotypes by gene

ABCA4. ABCA4 CORD begins in childhood or early adulthood, with central scotoma and progressive macular atrophy [11]. The fundus may initially be normal or show only loss of the foveal reflex, and diagnosis is delayed if FAF and OCT are not performed [9]. Most patients have rod involvement at presentation, which is associated with a worse prognosis; FAF shows a bull's-eye appearance with yellowish-white flecks and expanding macular atrophy [9, 11]. About 30% of childhood-onset cases have no flecks at presentation and about a quarter have no clinically identifiable retinal lesion, which leads to misdiagnosis and unnecessary neurological investigations [24]. Very rapid progression in childhood should prompt consideration of juvenile Batten disease (CLN3) [11].

GUCY2D. In a multicentre retrospective study (the Netherlands, Belgium and the United Kingdom) of 82 patients from 54 families, the 68 patients with AD CORD had progressive visual loss from the second decade, with a decline in best-corrected visual acuity (BCVA) of 0.022 logMAR (logarithm of the minimum angle of resolution) per year (p<0.001), with no difference between c.2513G>A and c.2512C>T (p=0.798), over a median follow-up of 7.2 years (interquartile range 2.2–14.2) [25]. The probability of blindness or severe visual impairment at 40 years was 32%, and the disease culminates in severe visual impairment in mid to late adulthood; the integrity of the EZ and the external limiting membrane (ELM) correlated with BCVA (ρ=0.744 and ρ=0.712) [25]. The 14 patients with AR LCA1 had onset in the first year and BCVA between no light perception and 1.00 logMAR, relatively stable [25]. In GUCY2D CORD, the ERG shows reduced cone amplitudes and a delayed and reduced 30 Hz flicker; a negative scotopic response may appear early, and rod dysfunction increases with time; FAF shows central hypoautofluorescence with a hyperautofluorescent ring [11].

GUCA1A. Onset is in the second or third decade, with photophobia, progressive loss of central acuity and altered colour vision; the fundus ranges from mild RPE changes to extensive macular atrophy, and FAF shows hypo- and hyperautofluorescent areas, with early foveal increase [11, 28]. The distinctive electrophysiological feature is a reduction in photopic amplitudes with preserved peak times, which reflects cone loss rather than generalised dysfunction; in most other COD there is reduction and delay [9, 11].

CRX. In CORD2, cone-mediated central vision fails first (reduced acuity, colour loss, photophobia, central field loss and macular pigmentary change) and then peripheral and night vision [26]. Macular degeneration is the most prominent and frequent feature of the CRX spectrum [6].

PRPH2. Onset is in the second or third decade, with poor central vision, photophobia and nyctalopia; the fundus ranges from bull's-eye maculopathy to macular atrophy, and FAF shows a characteristic speckled macular appearance in most patients [9, 11]. PRPH2 macular and pattern dystrophies present in the 4th–5th decade, with slow decline in acuity [29].

PROM1. AR forms are severe and panretinal, with severe loss of acuity generally by 20 years of age; AD forms due to p.(Arg373Cys) are macula-centred, and in the consecutive series most AD patients retained good vision until late adulthood; all patients in the series had central visual loss, with or without photophobia [30, 110]. The ERG ranges from a pattern ERG with reduced P50 and a normal ffERG to severe rod and cone dysfunction [11]. The ProgStar-4 natural history study (NCT02410122) includes patients with PROM1 [11].

RPGR. RPGR CORD is characterised by central visual loss, mild photophobia and myopia, with onset between the second and fourth decades in affected males [9]. In a longitudinal study, legal blindness at 40 years was significantly more frequent in RPGR COD/CORD than in RPGR RP, and high myopia predicted faster decline [9, 11]. FAF shows hyperautofluorescent parafoveal rings that enlarge with progression and are inversely related to ERG amplitude, with progressive disruption of the EZ [11]. In carriers, the phenotype ranges from asymptomatic to severe degeneration, with a sectoral pattern and tapetal-like reflex; on adaptive optics, this reflex corresponds to reduced cone density and increased reflectivity of the rod outer segments [32, 121]. In the Portuguese cohort, 23 female relatives in 5 of 11 families with hemizygous RPGR or RP2 males had clinical or subclinical signs, and three RPGR probands were heterozygous women [43].

KCNV2. In the international report of 117 patients, the mean age at onset was 3.9 years and all were symptomatic before 12 years; all had reduced acuity, 78.6% dyschromatopsia, 53.5% photophobia, 43.6% nyctalopia and 38.6% nystagmus; over a mean follow-up of 8.4 years, BCVA changed from 0.81 ± 0.27 to 0.90 ± 0.31 logMAR [98]. More than half of patients are symptomatic before 3 years, and about 1 in 10 from birth; high myopia (greater than 6.0 D) in more than 30%, together with photophobia and difficulty with night vision, is a suggestive combination [11]. In a separate series, legal blindness occurred before 25 years [34]. FAF has three features (increased central signal, decreased autofluorescence and a ring of increased signal) combined into five patterns, with prominent bull's-eye maculopathy; 96.5% of patients had the same OCT grade in both eyes, and about a quarter changed FAF group and about a third changed OCT grade over 5–6 years [122]. Outer nuclear layer thickness is a structural biomarker, with an intervention window estimated up to about 40 years and optimal in the first three decades [11, 123].

CDHR1. In a National Eye Institute (USA) series of 10 patients, the mean age at onset was 36 ± 8.5 years (5–45), final acuity ranged from 20/20 to 20/2000 (mean logMAR 0.8) and there were three subgroups (rod–cone dystrophy, CORD and maculopathy), with macular involvement in all and asymmetric atrophy in two [124]. Hypomorphic variants may mimic dry age-related macular degeneration with geographic atrophy [100].

CERKL. In the largest series (47 patients from 37 families, Moorfields and Japan), the mean age at first visit was 29.6 ± 13.9 years, the most frequent initial symptom was loss of central vision (40%), 57% had well-demarcated macular atrophy and 77% were double-null; among patients with electrophysiology, 53% had similar rod and cone dysfunction, 27% a rod–cone pattern, 10% a cone–rod pattern and 10% a macular pattern; more than half lost at least 15 letters on the ETDRS (Early Treatment Diabetic Retinopathy Study) scale in one eye within the first five years [117]. In a Brazilian cohort from São Paulo (52 patients from 50 families), 50 had CORD and 2 macular dystrophy, with onset between 7 and 40 years (median at presentation 18 years), initial BCVA between 0.1 and 2.7 logMAR, and a correlation between disease duration and loss of acuity in the 37 patients with two null alleles (R² 0.315 and 0.405) [41]. The contrast between the two cohorts shows that the CERKL phenotype does not fit the RP/CORD dichotomy and varies with population and genotype [41, 117].

RAB28. Presentation is in childhood or adolescence, with photophobia, reduced acuity, dyschromatopsia and progressive central loss, and the periphery is affected later; the fundus shows macular hyperpigmentation, bull's-eye, RPE atrophy and peripapillary atrophy; the ERG shows severely reduced photopic responses and reduced but relatively preserved scotopic responses [42, 125]. The four Portuguese patients with p.(His144Tyr) noticed reduced acuity between early childhood and 8 years, with temporal disc pallor, an abnormal foveal reflex without pigment and emmetropia in most [43]. The possible syndromic extension (two siblings with postaxial polydactyly) has no established causality [42].

ADAM9. CORD begins in childhood, with loss of central acuity, colour vision and photopic sensitivity, followed by peripheral loss; there are pigment deposits, mid-peripheral greyish-white discolouration, vascular attenuation and disc pallor [36, 37].

POC1B and TTLL5. CORD20 began in early childhood in a consanguineous family, with a slowly progressive course, photophobia, reduced acuity and dyschromatopsia without night blindness; SD-OCT showed fusion of the EZ and ELM lines into a blurred line at the fovea, and the cone ERG was unrecordable in all [78]. In CORD19, most adults have COD or CORD with onset in late adolescence, central scotoma and macular changes [46].

RPGRIP1. Symptoms appear on average at 0.87 years (nystagmus, reduced acuity, hypermetropia and photophobia); 44% were legally blind at the first visit (2–39 years), the ERG was extinguished or of CORD pattern, and the central macular architecture preserved an island of outer nuclear layer and EZ into adulthood; over a mean follow-up of 15.7 years, BCVA declined by 0.02 logMAR per year [107].

Other genes. RAX2 CORD11 has variable onset and a slowly progressive course [50]. CACNA1F CORDX3 has modestly progressive dysfunction on a background of CSNB2A [53]. In CNGA3, CNGB3, GNAT2 and PDE6C COD, progression is the main feature that separates them from achromatopsia [5, 108].

The table summarises the features that point to the gene from the phenotype.

3.5. Syndromic forms

Alström syndrome. In a series of 182 cases, CORD appeared between birth and 15 months (mean 5 months) in 100% of patients; obesity in 98% (mean 2.5 years), progressive sensorineural deafness in 88% (2–25 years, mean 9), infantile cardiomyopathy in 42% (between 2 weeks and 4 months), insulin resistance in 92%, type 2 diabetes in 68% (mean 16 years), short stature in 98% and hypogonadism in 78% of males; progressive kidney disease was universal [60]. The visual problems present as progressive cone dystrophy with visual impairment, photophobia and nystagmus between birth and 15 months; the first manifestation is usually nystagmus or infantile cardiomyopathy [6, 7]. The ffERG, needed to establish the diagnosis of CORD, is abnormal from early on, first with cone and then rod involvement; acuity falls to 6/60 or less by 10 years, and light perception is lost by 35 years, with many patients losing it by the end of the second decade [7]. OCT shows mild macular changes in early childhood that progress, retention of the central inner layers (foveal immaturity), intraretinal opacities and disc drusen; posterior subcapsular cataract is frequent even without diabetes [7]. Intelligence is normal in most patients [59].

Jalili syndrome. In a series of 7 patients from 6 families, the mean age at presentation was 6.7 years (3–16), mean BCVA about 20/246, nystagmus was present in 7 of 7 and photophobia in 6 of 7, with structural and functional progression in all [126]. Amelogenesis imperfecta affects the enamel of both dentitions; the three original siblings had an anterior open bite [57]. Two phenotypes have been proposed: onset in infancy with a progressive macular lesion, and onset in early childhood with a normal fundus, photopic flicker affected first and scotopic responses extinguished later [57, 127]. Nystagmus increases in photopic conditions [57].

Spondylometaphyseal dysplasia with CORD. It combines severe short stature of postnatal onset (adult height may be below 100 cm), progressive waddling gait and genu varum with early-onset visual impairment with photophobia, dyschromatopsia, nystagmus and hypermetropic astigmatism, in infancy or early childhood [61]. Radiology shows moderate platyspondyly with ovoid vertebrae, cupped ribs, serrated iliac crests, short tubular bones with rhizomelic predominance, metaphyseal irregularity and progressive coxa vara [61]. It is distinguished from Kozlowski-type spondylometaphyseal dysplasia (TRPV4) because, in lateral view, the vertebral bodies are ovoid and not flattened and, in anterior view, there is no overlap of the pedicles [128]. The retina shows pigmentary bull's-eye maculopathy in childhood and an ERG with cone and rod dysfunction; visual impairment progresses slowly in childhood and stabilises at the end of it, without total loss of acuity [61]. By 2022, 12 patients had been reported [120], and Orphanet records 18 cases [129]. Three Italian patients from two families had apparently isolated retinal dystrophy, with normal skeletal radiographs, metabolic assessment and liver ultrasound [62]. Low HDL cholesterol has been described in both forms of PCYT1A disease [120].

Other forms. In Bardet-Biedl syndrome, the retinal dystrophy is primarily a CORD with early macular involvement, presenting with night blindness followed by peripheral loss, reduced colour discrimination and loss of acuity; the diagnosis is usually made in the first decade, and CORD presents earlier in Alström syndrome than in Bardet-Biedl syndrome [8]. Hamel reported legal blindness before 20 years in Bardet-Biedl syndrome, with an estimated prevalence between 1/13,500 and 1/60,000 [10]. CORD with short stature (CFAP410) has onset in childhood and six cases or families described [63]. CFAP410 (formerly C21orf2) also causes axial spondylometaphyseal dysplasia (MIM 602271), AR, with moderate to severe short stature of postnatal onset, a narrow bell-shaped chest and pigmentary retinal degeneration; the ERG shows a severe defect of cone function and a mild one of rod function, visual impairment is noticed in infancy, progresses rapidly and may reach total loss of acuity in adulthood, and NEK1 is the other gene described [64]. Hamel also lists hypotrichosis with juvenile macular dystrophy (CDH3, sometimes with CORD), thiamine-responsive megaloblastic anaemia, a case with the mitochondrial variant NC_012920.1:m.8993T>G (MT-ATP6) and infantile Refsum disease [10]. The Bonn cohort found clinically unrecognised syndromic forms in patients labelled as isolated retinopathy: Alagille syndrome (JAG1) with bull's-eye maculopathy and operated heart disease, Senior-Løken syndrome (NPHP1) with a kidney transplant in adolescence revealed only after the genetic result, KIF11 with subtle systemic manifestations and two patients with NC_012920.1:m.3243A>G (MT-TL1) [16].

3.6. Ocular complications and functional impact

Inherited retinal dystrophies accumulate treatable copathologies over time, mainly cataract and cystoid macular oedema, which justifies regular reviews [18, 69]. The quantitative data on complications come from RP: about 50% of patients with RP develop cataract that eventually requires surgery, and cystoid macular oedema occurs in 10–50% depending on the series and detection method [4, 30]; the sources consulted give no specific frequencies for COD/CORD. In ABCA4 retinopathy, choroidal neovascularisation and subretinal fibrosis may occur after minor ocular trauma [24]. In CRX and CRB1, keratoconus and late lens opacities are described [26, 130]. Early loss of central vision compromises reading, schooling and career choice long before loss of mobility, which appears only with the peripheral loss of the second stage [10]. Inherited retinal dystrophies are the leading cause of legal blindness in working-age adults in England and Wales and the second in childhood [9].

4. Clinical Recognition and Warning Signs

4.1. When to suspect

Suspicion of cone disease arises from a combination of complaints that patients describe consistently: photophobia and glare, better performance in dim light, reduced central acuity that does not correct with glasses and difficulty distinguishing colours [10, 69]. In early-onset forms nystagmus is added; the combination of nystagmus with photophobia points to achromatopsia, aniridia, albinism and cone dystrophies [131]. In a patient with apparent RP, initial photopsias, abnormal central vision, abnormal colour vision or marked asymmetry suggest another disease, such as CORD [4]. The decisive clinical question is which symptom appeared first, reduced central vision or nyctalopia [10]. The French PNDS adds two practical criteria to separate cone dystrophy from a maculopathy: photophobia may be the presenting symptom in cone dystrophy, whereas in maculopathies it appears late and follows the severity of visual loss; and, for the same level of acuity, the colour vision change is more severe in cone dystrophy than in maculopathy, in which it follows the reduction in acuity [19]. Reduction of the peripheral field or difficulty with night vision points to a mixed dystrophy [19]. The absence of a family history does not exclude hereditary disease, but in an isolated case acquired causes of maculopathy should be excluded first: synthetic antimalarials, antiretrovirals, inhaled nitrites (poppers), exposure to recreational lasers or the sun, diabetes, vascular occlusions and inflammatory diseases (toxoplasmosis, multifocal choroiditis, placoid epitheliopathy, cat-scratch disease) [19].

4.2. Warning and emergency signs

Very rapid progression in childhood, especially with learning difficulties, behavioural changes or epileptic seizures, should prompt consideration of juvenile neuronal ceroid lipofuscinosis (CLN3), which may begin as isolated visual loss [11, 102]. Nystagmus acquired after 6 months requires brain magnetic resonance imaging to exclude chiasmal disease [131]. Ataxia, dysarthria or a family history of dominant neurological disease point to spinocerebellar ataxia type 7, which may begin as isolated retinal dystrophy [10]. Amelogenesis imperfecta in a child with photophobia, nystagmus and poor vision suggests Jalili syndrome [57]. In infants with high myopia, abnormal head posture or nystagmus and a family history of stationary night blindness, ophthalmological examination and molecular testing may make neuroimaging and electrophysiology under sedation unnecessary [53]. Acute worsening of vision in a known patient should prompt a search for cystoid macular oedema, cataract or neovascularisation, which are treatable [18].

4.3. Particularities of paediatric examination

In children under 2 years, ffERG can be performed with skin electrodes and OCT with a handheld device, with the child swaddled and asleep in the dark, but sedation gives more reliable results; between 2 and 6 years sedation allows a more complete examination, weighing the risks and using age-specific norms, because sedation may alter the ERG; visual fields are unreliable before 7 years [14]. The 2022 ISCEV standard provides an abbreviated protocol for patients of limited age or cooperation [15].

4.4. Newborn screening

The sources consulted describe no newborn screening programme for COD/CORD, and diagnosis depends on clinical recognition. Most patients with Alström syndrome pass newborn hearing screening, because the deafness is progressive and is detected on average at 7 years [59].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Clinical criteria

There are no validated formal diagnostic criteria for COD/CORD. The clinical diagnosis rests on early reduction of visual acuity and photophobia, fundus lesions, an ERG with reduced amplitudes and predominant cone involvement, and progression of these signs [10]. The ffERG is the key investigation, especially in the asymptomatic phase or with a normal fundus, and Hamel recommends confirming the diagnosis by repeating the test one to two years later [10]. The operational distinction between macular dystrophy (normal ffERG), COD (only photopic responses reduced) and CORD (photopic and scotopic responses reduced) is electrophysiological [16]. A young patient with apparently macular disease should undergo ffERG to exclude diffuse disease [14].

5.2. Electrophysiology

The 2022 International Society for Clinical Electrophysiology of Vision (ISCEV) standard defines six standard ffERG responses. DA 0.01, recorded after at least 20 minutes of dark adaptation with a 0.01 cd·s·m⁻² flash, reflects the rod bipolar cells; DA 3 and DA 10 are mixed responses with rod predominance (DA 10 better assesses the a-wave); the DA 3 oscillatory potentials complete the scotopic series; LA 3, after at least 10 minutes of adaptation to a 30 cd·m⁻² background, assesses the cone system, and the 30 Hz LA flicker, generated mainly by the cone On and Off bipolar cells, depends on the L and M cones [15]. After examinations with intense illumination (indirect ophthalmoscopy, angiography, FAF, fundus photography, OCT), at least 30 minutes in ambient light should elapse before the ERG [15]. The ISCEV extended protocols include the photopic negative response, the dark-adapted red flash, On–Off responses, stimulus–response series and the S-cone ERG, useful in blue cone monochromatism [15].

In COD/CORD, the first finding is usually delay of the 30 Hz flicker implicit time, followed by reduction of its amplitude and of the photopic a- and b-waves; scotopic function is preserved at the outset and affected later, and cone decline is faster in CORD than in COD [9, 11]. The AAO regards delays in cone b-wave implicit time as an early sign of diffuse retinal disease [14]. Two patterns point to the gene. In KCNV2, the dark-adapted response to dim flashes is very small and delayed and grows disproportionately with intensity, with distortion and broadening of the a-wave trough; the pattern ERG (PERG) P50 is undetectable; the mean reductions relative to controls are 55% in DA 0.01, 21% in the DA 10 a-wave, 48% in the LA 30 Hz flicker and 74% in the LA 3 b-wave, and the decline with age is similar to normal [11, 98]. In GUCA1A, photopic amplitudes are reduced with preserved peak times [11]. The multifocal ERG (mfERG) stimulates only the central retina, detects residual macular function and, with the ffERG, distinguishes cone–rod from rod–cone degeneration; it is also used to follow central function [4, 10]. In advanced forms the ERG becomes undetectable above noise [4].

5.3. Imaging and psychophysics

FAF and OCT are indispensable, because the fundus may be normal at the outset [9]. In maculopathies, the AAO recommends using fundus photography and FAF sparingly because of the risk of phototoxicity, preferring autofluorescence with reduced illumination (25%), longer wavelengths, infrared autofluorescence or near-infrared reflectance [14]. OCT should be performed with high-density cubes and recording of central thickness as a baseline, and is used to monitor cystoid macular oedema, epiretinal membranes and schisis [14]. Kinetic perimetry documents driving, disability and legal blindness; in the USA, legal blindness is defined by an acuity of 20/200 or worse, or by a horizontal field diameter of 20° or less with the III4e target in the better eye [4, 14]. Microperimetry and the full-field stimulus threshold (FST) test are useful when fixation is unstable or the ERG is unrecordable [14]. The French PNDS regards ffERG according to the ISCEV standard as indispensable in any maculopathy, with the sole exception of a typical picture of Best disease with AD inheritance, because it is what separates maculopathy from cone dystrophy and mixed dystrophies and informs on the risk of peripheral involvement [19]. The same document regards FAF as indispensable and states that it has replaced fluorescein angiography, which is not indicated in inherited dystrophies [19]. In the infant, it recommends rapid macular and, if possible, temporal OCT scans, to detect an incipient mixed dystrophy; in the older child and adult, the assessment includes acuity, visual field, colour fundus photography, macular and temporal OCT with ganglion cell fibre study, macular and wide-field FAF, ffERG and, if the ffERG is normal in a disease with deposits or a toxic cause is suspected, an electro-oculogram [19].

Colour vision is studied with the Farnsworth-Munsell 100-hue test, the saturated and desaturated Panel D-15 and the Rayleigh anomaloscope, the latter being the most discriminating in the differential with achromatopsia; Ishihara and Hardy-Rand-Rittler (HRR) plates screen for red–green defects [5]. Adaptive optics shows the remaining cone mosaic, but is not in widespread clinical use [4, 5].

5.4. Systemic assessment

The first aim of the assessment is to decide whether the disease is syndromic [69]. The history includes a three-generation pedigree with consanguinity, age at onset, neurological symptoms, developmental delay, obesity, diabetes, deafness, kidney disease, cardiomyopathy and retinotoxic drugs [14, 69]. The examination records weight, height and head circumference, blood pressure, dysmorphic features, skeletal anomalies, postaxial polydactyly, teeth, neurological signs, heart murmurs and acanthosis nigricans [69]. In apparently isolated dystrophies, biochemical investigation may include electrolytes, renal and liver function, fasting glucose and phytanic acid; extended metabolic investigation (very long-chain fatty acids, apolipoprotein B, ornithine, vitamins A and E), full blood count with a search for vacuolated lymphocytes, renal ultrasound and echocardiogram are performed according to the signs [69]. The AAO recommends including the genes of syndromic forms in the panel, even without systemic signs, because these may appear later [14].

5.5. Genetic testing: indications and strategy

The AAO Task Force, in the February 2014 version that updates the 2012 recommendations, recommends offering genetic testing to patients with findings suggestive of Mendelian disease whose causal gene has been identified, ensuring counselling by a physician with experience in inherited disease or by a certified genetic counsellor, using laboratories certified under CLIA (Clinical Laboratory Improvement Amendments) standards, giving the patient a written copy of each report, avoiding direct-to-consumer tests, avoiding unnecessary parallel testing and avoiding routine testing in complex diseases [132]. For diseases with many genes, a single panel designed for all the genes is the most effective strategy [132]. The 2014 recommendation to restrict exome and genome to research in tertiary centres has been overtaken by subsequent practice [14, 21, 132]. The AAO, in 2022, considers testing appropriate for most patients with inherited retinal dystrophy and the retinal dystrophy NGS panel an efficient first step; an unequivocal positive result does not need to be repeated, and a negative or inconclusive result may be revisited [14]. The AAO Task Force and ERN-EYE recommend genetic testing for all people with presumed or suspected inherited retinal dystrophy [18, 21]. Genetic testing is required for eligibility for clinical trials and for approved gene therapies [14]. In France, the 2021 PNDS provides for NGS panel sequencing (at the time with 208 retinal dystrophy genes, with exon copy number analysis), with parental DNA whenever possible, and the France Genomic Medicine Plan 2025 (PFMG2025) included maculopathies among the pre-indications for whole genome sequencing, which may be proposed as first-line; when cone dystrophy is suspected, the genome may preferably be requested as a trio (proband and parents) [19]. Interpretation follows ACMG/AMP recommendations, and identification of variants in an unexpected gene should lead to review of the clinical diagnosis [19].

In the Bonn cohort, the two-tier strategy combined Sanger sequencing (with multiplex ligation-dependent probe amplification, MLPA, for ABCA4) when the phenotype suggested ABCA4, PRPH2 or BEST1, followed by an NGS panel of 48 macular and cone dystrophy genes with copy number variation (CNV) analysis, RPGR ORF15 amplicons and RP, LCA and syndrome genes; the yield was 74% (185 of 251), with 193 variants in 22 genes, of which 33% were novel [16]. The detection rate was 89% in apparent AR inheritance, 84% in apparent AD and 68% in sporadic cases; of the 66 unsolved patients, 85% were sporadic [16]. In the Portuguese cohort of 230 probands, with exome, CNV analysis and microarray genotyping, a genetic diagnosis was achieved in 76% of families and CNV accounted for about 10% of mutated alleles [43].

These percentages are proportions of patients with a molecular diagnosis in cohorts with their own inclusion criteria, and are not equivalent to the clinical sensitivity of a test for a defined disease [14, 16].

5.6. Limits of testing

A negative result does not exclude an inherited retinal dystrophy, because it may reflect the panel design [14, 18]. RPGR exon ORF15 is repetitive and purine-rich, is difficult to sequence by NGS and may not be covered in panels; a man with an XL-pattern dystrophy or an isolated case needs sequencing targeted at ORF15 [4, 32]. Multiexon deletions of TTLL5 and other genes make CNV analysis mandatory when one or no variant is found in a compatible recessive gene [43, 46]. The exome does not detect inversions, translocations, expansions or deep intronic or regulatory variants; the genome is more comprehensive, but cases remain unsolved due to rearrangements or alterations of distant enhancers [9]. Non-coding variants in CRB1 and other retinal dystrophy genes have been described, and deep intronic variants of ABCA4 explain about 10% of patients with Stargardt disease [4, 21]. In the Bonn cohort, 7 of 60 unsolved patients (12%) had a single variant in a recessive gene and a compatible phenotype (five in ABCA4) [16].

5.7. Report content and interpretation

The report should state the gene, the transcript with version (preferably MANE Select), the variant in HGVS nomenclature (c. and p.), the zygosity, the classification according to ACMG/AMP (American College of Medical Genetics and Genomics and Association for Molecular Pathology) and the correlation with the phenotype [18, 83]. The ACMG classification has five classes, and «likely pathogenic» or «likely benign» corresponds to a certainty greater than 90% [18]. Variants of uncertain significance (VUS) are reclassified with segregation studies: absence of the variant in both parents proves de novo occurrence (strong evidence), and unequivocal cosegregation over three or more generations in an AD or XL family may justify moving from class 3 to 4 or 5; gene-specific phenotypic findings, splicing assays and in silico predictions serve as support [18]. In achromatopsia and recessive diseases in general, two VUS or one pathogenic variant with a VUS neither establish nor exclude the diagnosis [5]. When an exome shows apparent homozygosity and one parent is not a carrier, a deletion on the other allele, uniparental disomy or non-paternity should be considered, and the study completed with chromosomal microarray (CMA) in a trio [83]. A well-documented pathogenic variant may be incorrectly numbered in the literature (such as PROM1 «c.1118C>T»), and a variant previously regarded as causal may be reclassified (GUCA1A p.(Pro50Leu), RIMS1 p.(Arg820His)) [11, 22, 31]. In the face of a negative result, genetic reassessment should be considered every 2–5 years, and reanalysis of an existing exome or genome is simpler and cheaper than a new test [18].

5.8. Prenatal and preimplantation diagnosis

Prenatal diagnosis and preimplantation genetic testing are possible when the family's causal variants have been identified [5, 69]. Hamel stressed the ethical question of invasive procedures in a disease that is not life-threatening [10]. The detailed reproductive discussion is in section 8.

5.9. Practical algorithm

The following algorithm integrates the AAO recommendations, the ISCEV standard and the experience of the reference cohorts. The first step is the history (order of symptoms, age at onset, three-generation pedigree and systemic symptoms) and the ophthalmological examination with BCVA, refraction, colour vision and biomicroscopy [14, 69]. The second is multimodal imaging with low-illumination FAF and SD-OCT, which demonstrates the disease even with a normal fundus [9, 14]. The third is ffERG according to the ISCEV standard, with mfERG or PERG when there is doubt about macular involvement, to classify the patient as macular dystrophy, COD or CORD and to recognise specific patterns (KCNV2, GUCA1A, preserved S cones in blue cone monochromatism) [11, 15, 16]. The fourth is targeted systemic assessment [69]. The fifth is the inherited retinal dystrophy NGS panel with CNV, RPGR ORF15 and syndromic genes, preceded by pre-test genetic counselling [14, 18]. The sixth, in the face of a single variant in a recessive gene, a VUS or a negative result, is segregation study, CNV analysis, CMA, exome or genome, and periodic reanalysis [18, 83]. When the electrophysiological diagnosis is doubtful, repeating the ffERG one to two years later documents the progression that separates COD from achromatopsia [5, 10].

6. Differential Diagnosis

6.1. Comparative table

6.2. Achromatopsia

Achromatopsia is the most common cone dysfunction syndrome, with an estimated prevalence of about 1/30,000 [5, 11]. It presents at birth or in early infancy with pendular nystagmus in the first weeks of life, followed by marked photophobia, low acuity and loss of colour vision on all three axes; hypermetropia is frequent [5, 11]. Acuity is 20/200 or worse in the complete form and may reach 20/80 in the incomplete form, usually stable, and nystagmus and photophobia may improve slightly [5]. FAF has four patterns (normal, central increase, central reduction, central reduction with a hyperautofluorescent ring) and OCT is classified into five grades (I, continuous EZ; II, EZ disruption; III, absence of the EZ; IV, hyporeflective zone; V, outer retinal atrophy with loss of the RPE); in a series of 50 patients followed up, structure was predominantly stable [11]. Foveal hypoplasia is present in 60–70% of patients with CNGA3 or CNGB3 and in all patients with ATF6, and is absent in cases due to GNAT2, PDE6C and PDE6H; cases due to GNAT2 and PDE6C have relatively preserved S-cone function [11].

The diagnostic problem is that the same genes cause progressive cone dystrophy, and that COD/CORD genes (ABCA4, AIPL1, CABP4, CNNM4, CDHR1, GUCY2D, KCNV2, RAB28, RPGRIP1) have been found in patients misdiagnosed as having achromatopsia [5]. In COD, cone function may be normal at birth and symptoms appear later, with onset between childhood and the seventh decade; scotopic thresholds may be elevated [5]. The distinction is difficult especially with onset in early childhood, and the best discriminator is progression [5, 108]. Genetic reclassification works in both directions: in Spain, 37 patients diagnosed with RP were reclassified as cone-dominant phenotypes after testing, including cases due to GUCA1A, CNGB3, CNGA3, GNAT2, PDE6C, PDE6H and ATF6 [12].

6.3. Blue cone monochromatism and Bornholm eye disease

Blue cone monochromatism is XL and results from absence or marked reduction of the L and M opsins by three mechanisms: deletions of the locus control region (generally with a more severe phenotype), a two-step process with a single hybrid L/M gene inactivated by a missense variant (c.607T>C p.(Cys203Arg), NM_020061.6 in OPN1LW, is the most common) and L/M interchange haplotypes in exon 3 with aberrant splicing (the LIAVA haplotype is among the most frequent) [11, 67, 114]. The clinical picture resembles that of achromatopsia (photophobia, nystagmus, low acuity), but the fundus is myopic and normal, the S cones function and the photopic sensitivity peak is about 440 nm, instead of the 507 nm of the rods [5, 11]. Cone responses are obtained with blue flashes on a yellow background and with the S-cone ERG of the ISCEV extended protocol [5, 15]. The dysfunction is congenital and usually stationary, with a prognosis different from that of CORD, which should be explained to families [9, 114]. Carriers are asymptomatic, although adaptive optics shows reduced cone density due to random X inactivation [11]. Bornholm eye disease combines dichromacy, myopia, acuity of 20/40 to 20/80 from birth, RPE thinning with visible choroidal vessels and a reduced cone ERG [11].

6.4. Retinitis pigmentosa, LCA and macular dystrophies

In typical RP, nyctalopia is the first symptom and remains isolated for years with normal acuity, and the pigment is peripheral; in RP with early macular involvement, nyctalopia continues to predominate and the ERG shows rod predominance; when the patient is seen at a late stage, the ERG may be undetectable and the distinction depends on the order of symptoms [10]. LCA presents with visual impairment from birth, nystagmus, acuity below 1/20 and a flat ERG; an interval of several years before worsening favours CORD [10]. Stargardt disease spares the periphery and has yellow flecks, bull's-eye and dark choroid; in ABCA4 CORD, the onset may be similar, but peripheral signs appear within a decade [10]. Macular dystrophies have a normal ffERG, although they may progress to COD or CORD [16, 70]. In cone dystrophy, the rods remain at least partly spared until late and macular lesions may be absent for years despite reduced acuity, whereas in advanced CORD the rods are unrecordable [10].

A case published in 2026 illustrates a nomenclature pitfall: a 65-year-old woman with progressive central loss, photophobia, dyschromatopsia, macular atrophy, ffERG with normal photopic and scotopic amplitudes and mfERG with bilateral central dysfunction, carrying the CRX variant NM_000554.6:c.166G>A p.(Ala56Thr) classified as likely pathogenic, was described as CORD [134]. With a normal ffERG, the phenotype corresponds, by electrophysiological criteria, to CRX-associated macular dystrophy [16].

Occult macular dystrophy (Miyake disease; OMIM 613587; ORPHA:247834) is the extreme example of cone dysfunction confined to the macula: the fundus is normal or near normal, the ffERG is normal and only OCT and mfERG demonstrate the disease, so the French PNDS includes it among the differentials of maculopathies with a preserved ffERG [19, 133]. The classical form is AD and is due to missense variants in RP1L1 (8p23.1), the most common of which is NM_178857.6:c.133C>T p.(Arg45Trp), in the first doublecortin domain, with most of the others in a second hotspot between residues 1196 and 1201 [133]. In a French multicentre cohort of 20 patients from 19 families (REFERET and Rennes), 12 had occult macular dystrophy, 9 of them with p.(Arg45Trp); the most frequent symptoms were reduced acuity, photophobia and dyschromatopsia, the mean age at onset was 31.5 years (6 to 66), median BCVA was 0.6 logMAR and declined by about one ETDRS line every two years over a median of 3.2 years of follow-up, and the penetrance of AD forms was estimated at 85% [133]. The ffERG was normal in most, but two heterozygous patients had mild cone dysfunction and one patient homozygous for p.(Arg45Trp), the son of asymptomatic consanguineous parents, had generalised cone–rod dysfunction with onset at 9 years; biallelic null variants of the same gene cause AR RP (RP88) [133]. These data show that RP1L1 crosses the boundary between macular dystrophy, COD and CORD and that ffERG should be performed even when the picture appears purely macular [133]. The annex of the French PNDS also describes, among rare non-syndromic maculopathies, AD forms due to CRX and PROM1 with macular thinning and hypoautofluorescence, an AR form due to CRB1 in young adults with thickening, hyperreflective dots and cysts, and an AR maculopathy due to RP1 with macular loss of the ellipsoid line, with or without foveolar sparing and with a hyperautofluorescent border [19].

6.5. Stationary disorders and syndromic forms

CABP4 cone–rod synaptic disorder has low but stable acuity, small-amplitude nystagmus, photophobia, altered colour vision, hypermetropia and a normal fundus, with severely reduced rod and cone responses due to a synaptic signalling defect and not to degeneration; there is no nyctalopia [68]. Congenital stationary night blindness (CSNB) has a structurally normal retina and a normal fundus [70]. Among the syndromic forms, Alström syndrome is distinguished from achromatopsia by cardiomyopathy, obesity, sensorineural deafness, type 2 diabetes, liver disease and renal dysfunction, and on OCT by retention of the central inner layers; atrophy or cavitation of the central outer retina is common in achromatopsia and is not described in Alström [7]. Compared with Bardet-Biedl syndrome, visual problems appear from birth to 2 years in Alström and at a mean of 8.5 years in Bardet-Biedl, polydactyly is common in Bardet-Biedl and not described in Alström, and deafness (88% versus about 5%) and diabetes (68% versus 5–10%) are more frequent in Alström [59]. ALMS1 explains less than 1% of LCA and early-onset dystrophies, so a child labelled as having non-syndromic LCA may have Alström syndrome and needs cardiac and metabolic surveillance [6, 59]. PHARC syndrome resembles Refsum disease, but phytanic and pristanic acids are normal [120]. Liberfarb syndrome (PISD), described in five patients of Portuguese ancestry with a homozygous intronic deletion, combines spondyloepimetaphyseal dysplasia, progressive microcephaly, intellectual disability, chorioretinal degeneration and sensorineural deafness [120]. Other diseases with retinal dystrophy to consider are Cohen, Joubert and Senior-Løken syndromes, Refsum disease, abetalipoproteinaemia and peroxisomal disorders [69, 113].

7. Treatments and Risk Management Strategies

7.1. Current situation

There is no proven treatment that halts the progression of COD/CORD or restores lost vision [9, 10]. No medicinal product or gene therapy is authorised by the FDA (Food and Drug Administration, USA) or by the European Commission, on the opinion of the European Medicines Agency (EMA), for these diseases, and there is therefore no summary of product characteristics or doses to record [9, 18]. The only authorised retinal gene therapy, voretigene neparvovec (Luxturna®), is intended for retinal dystrophy associated with biallelic RPE65 variants and does not apply to any COD/CORD gene [14, 23]. A search of ClinicalTrials.gov on 10 October 2026, with the terms «cone-rod dystrophy», «cone dystrophy», GUCY2D, CNGA3, CNGB3, achromatopsia, RPGR, blue cone monochromatism and PDE6C, identified no interventional trial specifically targeting COD/CORD; the genetic trials found concern GUCY2D LCA1, RPGR X-linked RP (XLRP) and CNGA3 or CNGB3 achromatopsia [17]. A negative search of one registry does not prove the absence of trials in other registries. Current management is that of typical RP, with emphasis on filter glasses, low vision rehabilitation and early educational and vocational guidance [10].

7.2. Symptomatic measures and rehabilitation

Symptomatic management includes refractive correction, glasses or contact lenses with filters for photophobia and low vision aids [9]. Red or red-orange tinted lenses reduce photophobia and may improve acuity in cone diseases, and have been advocated since the original description of Jalili syndrome; in achromatopsia dark red lenses are used, which reduce rod saturation, and in blue cone monochromatism magenta-tinted lenses [5, 7, 11, 57]. In the early phases of CORD in Alström syndrome, prescription lenses with a red-orange tint reduce photodysphoria [7]. The extrapolation of these measures from achromatopsia to COD/CORD rests on the common mechanism of photophobia and not on comparative trials. In RP, lenses with a 550 nm cut-off filter (which filter 97–99% of the energy below 550 nm) are used for glare, contrast and adaptation, and glasses blocking UV-A and UV-B are recommended [4].

Low vision aids include high-power magnifiers, video magnification systems, digital devices and appropriate lighting [4, 5]. At school, the child should sit at the front and away from windows [5]. In diseases in which blindness is foreseeable, such as Alström syndrome, early educational planning includes teaching Braille, mobility training, independent living skills and computer skills (voice recognition, screen-reading software), with large-print materials while there is useful vision [7, 8]. As many patients with early-onset CORD are severely disabled by the end of the second decade, Hamel recommended directing training towards adapted occupations [10]. The AAO recommends low vision assessment at baseline and every 1–2 years as needed, with vocational rehabilitation, mobility training, assistive technologies, a guide dog, mental health support and information on registries and trials [14]. In the USA, early intervention covers the period from birth to 3 years and is followed by an individualised education plan [130]. Children may need psychological and educational support from a multidisciplinary team [69].

The French PNDS, written for diseases with central scotoma and applicable by extension to COD, details rehabilitation [19]. Filter glasses should have a wraparound frame with wide temples; there are mini-cameras attached to glasses that read a text pointed at with the finger, and voice and character recognition software; therapeutic education focuses on the use of eccentric fixation and of optical, non-optical and electronic aids, and coordination between professionals is preferred to isolated interventions [19]. Braille and institutional care are rarely needed in maculopathies; in CORD with a foreseeable course to legal blindness the educational planning described above is maintained; a mobility instructor, guide dog, occupational therapy (especially in syndromic forms) and physiotherapy for postural musculoskeletal pain complete the provision [19]. At school, the child faces the board, with adapted lighting, a computer or tablet to photograph the board, materials in digital format, extra time in examinations, a school support assistant as needed and, if justified, an individualised reception protocol [19]. In French adults, an acuity below 5/10 and/or a central scotoma preclude driving, and vocational reorientation involves the occupational physician, the social worker and specialised rehabilitation centres [19]. The risk of depression and anxiety should be assessed regularly, especially in the phase in which acuity is declining, and a psychology consultation should be offered to the patient and family [19].

7.3. Gene-dependent advice

Molecular diagnosis changes lifestyle advice [9, 28]. In ABCA4 retinopathy, it is recommended to avoid vitamin A supplements, which in the animal model accelerate A2E accumulation, and to avoid bright light with filter glasses, in addition to not smoking and wearing eye protection in sport, because minor trauma may precipitate subretinal fibrosis [9, 24]. The French PNDS goes further in Stargardt disease: it advises against violent and combat sports with a risk of head impact, because of the risk of dense retinal haemorrhages that progress to subretinal fibrosis, and considers filter glasses and a peaked cap mandatory, with blue-light filters or suppression of blue light from screens [19]. For all maculopathies, it recommends not smoking, a varied diet rich in fruit and vegetables, fish three times a week and regular physical activity, even if moderate (one hour a day), general recommendations without trials in COD/CORD [19]. In GUCA1A retinopathy, some clinicians advise sleeping with the light on to avoid nocturnal accumulation of cGMP; this is an opinion based on mechanism, without a clinical trial and without guideline endorsement [9, 11]. The two pieces of advice are opposite and show that generic advice on light protection or supplementation should not be given without knowing the gene.

7.4. Treatment of complications and associated manifestations

The treatable complications are cataract, macular oedema and inflammation [10]. In RP, cystoid macular oedema is treated with systemic (oral acetazolamide) or topical (dorzolamide) carbonic anhydrase inhibitors, with the possibility of rebound oedema [4]. The sources consulted give no doses or efficacy data specific to COD/CORD, the use of these drugs in these diseases is an off-label extrapolation from RP, and the sources diverge on the evidence in RP. In cataract surgery in patients with RP, the increased risk of postoperative inflammation and cystoid macular oedema justifies avoiding iris manipulation and prolonging anti-inflammatory treatment [4]. Choroidal neovascularisation, described in ABCA4 retinopathy, is treated with intravitreal anti-angiogenic agents [24]. The French PNDS restricts intravitreal anti-VEGF injections to the active phase of neovascularisation and regards them as useless in the fibrosis phase; neovascularisation is rare in Stargardt disease, occurs in about 15% of patients with Best disease and is constant at around 50 years in Sorsby dystrophy [19]. The PNDS indicates no drug or dose; ranibizumab, bevacizumab and aflibercept are used in macular dystrophies with labelling limitations. In Jalili syndrome, restorative and preventive dental care for the amelogenesis imperfecta is needed [57]. In spondylometaphyseal dysplasia with CORD, genu varum and coxa vara may require corrective osteotomies, and coxa vara may lead to slipped capital femoral epiphysis [61]. In Alström and Bardet-Biedl syndromes, management of the cardiac, metabolic, renal and hearing manifestations follows the respective GeneReviews [7, 8].

7.5. Supplements and interventions without demonstrated benefit in COD/CORD

The nutritional recommendations for RP do not transfer to COD/CORD without knowing the gene. Vitamin A palmitate (15,000 IU per day, according to the 1993 Berson trial in RP) should not be used in ABCA4 disease, is not recommended before 18 years, is teratogenic and requires monitoring of serum vitamin A, liver function and bone density; high-dose vitamin E supplements (for example, 400 IU per day) should be avoided in RP, and docosahexaenoic acid and lutein have had limited results [4]. None of these interventions has been tested in trials in COD/CORD, and vitamin A is contraindicated in the most frequent form of AR CORD, the one associated with ABCA4 [9, 10]. The intraocular ciliary neurotrophic factor (CNTF) implant was safe in RP but without benefit in phase II, and in CNGB3 achromatopsia it did not improve cone function, although patients reported reduced photosensitivity with slower dark adaptation [4, 5]. Prolonged light deprivation was ineffective in RP [4]. The Argus II epiretinal prosthesis was approved by the FDA for end-stage RP with light perception or worse [4]; the sources consulted do not describe its use in CORD.

7.6. Investigational gene and cell therapies

RPGR. RPGR gene therapy trials include men with XLRP; patients with an RPGR COD/CORD phenotype are not the population studied, and efficacy in that phenotype is unknown [135, 136]. Laruparetigene zovaparvovec (laru-zova, AGTC-501; rAAV2tYF-GRK1 vector with the complete codon-optimised ORF15, subretinal administration; Beacon Therapeutics) was tested in the randomised, controlled phase 2/3 VISTA trial (NCT04850118) in 85 men aged 12 to 48 years [135, 137]. Topline results announced on 21 September 2026 indicate that the primary endpoint, the proportion of patients with a gain of at least 15 letters in low-luminance visual acuity (LLVA) at month 12, was met in 31.0% in the high-dose group (6.8×10¹¹ vector genomes per eye; p=0.0019) and in 24.1% in the low-dose group (3.7×10¹¹; p=0.0106), versus 0% in the untreated control group [135, 137]. Ocular adverse events were mainly mild or moderate and procedure-related, with two serious ocular adverse events in the low-dose group attributed to the procedure [135]. The product received FDA RMAT (Regenerative Medicine Advanced Therapy) designation in February 2025, and the sponsor plans to initiate a biologics licence application (BLA) by rolling submission at the end of 2026 [135]. These data come from a sponsor press release reproduced by two independent specialist publications, without peer-reviewed publication or confirmation in an official regulatory source. A bilateral phase 2 trial is under way (NCT07174726, n=10, started in September 2025) [17, 135].

Botaretigene sparoparvovec (bota-vec, AAV5-hRKp.RPGR; MeiraGTx and Johnson & Johnson) was tested in the phase 3 LUMEOS trial (NCT04671433), with 95 patients randomised to bilateral high or low dose or to a deferred-treatment control; the primary endpoint, navigation of a reduced-light maze at 52 weeks, was not met (announced in May 2025) [136, 138]. Of the 55 treated patients, 22 had benefit in several secondary endpoints (LLVA and static perimetry), all had at least one treatment-emergent adverse event (86% mild or moderate) and 53% had at least one product-related event; the extension NCT04794101 remains active [136, 138]. Other programmes for XLRP are intravitreal 4D-125 (NCT04517149, phase 1/2, n=21), FT-002 (NCT05874310, NCT06492850) and cotoretigene toliparvovec (BIIB112; NCT03116113, phase 1/2, n=50, completed) [17].

GUCY2D. ATSN-101 (subretinal AAV5 with GUCY2D; Atsena) was tested in a multicentre, open-label, unilateral, dose-escalation phase 1/2 trial (NCT03920007) in 15 patients with LCA1 due to biallelic variants [85]. There were no serious product-related adverse events, and ocular inflammation was mild and reversible with corticosteroids; at the high dose, dark-adapted full-field sensitivity improved by 20.3 dB (95% confidence interval, 95% CI: 6.6–34.0) in treated eyes versus 1.1 dB (−3.7 to 5.9) in untreated eyes at 12 months (p=0.012) [85]. CORD6 is an AD gain-of-function disease, and adding a normal copy of the gene does not correct that mechanism; ATSN-101 does not apply to CORD6 [11, 85]. For the dominant forms, AAV-delivered CRISPR/Cas9 inactivation of GUCY2D has been studied in mice and macaques, a preclinical approach [11].

AIPL1. Four children aged 1.0 to 2.8 years with severe AIPL1 retinal dystrophy received subretinal rAAV8.hRKp.AIPL1 in one eye, manufactured under an MHRA (UK regulatory agency) «Specials» licence; after a mean of 3.5 years, acuity in the treated eye improved from light perception (about 2.7 logMAR) to 0.9 logMAR, untreated eyes became unmeasurable and there was one case of cystoid macular oedema [139]. This is a special-use human study, not a marketing authorisation, and its relevance to COD/CORD is indirect [6, 139].

Achromatopsia. In the Tübingen phase 1 trial (NCT02610582), nine patients with CNGA3 achromatopsia received unilateral subretinal AAV8.CNGA3; there were no substantial safety issues, and acuity improved by 2.9 letters (95% CI 1.65–4.13) and contrast sensitivity by 0.33 log (95% CI 0.14–0.51) at 12 months [140]. At 3 years, the benefits persisted, but most outcomes were not significant in comparison with the untreated eye, and amblyopia was suggested as a possible limitation [141]. In the phase 1/2 trial of AAV8-hCARp.hCNGB3 (NCT03001310), in 23 patients with CNGB3 (11 adults and 12 children aged 3 years or older), there was intraocular inflammation in 9, with two dose-limiting events, and no consistent pattern of improvement at 24 weeks [142]. Long-term follow-up (NCT03278873) ended in April 2024, and two trials (NCT02935517, NCT02599922) have had unknown status since 2022 [17].

Preclinical. There are animal model studies for GUCA1A (RNA interference silencing in the p.(Tyr99Cys) mouse, with increased photoreceptor survival), PRPH2 (gene therapy in the Prph2rd2/rd2 mouse, cone transplantation, PARP inhibitor), CDHR1 (rescue of cones and rods for 23 months in the Cdhr1−/− mouse), KCNV2 (gene therapy in retinal organoids; small gene, suitable for AAV), RPGRIP1 (mouse, dog and organoids), CERKL (phosphatidylcholine in zebrafish) and blue cone monochromatism (two mouse models) [11, 34, 40, 48, 100, 143]. None of these studies involved patients. The OpCT-001 cell therapy (NCT06789445, phase 1/2, n=54) is recruiting patients with «primary photoreceptor disease» [17].

7.7. Regulatory status

7.8. Clinical trials relevant to COD/CORD

These trials did not test patients with COD/CORD, and the results cannot be transposed to the cone–rod phenotype, even when the gene is the same. Endpoints differ between trials (LLVA, navigation, FST, acuity), as do populations and durations, so indirect comparison between products is not legitimate. Relative gains should be read with the absolute rates: in VISTA, one third of high-dose patients had a 15-letter gain in LLVA, and two thirds did not. Phase 1/2 trials with the untreated fellow eye as control have an open-label design. LUMEOS was negative on the primary endpoint and the achromatopsia therapies had modest benefit, which shows that safety and transgene expression do not guarantee functional benefit [136, 141, 142].

7.9. Developments from October 2025 to October 2026

The VISTA topline results (21 September 2026) are a sponsor press release, not a peer-reviewed article or a regulatory decision [135, 137]. Acceptance of the MCO-010 BLA for RP (September 2026) appears in a single specialist publication and has not been confirmed in an official FDA source [135]. The Brazilian cohort of 52 patients with CERKL (published in September 2026) and the case of RAB28 CORD with a de novo deletion (2026) are human observational studies [41, 83]. ClinGen classified the AD relationship between AIPL1 and retinal dystrophy as disputed in April 2025 [97]. None of the sources consulted describes a new regulatory authorisation for COD/CORD in this period.

7.10. Agents to avoid, pregnancy, perioperative period and transition

In ABCA4 disease, vitamin A supplements should be avoided [9, 24]. The French PNDS extends the precaution to mere suspicion of Stargardt disease and also recommends avoiding quinine derivatives [19]. Exposure to retinotoxic drugs should be recorded at the initial assessment [14]. High-dose vitamin A is teratogenic, which is relevant for any woman with retinal dystrophy taking it by extrapolation from RP [4]. The sources consulted do not describe effects of pregnancy on the course of COD/CORD or specific lactation recommendations. In cataract surgery, the precautions described for RP apply (avoid iris manipulation and prolong anti-inflammatory treatment) [4]. In early-onset forms, counselling should be repeated later in life, when the patient reaches adulthood and reproductive and occupational questions become their own [14]. The French PNDS provides for transition to adult services at the end of adolescence, to avoid interruption of follow-up [19].

7.11. Guideline recommendations and divergences

There is no guideline dedicated to COD/CORD. The applicable recommendations come from documents on inherited retinal dystrophies in general. The AAO (2022) recommends initial assessment and follow-up every 1–2 years with BCVA, SD-OCT, FAF, perimetry and ERG when appropriate, genetic testing with a panel that includes syndromic genes and low vision assessment every 1–2 years [14]. The AAO (2014) recommends offering genetic testing with counselling, a certified laboratory and a report given to the patient, and advises against testing asymptomatic minors for diseases without treatment [132]. ERN-EYE (2021) advocates universal access to genomic testing in Europe [21]. The ISCEV standard (2022) defines the ffERG [15]. The main divergence is temporal: the restriction of exome and genome to research, advocated by the AAO in 2014, has been replaced by the recommendation to test all people with suspected inherited retinal dystrophy (AAO and ERN-EYE) and by the clinical use of broad panels, exome and genome [18, 21, 132]. The follow-up interval also differs between sources: 1–2 years for the complete assessment according to the AAO, annual assessment for treatable complications according to Lam and colleagues, and ffERG every 3–5 years in CRX according to GeneGuidance [14, 18, 26].

The HAS PNDS for genetic maculopathies (July 2021) is the only national guideline consulted that addresses COD, albeit only as a differential [19]. There are four divergences from the other sources. On follow-up, the PNDS sets an annual ophthalmological consultation and reassessment at a reference or competence centre every 2–3 years (the follow-up section states three years), more frequent than the AAO's 1–2 years and coinciding with the annual assessment of Lam and colleagues [14, 18, 19]. On genetic strategy, the PNDS allows whole genome sequencing as first-line within the PFMG2025 framework, and as a trio when cone dystrophy is suspected, whereas the AAO (2022) presents the NGS panel as an efficient first step [14, 19]. On testing minors, the PNDS excludes testing an unaffected minor for a dominant disease and only allows testing of minors with clinical signs, whereas the AAO (2014) accepts exceptions in extraordinary circumstances with written counselling and consent [19, 132]. On light protection, the PNDS recommends light protection for all maculopathies and makes it mandatory in ABCA4, which is consistent with ABCA4 disease but not with the untested suggestion of sleeping with the light on in GUCA1A retinopathy; in COD/CORD, the advice should depend on the gene [9, 11, 19].

8. Reproductive Options and Family Counselling

8.1. Principles

Genetic counselling is always indicated in COD/CORD, because all modes of inheritance are possible, and requires a precise phenotypic diagnosis, especially in sporadic cases [10]. In a sporadic patient with RP, CORD or macular dystrophy without a definitive diagnosis after complete investigation, bilateral and symmetric findings indicate a genetic aetiology and a high recurrence risk, and AR inheritance is the most likely mode [69]. The Bonn cohort shows the limits of this rule: of the solved sporadic cases, 71% were AR, 27% AD (due to de novo variants or reduced penetrance), one was XL and two mitochondrial; an apparently dominant two-generation pedigree may correspond to AR disease with pseudodominance (three cases, all due to ABCA4) [16]. Molecular diagnosis is therefore the basis of risk calculation.

Pre-test counselling should explain the benefits and limits of testing: targeted panels may miss differentials, broad tests generate unexpected or uncertain findings, apparently isolated forms may turn out to be syndromic, and a positive result does not guarantee eligibility for trials or therapies [18]. Post-test counselling interprets the result in the clinical context and identifies relatives at risk, and should be carried out by a specialist physician or a genetic counsellor [14, 18]. In the USA, less than 1% of the approximately 5000 certified genetic counsellors have experience in ophthalmology, and only 1.5% of 207 people with inherited retinal dystrophy in a university system (2008–2018) had testing ordered in the ophthalmology clinic [18].

8.2. Autosomal recessive inheritance

In AR forms (ABCA4, KCNV2, ADAM9, CDHR1, CERKL, RAB28, POC1B, TTLL5, RPGRIP1, biallelic PROM1 and others), the parents of a patient are obligate, asymptomatic heterozygotes; each sibling has a 25% probability of being affected, 50% of being a carrier and 25% of not being a carrier; the children of a patient are obligate carriers and aunts and uncles have a 50% probability of being carriers [5]. In ABCA4 disease, the carrier frequency in the population (about 1 in 50 according to the 1998 estimate) makes it possible for a patient's partner to be a carrier, with a 50% risk for each child (pseudodominance) [16, 73]. In populations with consanguinity or a founder effect (CERKL variants in Yemenite Jews, CDHR1 in the Faroe Islands, RAB28 in Lisbon), carrier testing of the partner becomes relevant [39, 43, 104]. In the Portuguese cohort, about 51% of solved probands had homozygous recessive variants, often in regions of homozygosity suggesting founder variants [43].

8.3. Autosomal dominant inheritance

In AD forms (GUCY2D, GUCA1A, CRX, PRPH2, PROM1 p.(Arg373Cys), RAX2), each child of a patient has a 50% probability of inheriting the variant [69]. Variable expressivity (COD, CORD and macular dystrophy in the same family due to GUCA1A p.(Tyr99Cys); LCA to late-onset macular degeneration due to CRX) prevents prediction of disease severity in offspring from the parent's phenotype [26, 86]. Reduced penetrance exists in some AD families, and the PRPH2 p.(Arg172Trp) variant ranges from non-penetrance to severe CORD [9, 69]. De novo CRX variants are frequent in severe presentations, and an isolated case may be AD [16, 26].

8.4. X-linked inheritance

In XL forms (RPGR, CACNA1F), a female carrier transmits the variant to 50% of her sons (who will be affected) and 50% of her daughters (who will be carriers); an affected man transmits it to all his daughters and none of his sons; male-to-male transmission excludes XL inheritance [32]. XL inheritance should be considered when there are two or more affected boys or typical findings of XL dystrophy, and the mothers of isolated boys should have careful fundus examination and ERG; in XLRP, 90% of carriers have fundus or ERG changes [69, 70]. Severity in female carriers of RPGR variants follows skewed X inactivation: 57% of carriers with extreme skewing (≥80:20) were severely affected, versus 8% of the others, and most of those who progressed to moderate or severe loss were over 30 years of age [118]. In the Portuguese cohort, 23 female relatives in 5 of 11 families had clinical or subclinical signs and three probands were heterozygous women [43]. A symptomatic carrier should be followed as a patient.

8.5. Special situations

Apparent homozygosity with a non-carrier parent may result from a de novo deletion of the other allele, as in the case of RAB28 CORD with a de novo 4p16.1p15.33 deletion; in that situation, the risk to siblings is low (with the caveat of germline mosaicism) and the patient's children are obligate carriers [83]. Uniparental isodisomy has been described as a cause of Jalili syndrome [57]. PRPH2/ROM1 digenic inheritance causes RP and not CORD, but should be considered when a family with a PRPH2 variant has a non-Mendelian inheritance pattern [4, 93]. In men with biallelic truncating TTLL5 variants, male infertility should be discussed [46, 47].

8.6. Cascade testing, carriers and minors

Testing of relatives and carriers is possible when the causal variant is known; fundus examination and electrophysiology help, but genetic testing is the recommended method [69]. Carrier testing applies to recessive and XL inheritance [18]. The AAO advises against genetic testing of asymptomatic minors for diseases without treatment, except in extraordinary circumstances, with formal counselling, a written opinion from the counsellor or physician and the written agreement of all parents with parental responsibility [132]. The ACMG and the American Academy of Pediatrics advise against routine testing of minors for adult-onset diseases without treatment, and predictive testing of asymptomatic individuals with a known familial variant should be done with caution [18]. In families with childhood-onset disease, a normal examination at 20 years is more reassuring than in adult-onset diseases [70]. Presymptomatic detection may occur incidentally, as in a 7-year-old boy with 20/20 acuity and an RPGR ORF15 variant [18]. In France, the PNDS requires written consent for any genetic study, only allows testing of a minor with clinical signs and with the agreement of the parents or guardian, excludes testing an unaffected minor for a dominant disease and recommends discussing with the parents the psychological impact of systematic clinical examination of the siblings of an affected child [19]. In AR disease, parental DNA is needed to confirm by segregation that the two variants are in trans [19].

8.7. Prenatal and preimplantation diagnosis and DNA banking

Prenatal diagnosis and preimplantation genetic testing are possible after molecular identification, and counselling is ideally provided before pregnancy [5, 69]. In a disease that is not life-threatening, performing invasive procedures raises an ethical question that should be discussed with the couple [10]. The French PNDS describes prenatal and preimplantation diagnosis in maculopathies as very strictly regulated possibilities with numerous restrictions, conditioned by the current limit of the distinction between rare non-pathogenic and pathogenic variants, and recommends that a patient with an ABCA4 variant and plans for a family may offer testing to the partner, explaining that a negative result does not exclude intronic or not yet classified variants, in a population in which, according to the PNDS, about 1 in 50 people is a carrier [19]; molecular series estimate about 1 in 20 carriers of a potentially pathogenic allele when frequent hypomorphic alleles, such as c.5603A>T p.(Asn1868Ile), are included [144]. In a dominant disease, the 50% risk per pregnancy does not equate to certain disease in the carrier, because of variable penetrance and expressivity [19]. When no diagnosis is obtained, DNA (and possibly a fibroblast line) should be stored for future reanalysis [69]. Counselling should be repeated later in the lives of patients with early-onset forms [14].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There is no population-based study that directly measures the prevalence of COD/CORD. The available values measure different things and should not be confused. Orphanet gives for CORD a European point prevalence of 2.5/100,000 (class 1–9/100,000), with the status «not yet validated» [1]. Hamel estimated, in 2007, a prevalence of 1/40,000, about ten times lower than that of RP, without a defined population denominator [10]. Gill and colleagues cite an incidence of 1/20,000 to 1/100,000, attributed to earlier studies [9]. In Spain, a study of 6089 affected individuals from 4403 families from all autonomous communities calculated a minimum prevalence of 1:27,436 (CI 1:26,192–1:28,804) for cone-dominant phenotypes, a group that includes most COD and CORD, achromatopsia and also macular dystrophies; non-syndromic RP had a minimum prevalence of 1:13,121 [12]. This estimate is a minimum, depends on recruitment (26.7% of cases from Madrid) and does not isolate CORD [12]. For comparison, the global prevalence of inherited retinal dystrophies is estimated at between 1/1000 and 1/4000, and that of RP at about 1/4000 [12, 21, 70].

For the specific entities, the data are as follows. KCNV2-associated cone dystrophy has a validated Orphanet prevalence below 1/1,000,000 (45 cases); a 2026 population-genomic study estimated a clinical prevalence of 1/865,000 and, from gnomAD (807,162 individuals), 1/343,926 considering only known pathogenic variants, values that act as bounds dependent on variant classification [3, 34]. Achromatopsia has a validated worldwide prevalence of 2.7/100,000 and blue cone monochromatism of 1.0/100,000 [65, 66]. Alström syndrome has estimates between 1:100,000 and 1:1,000,000, with about 950 individuals identified worldwide [7, 59]. Jalili syndrome, spondylometaphyseal dysplasia with CORD and CORD with short stature have a prevalence below 1/1,000,000 [58, 63, 129]. Red–green colour defects, a frequent differential, were found in 5.6% of non-Hispanic white boys, 3.1% of Asian, 2.6% of Hispanic and 1.4% of Black boys, and in 0.0–0.5% of girls, in a study of 4177 preschool children in southern California [114, 145].

9.2. Genetic distribution by region

In the USA, COD/CORD data come mainly from tertiary centre series, such as the National Eye Institute series with CDHR1 [124], and from free testing programmes associated with registries (Foundation Fighting Blindness with the My Retina Tracker registry) [21]. In the United Kingdom, in a cohort of 3195 families with a molecular diagnosis from Moorfields Eye Hospital, the most frequent genes were ABCA4 (20.8% of families; Stargardt disease and CORD), USH2A, RPGR (5.1%; RP, cone dystrophy or CORD), PRPH2 (4.6%) and BEST1; CNGB3 explained 1.4%, GUCY2D 1.2%, PROM1 1.2% and CNGA3 1.1%, and RPGR about 40% of XL retinopathies [146]. This is a tertiary centre with referral bias, and the percentages are not population prevalences [146]. In Germany, the Bonn cohort found ABCA4 in 37%, PRPH2 in 12% and BEST1 in 8% of patients with macular dystrophy, COD or CORD [16]. In the Netherlands, Belgium and the United Kingdom, the Thiadens cohort gave ABCA4 in 26% of AR CORD and RPGR in 4 of 5 XL CORD [13]. In Spain, ABCA4 explained 82.7% of solved AR cases of cone-dominant phenotypes and PRPH2 42.2% of AD cases [12]. In a large French cohort cited by Birtel, PRPH2 explained 3.4% of all cases and 11.8% of AD cases [16]. In Japan, GUCA1A explains only 0.25% of families with inherited retinal dystrophy, unlike in Europe [87].

9.3. Founder variants and populations

9.4. Portugal and Brazil

In Portugal, the first study of the genetic landscape of inherited retinal dystrophies included 230 probands (110 men and 120 women) and 89 relatives from the Instituto de Oftalmologia Dr. Gama Pinto, in Lisbon, studied over six years by exome, CNV analysis and microarray genotyping [43]. The clinical diagnoses were RP (47%), CORD (14%, 32 probands), LCA (10%), Usher syndrome (6%), Stargardt disease and macular dystrophy (6%), cone dystrophy (5%, 11 probands) and achromatopsia (2%) [43]. A genetic diagnosis was achieved in 76% of families, and the most frequent genes were EYS, ABCA4, RPGR and USH2A, a landscape distinct from the Spanish one [43]. RAB28 p.(His144Tyr) CORD in four patients from a region in the north of the Lisbon district and DRAM2 CORD in two sisters are the CORD-specific findings [43]. Liberfarb syndrome (PISD) was described in five patients of Portuguese ancestry [120]. The ERN-EYE survey (2018, updated in 2020) indicated that Portugal had no national genetic testing initiative, that ophthalmologists could not prescribe the test, that the exome was not accessible in clinical practice and the genome only in research, that panels and Sanger sequencing were reimbursed but exome and genome were not, that there was a shortage of specialists in genetic ophthalmology and that samples were sent abroad [21]. These data come from a survey of network members and may be out of date.

In Brazil, the cohort of the Instituto de Genética Ocular in São Paulo identified 52 patients from 50 families with CERKL dystrophy among 2841 inherited retinal dystrophy records (2006–2025), 50 of them with CORD, with consanguinity in 15 of 50 families and a predominance of the p.(Arg257Ter) variant attributed to Iberian immigration [41]. Two Brazilian families contributed to the identification of PCYT1A in spondylometaphyseal dysplasia with CORD [81]. Hamel mentions a CORD9 locus mapped in a Brazilian family [10]. The sources consulted give no prevalence estimates of COD/CORD for Portugal or Brazil, which does not mean that there are no published data.

9.5. Special populations

In children, electrophysiological assessment requires adaptations (skin electrodes, sedation, age-specific norms) and the diagnosis of ABCA4 disease without visible lesions is often delayed [14, 24]. Female carriers of RPGR variants may have clinically significant disease and should be examined [43, 118]. Patients with syndromic forms need multidisciplinary follow-up from diagnosis [7]. In populations with high consanguinity, the proportion of recessive cases and founder variants is greater [43, 127].

9.6. Reference networks and patient associations

ERN-EYE (European Reference Network for Rare Eye Diseases) is organised into four clinical groups (Retina, Neuro-ophthalmology, Paediatric and Anterior segment) and six transversal groups (Low vision, Genetic diagnosis, Registries, Research, Education and Communication), and promotes access to genomic testing in Europe [20, 21]. Rare eye diseases, more than 900, are the leading cause of visual impairment and blindness in children and young adults in Europe [21]. Patient associations with a verified website include Retina UK (https://retinauk.org.uk/), PRO RETINA Deutschland (https://www.pro-retina.de/), the Foundation Fighting Blindness in the USA (https://www.fightingblindness.org/) and Retina Brasil (https://retinabrasil.org.br/); the AAO also cites Retina International, Fighting Blindness Canada, the American Foundation for the Blind and CNIB [14]. In the United Kingdom, the reference book lists RNIB, the Macular Society, RP Fighting Blindness, Fight for Sight and SENSE [69]. For achromatopsia there are associations in the USA (Achroma Corp), Germany (Achromatopsie Selbsthilfeverein) and Italy (Associazione Acromati Italiani) [5]. The FFB My Retina Tracker registry (NCT02435940) and the Universal Rare Gene Study (NCT05589714) collect patient data for future trials [17].

In France, care is organised in the SENSGENE rare sensory disease health filière (https://www.sensgene.com/), with the reference centres REFERET (retinal and macular disorders of genetic origin, Centre hospitalier national d'ophtalmologie des Quinze-Vingts, Paris), MAOLYA (genetic sensory disorders, CHU de Montpellier, coordinating centre of the PNDS), CARGO (rare disorders in ophthalmic genetics, CHU de Strasbourg) and OPHTARA (rare ophthalmological diseases, Hôpital Necker-Enfants malades, Paris), and a network of regional competence centres, including the visual exploration and neuro-ophthalmology department of the CHRU de Lille [19]. The PNDS recommends that follow-up be directed by an expert from one of these centres, who organises the local network, and that the attending physician coordinate 100% coverage (long-term condition outside the list) and the application to the Maison départementale des personnes handicapées (MDPH) [19]. The French associations listed include Retina France, Fondation Stargardt, Association Valentin Haüy, Fédération des Aveugles de France, SOS Rétinite, IRRP and RETGEN; referral to associations is proposed systematically, with the choice left to the patient [19].

10. Illustrative Clinical Case

10.1. Sporadic CORD due to a paternal RAB28 variant and a de novo 4p deletion

Park and colleagues described, in 2026, a 7-year-old Korean girl referred to a university hospital for poor vision and intermittent exotropia; the school had noticed a possible colour vision deficit, and the parents and younger brother had no complaints [83]. BCVA was 20/40 in both eyes; HRR pseudoisochromatic plates showed a severe red–green defect and a mild to moderate blue–yellow defect, and there was an exotropia of 25 prism dioptres. The fundus showed macular atrophy and temporal disc pallor; FAF showed bull's-eye maculopathy with a hyperautofluorescent fovea, and SD-OCT showed photoreceptor loss with sparing of the periphery and a central macular thickness of 108 μm in both eyes (Fig. 1: https://pmc.ncbi.nlm.nih.gov/articles/PMC13455248/figure/Fig1/) [83]. The ffERG showed markedly reduced photopic responses (LA 3.0 and 30 Hz flicker) and relatively preserved scotopic responses (DA 0.01 and DA 3.0), with slightly reduced amplitudes, a CORD pattern (Fig. 2: https://pmc.ncbi.nlm.nih.gov/articles/PMC13455248/figure/Fig2/) [83]. The child had no dysmorphic features or developmental delay, and the parents had normal acuity, colour vision and fundus. She underwent bilateral lateral rectus recession and correction of epiblepharon; at the last visit, at 9 years, acuity was 20/60 in the right eye and 20/40 in the left, with a spherical equivalent of −3.0 and −1.5 dioptres [83].

Clinical exome sequencing (panel of more than 4800 genes, interpretation according to the 2015 ACMG/AMP criteria and gnomAD v4.1.0 frequencies) showed the RAB28 variant NM_001017979.3:c.68C>T p.(Ser23Phe) in apparent homozygosity [22, 83]. Sanger sequencing of the parents revealed that only the father was heterozygous, which did not explain an AR disease. Trio chromosomal microarray identified a deletion of about 3.4 Mb at 4p16.1p15.33 (arr[GRCh37] 4p16.1p15.33(10379065_13755445)×1) present only in the patient, and therefore de novo, which includes RAB28 and the genes CLNK, HS3ST1 and NKX3-2 (Fig. 3: https://pmc.ncbi.nlm.nih.gov/articles/PMC13455248/figure/Fig3/) [83]. The final diagnosis was sporadic AR CORD due to a paternally inherited variant in trans with a de novo deletion of the other allele. The variant was classified with the PM2 criterion and had been described in the homozygous state in a Korean patient and a Haitian patient [83, 105].

The case teaches three practical points. First, the clinical pattern (reduced acuity and colour defect at school age, bull's-eye, ffERG with photopic predominance) is that of CORD and justifies the retinal dystrophy panel before any neurological investigation. Second, apparent homozygosity on an exome with a non-carrier parent should prompt a search for a deletion, uniparental disomy or false paternity, with segregation study and CMA; joint analysis of point variants and CNV is needed so as not to miss the diagnosis [18, 83]. Third, the recurrence risk for siblings is low, with the caveat of germline mosaicism, while the patient's children will be obligate carriers [83]. The ophthalmological management described (strabismus surgery) addresses a comorbidity of the case and is not treatment of CORD.

10.2. Long-term course with the same variant

Rao and colleagues followed a Haitian woman homozygous for the same RAB28 variant p.(Ser23Phe): she presented at 16 years with four years of blurred vision and an acuity of 20/125 in each eye, which remained relatively stable; at 27 years, the cone ERG was undetectable and the rod ERG borderline, kinetic fields were full with the V-4e target and undetectable with the I-4e, microperimetry showed an absolute central scotoma and the atrophic area expanded by less than 100 µm over six years [42, 105]. The figures of this article were not consulted; the summary is based on the text of the abstract and on the GeneGuidance curation. The two cases show, with the same variant, a CORD phenotype with childhood onset, marked central loss and slow structural progression.

11. Prognosis and Long-Term Follow-up

11.1. Prognosis

The visual prognosis of COD/CORD is worse than that of RP, because loss of central vision is early [9, 10]. In the Thiadens cohort, the mean age at legal blindness was 35 years in CORD and 48 years in COD, and ABCA4 and onset before 20 years were associated with faster progression [13]. The earlier the onset, the worse the prognosis, albeit with considerable intrafamilial variability [70]. Gene-specific data allow a more precise prognosis: in GUCY2D CORD, BCVA declines by 0.022 logMAR per year and the probability of blindness or severe visual impairment at 40 years is 32% [25]; in KCNV2 disease, BCVA changed from 0.81 to 0.90 logMAR over 8.4 years, with legal blindness before 25 years in one series [34, 98]; in RPGRIP1 disease, the decline is 0.02 logMAR per year after a rapid initial phase [107]; in CERKL disease, more than half of patients lose at least 15 letters in one eye in five years [117]; in RPGR CORD, legal blindness at 40 years is more frequent than in RP due to the same gene [9]; in AD PROM1 disease, most retain good vision until late adulthood, unlike the AR forms [110]. In Alström syndrome, acuity is 6/60 or worse by 10 years and light perception is lost by 35 years [7]; in spondylometaphyseal dysplasia with CORD, visual impairment stabilises at the end of childhood without total loss of acuity [61]. None of these estimates describes patients treated with disease-modifying therapies, which do not exist.

The structural biomarkers proposed as trial endpoints are the integrity of the EZ and ELM on SD-OCT (GUCY2D), outer nuclear layer thickness (KCNV2) and the area of hyperautofluorescent rings on FAF (RPGR) [11, 25, 123].

11.2. Follow-up

The AAO (2022) recommends, for cone–rod degenerations (category 2), an initial visit with history, pedigree, BCVA (ETDRS or equivalent), colour vision (optional), biomicroscopy, intraocular pressure, indirect ophthalmoscopy, colour fundus photography, SD-OCT, short-wavelength FAF with reduced illumination, kinetic and static perimetry, microperimetry (if available), ffERG and mfERG when appropriate and genetic testing, followed by reassessments every 1–2 years [14]. An undetectable ERG should not be repeated; static perimetry, microperimetry and mfERG have uncertain value in advanced disease with unstable eccentric fixation or very reduced acuity, and FST is useful in these situations [14]. In traditionally stationary cone conditions, such as achromatopsia, the AAO recommends a complete assessment at baseline and annual examination thereafter, because some progress slowly [14]. Lam and colleagues recommend an annual assessment to detect treatable complications (cataract, cystoid macular oedema) and prompt return in case of acute change in vision [18]. The French PNDS for genetic maculopathies recommends an annual examination by the attending ophthalmologist and a reassessment at the reference or competence centre every 2–3 years, shortened if acuity declines and extended when it stabilises; the consultation includes visual field, FAF and SD-OCT, adjustment of optical correction, search for macular oedema and neovessels, psychological support, genetics consultation after the test result and assessment of fitness to drive (acuity and binocular field) and for the workplace [19].

12. Summary and Final Considerations

Cone and cone–rod dystrophies are inherited diseases in which the cones degenerate first, or simultaneously with the rods, and which present with reduced central acuity, photophobia and dyschromatopsia, followed, in CORD, by nyctalopia and peripheral loss. The distinction between macular dystrophy, COD and CORD is electrophysiological and may change over time. Genetic heterogeneity is great, with at least 30 genes; ABCA4 dominates the recessive forms, GUCY2D, PRPH2, GUCA1A and CRX the dominant forms and RPGR the X-linked forms, and the contribution of each gene varies between populations, with founder variants in the Iberian Peninsula, the Faroe Islands, Lisbon and other populations.

Diagnosis requires ffERG according to the ISCEV standard, multimodal imaging and panel-based genetic testing that includes RPGR ORF15, CNV analysis and the genes of syndromic forms, with a yield of between about 55% and 76% in published cohorts. A negative result does not exclude the disease, variant nomenclature should be checked on the MANE transcript, and the literature contains refuted attributions, such as that of CORD7 to RIMS1, and reclassified variants, such as GUCA1A p.(Pro50Leu). Achromatopsia and blue cone monochromatism are distinguished mainly by the absence of progression and, in the latter, by preserved S-cone function.

There is no authorised treatment for COD/CORD. Management rests on refractive correction, filter lenses, low vision rehabilitation, educational and vocational support, treatment of complications and gene-dependent advice, such as avoiding vitamin A in ABCA4 disease. The most advanced gene therapy trials address RPGR XLRP, GUCY2D LCA1 and achromatopsia, and their results do not transfer to cone–rod phenotypes. Follow-up every 1–2 years, with annual assessment of treatable complications, genetic counselling adapted to the mode of inheritance and periodic reanalysis of cases without a diagnosis complete the approach.

13. References

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