Cone-rod dystrophy and hearing loss 2

Mendelian MONDO:0020780 Pathograph 15 Show in embeddings browser Inherited retinal dystrophy Sensorineural hearing loss Ciliopathy

Cone-rod dystrophy and hearing loss 2 is a rare autosomal recessive dual-sensory disorder caused by biallelic truncating variants in CEP250, which encodes C-Nap1. C-Nap1 sits at the proximal ends of the two parent centrioles and, with rootletin and NEK2, holds them together; in photoreceptors the mother centriole is the basal body of the connecting cilium, and C-Nap1 is expressed in that cilium and interacts with CEP78, the protein mutated in the sibling disorder cone-rod dystrophy and hearing loss 1. The disorder is repeatedly described in the literature as atypical Usher syndrome, and it is worth being precise about what that means. It is Usher-like in combining retinal degeneration with sensorineural hearing loss. It is not Usher syndrome in mechanism - C-Nap1 is not a component of the Usher protein interactome that organises the stereocilia hair bundle - and it differs clinically in ways that matter: the hearing loss is postlingual and progressive rather than congenital, vestibular function is spared, and the retinal disease is cone-predominant and often mild rather than the rod-first retinitis pigmentosa of classical Usher syndrome. The presentation is asymmetric between the two organs and between patients. Some individuals come to attention through vision, some through hearing, and in reported series a minority have appeared to have only one of the two. Because the ophthalmological changes can be very subtle, high-resolution retinal imaging has been recommended to detect them.

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1
Inheritance
6
Pathophys.
10
Phenotypes
2
Gaps
15
Pathograph
1
Genes
1
Medical Actions
3
Differentials
5
Models
12
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic CEP250 variants, homozygous in consanguineous families and compound heterozygous elsewhere. Every reported patient in the largest series carried truncating alleles only.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:39610034 SUPPORT Human Clinical
"Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors dysfunction without vestibular signs."
States the recessive biallelic mechanism and the defining sensory combination without vestibular involvement.
PMID:39610034 SUPPORT Human Clinical
"All patients harbored isolated truncating variants."
Records that the reported allelic spectrum in this series is truncating.
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Discussions and Knowledge Gaps

2
Why does loss of a ubiquitously expressed centriole-linker protein produce disease confined to photoreceptors and cochlear hair cells, and what decides whether a given patient presents through the eye, through the ear, or with only one of the two?
KNOWLEDGE GAP OPEN gap_crdhl2_organ_selectivity_and_presentation
Attached to
pathophysiology#Loss of C-Nap1 from the Centriole pathophysiology#Photoreceptor Connecting Cilium Dysfunction genetic#CEP250
C-Nap1 is a general centrosomal protein and centriole cohesion is a general cell-cycle process, yet the disease is restricted to two post-mitotic sensory cell types. The obvious hypothesis is the ciliary one - the mother centriole is the basal body of the photoreceptor connecting cilium and C-Nap1 is expressed there - but what C-Nap1 does at that structure has not been established, and it does not by itself explain the hair cell. The variability is at least as unexplained. Reported patients with the same class of truncating allele have had a cone-rod dystrophy with hearing loss, apparently isolated hearing loss with a normal retina, or apparently non-syndromic retinitis pigmentosa. In the largest series the dual-sensory presentation was the majority but not the whole of it - five of seven patients - and the largest series raised the possibility that loss- and gain-of-function effects coexist, which it noted would complicate gene therapy. Nothing currently predicts which presentation a genotype will produce.
Show evidence (3 references)
PMID:39610034 SUPPORT Human Clinical
"The coexistence of loss- and gain-of-function effects may exist, complicating the development of gene therapy."
The authors' statement that the variant mechanism itself is unresolved, and its therapeutic consequence.
PMID:39610034 SUPPORT Human Clinical
"Two patients appear to present either isolated hearing loss or visual impairment, but further investigations are needed to confirm a possible non-syndromic presentation."
Records the single-organ presentations that the gap asks about, with the authors' own caveat.
PMID:39610034 SUPPORT Human Clinical
"Most patients (5/7) exhibit both retinal dystrophy and SNHL."
Quantifies how often the dual-sensory presentation actually occurs in the largest series, which is what makes the single-organ cases a minority rather than an anomaly.
How much of the retinal phenotype in the family that established CEP250 is attributable to CEP250, given that a second ciliary-gene nonsense allele segregated in the same pedigree?
KNOWLEDGE GAP OPEN gap_crdhl2_second_locus_attribution
Attached to
genetic#CEP250 pathophysiology#Progressive Cone-Predominant Photoreceptor Degeneration
The discovery family carried nonsense variants in two ciliary genes, CEP250 and C2orf71. Individuals homozygous for both had early-onset severe retinitis pigmentosa; individuals homozygous for CEP250 with a single mutant C2orf71 allele had only mild retinal degeneration. The authors read this as an additive effect. That reading has since been supported indirectly, in that CEP250 families without a second locus also show mild retinal disease - but the contribution of a heterozygous C2orf71 allele to even the mild phenotype has not been separately assessed, and no series has been powered to test digenic contribution. The practical consequence is that severe early-onset retinal disease should not be quoted as part of the CEP250 phenotype on the strength of that pedigree.
Show evidence (3 references)
PMID:24780881 SUPPORT Human Clinical
"The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins."
The authors' own attribution of the severe phenotype to two loci acting together.
PMID:34223797 SUPPORT INDIRECT Human Clinical
"Our patients with CEP250 variants exhibited nonsense and frameshift variants suggesting that this phenotype of mild RP with progressive SNHL may be specific for biallelic CEP250 nonsense or frameshift variants that lead to defective proteins in the absence of pathogenic variants in other genes."
A later series proposing exactly this reading - that mild retinal disease with progressive hearing loss is what CEP250 alone produces - stated as a suggestion rather than a demonstration, which is why the gap remains open.
PMID:30459346 SUPPORT Human Clinical
"The analysis of the targeted panel and WES results showed no additional putative pathogenic mutations, except for one heterozygous missense variant in USH2A (rs773526991: c.4561C > T/p.Arg1521Cys), presenting an allele frequency of 0.00002 in ExAC and for which the in silico tools implied a..."
A second independent CEP250 patient carrying an unexplained monoallelic variant in another retinal gene, which broadens the gap beyond the C2orf71 finding in the discovery family.
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Pathophysiology

6
Biallelic CEP250 Truncating Variants
Nonsense, frameshift and splice variants on both CEP250 alleles. The truncated products lose the C-terminal region of C-Nap1: the allele in the original family removes the NEK2-phosphorylation region, and a nonsense allele reported in a deafness family produces a protein that no longer reaches the centrosome at all.
CEP250 hgnc:1859 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CEP250 (hgnc:1859). hgnc:1859 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Loss of C-Nap1 from the Centriole A truncated C-Nap1 does not occupy its normal position at the proximal centriole.
Show evidence (2 references)
PMID:24780881 SUPPORT Human Clinical
"CEP250 expression analysis of the mutant allele revealed the generation of a truncated protein lacking the NEK2-phosphorylation region."
Characterises the molecular consequence of the founder allele.
PMID:29718797 SUPPORT Human Clinical
"WES of the proband identified compound heterozygous variants c.361C>T, p.R121*, and c.562C>T, p.R188* in CEP250. The variants were found to co-segregate with the disease in five members of the family."
Documents biallelic truncating variants segregating with the cone-rod-dystrophy-plus-hearing-loss phenotype.
Loss of C-Nap1 from the Centriole
C-Nap1 docks at the proximal ends of both parent centrioles and anchors the rootletin fibres that hold them together; NEK2 phosphorylation of C-Nap1 is what releases that linkage at mitosis. Losing the protein from the centriole therefore removes the anchor for centriole-centriole cohesion. Because the mother centriole is also the basal body from which a primary cilium is built, the same lesion is felt at the ciliary base.
centriole-centriole cohesion GO:0010457 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased centriole-centriole cohesion (GO:0010457). GO:0010457 is a biological process from the Gene Ontology. ↓ DECREASED
centriole GO:0005814 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves centriole (GO:0005814). GO:0005814 is a cellular component from the Gene Ontology.
Downstream
Photoreceptor Connecting Cilium Dysfunction The photoreceptor connecting cilium is built on the mother centriole that C-Nap1 anchors, and C-Nap1 is itself expressed there.
Cochlear Hair Cell Degeneration Cep250 is expressed in cochlear hair cells, which degenerate when it is lost. This is a parallel branch from the same molecular lesion, not a consequence of the retinal branch.
Show evidence (1 reference)
PMID:37759551 SUPPORT Other
"C-Nap1 is expressed in photoreceptor cilia and interacts with other ciliary proteins, including Rootletin and NEK2 [9]."
Establishes the protein's ciliary localisation and its rootletin and NEK2 partners, the components of the centriole linker.
Photoreceptor Connecting Cilium Dysfunction
The connecting cilium is the only conduit between the photoreceptor inner segment, where outer-segment proteins are made, and the outer segment, where they work. Disorders of the photoreceptor cilium are a recognised cause of retinal degeneration for this reason. What C-Nap1 contributes at that structure is not established in detail; that it is present there and interacts with ciliary partners including CEP78 is what links the gene to the retinal phenotype.
retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology. retinal rod cell CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology.
photoreceptor connecting cilium GO:0032391 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves photoreceptor connecting cilium (GO:0032391). GO:0032391 is a cellular component from the Gene Ontology.
Downstream
Progressive Cone-Predominant Photoreceptor Degeneration Photoreceptors with a defective connecting cilium degenerate progressively.
Show evidence (2 references)
PMID:37656476 SUPPORT Other
"Degeneration of retinal photoreceptors is frequently observed in diverse ciliopathy disorders, and photoreceptor cilium gates the molecular trafficking between the inner and the outer segment (OS)."
States the general role of the photoreceptor cilium that makes this node the link between the centriolar lesion and photoreceptor loss.
PMID:27588452 SUPPORT Human Clinical
"CEP78 was reported previously to interact with c-nap1, encoded by CEP250 that we reported earlier to cause atypical Usher syndrome."
Establishes the CEP78-C-Nap1 interaction that ties this disorder to its sibling disorder at the same subcellular site.
Progressive Cone-Predominant Photoreceptor Degeneration
Progressive photoreceptor dysfunction that in most reported patients affects cones earlier or more than rods, producing a cone-rod rather than a rod-cone pattern. Severity is variable and often mild: in the Japanese family the electrophysiological abnormality was slight and reduced foveal cone density was visible only on adaptive-optics imaging. Reduced retinal thickness and photoreceptor loss are reproduced in Cep250-null mice.
retinal cone cell CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
Animal models
Cep250 knockout mouse (exon 6-7 deletion) Mouse recapitulates Full-field electroretinography declines gradually with age and histology confirms late-onset retinal degeneration.
Cep250 p.R188* knock-in mouse Mouse recapitulates Homozygous knock-in mice show significantly reduced retinal thickness and reduced electroretinographic responses.
Cep250 global knockout mouse (retinal transcriptome and metabolome line) Mouse measures Reads out the transcriptional and metabolic consequences of Cep250 loss in the retina, implicating cGMP-PKG and MAPK signalling and arginine metabolism.
Show evidence (5 references)
PMID:29718797 SUPPORT Human Clinical
"Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea."
Documents the cone-predominant retinal phenotype and its mildness.
PMID:39610034 SUPPORT Human Clinical
"CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction."
Records that the photoreceptor dysfunction is usually progressive.
PMID:34223797 SUPPORT Human Clinical
"ffERG was obtained on one of the three patients (CEP250–1) which showed a mild cone dystrophy with normal rod function (table 1)."
A CEP250-labelled patient in whom the cone system was affected and rod function was normal, which is the cone-predominant pattern this node describes.
+ 2 more references
Cochlear Hair Cell Degeneration
Loss of cochlear inner and outer hair cells. This is the auditory branch of the same molecular lesion; it is demonstrated in Cep250-null mice, where hair-cell degeneration accompanies a rising auditory brainstem response threshold, and it is the proposed basis of the hearing loss in patients.
cochlea auditory hair cell CL:4023120 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cochlea auditory hair cell (CL:4023120). CL:4023120 is a cell type from the Cell Ontology.
Animal models
Cep250 knockout mouse (cochlear characterisation) Mouse recapitulates Cep250 is expressed in mouse inner and outer hair cells, and the null mice lose them, with progressive hearing loss on auditory brainstem response.
Cep250 CRISPR knockout mouse (cochlear morphology line) Mouse recapitulates Homozygous nulls lose cochlear hair cells and lose hearing, with the deficit concentrated in the high frequencies, while vestibular function is spared and heterozygotes are unaffected.
Downstream
Progressive Postlingual Sensorineural Hearing Loss Hair-cell loss produces a sensorineural hearing loss that worsens with age, matching the postlingual progressive pattern seen in patients.
Show evidence (1 reference)
PMID:37759551 SUPPORT Model Organism
"In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice."
States the hair-cell mechanism and its correspondence with the human hearing loss.
Progressive Postlingual Sensorineural Hearing Loss
Sensorineural hearing loss that begins after speech acquisition and worsens. The distinction from classical Usher syndrome is not cosmetic: congenital profound deafness is the presenting feature of Usher type 1, whereas here the hearing loss may be slight enough to be found only on formal audiometry and may be the only complaint the patient has.
Animal models
Cep250 knockout mouse (exon 6-7 deletion) Mouse recapitulates Auditory brainstem response thresholds rise significantly by 20 months, giving an adult-onset progressive hearing loss like the patients'.
Show evidence (2 references)
PMID:34223797 SUPPORT Human Clinical
"Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL."
The CEP250-specific finding from a series that also covered three other genes; it records both the mild retinal disease and the progressive non-congenital hearing loss.
PMID:30459346 SUPPORT Human Clinical
"Patient RP1973 suffered from bilateral moderate-severe progressive hearing loss manifested at 13 years old (Fig. 3b) and late-onset progressive diminution of vision in both eyes with photophobia (first ophthalmologic examination at 44 years old)."
A single CEP250-biallelic patient in whom the hearing loss declared itself at 13 and the visual decline three decades later, which is the postlingual progressive pattern with hearing-first presentation.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Cone-rod dystrophy and hearing loss 2 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

10
Ear 2
Progressive sensorineural hearing impairment HP:0000408 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:34223797 SUPPORT Human Clinical
"Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL."
The CEP250-specific statement of the hearing phenotype.
PMID:37759551 SUPPORT Human Clinical
"Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration."
Documents progressive sensorineural hearing loss as the sole feature in one family.
PMID:34223797 SUPPORT Human Clinical
"Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms."
Progressive SNHL in all three CEP250 patients of the four-gene series, with the age-of-onset range.
Postlingual sensorineural hearing impairment HP:0008596 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Postlingual sensorineural hearing impairment (HP:0008596). HP:0008596 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39610034 SUPPORT Human Clinical
"CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction."
States that the hearing loss is postlingual.
Eye 8
Cone-rod dystrophy Cone/cone-rod dystrophy HP:0000548 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cone/cone-rod dystrophy (HP:0000548), qualified as course progressive. HP:0000548 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (3 references)
PMID:30459346 SUPPORT Human Clinical
"Furthermore, we detected two novel nonsense mutations in CEP250 in a patient with a disease mimicking Usher syndrome that associates visual impairment due to cone-rod dystrophy and progressive hearing loss."
Documents cone-rod dystrophy as the retinal phenotype in a CEP250-biallelic patient.
PMID:29718797 SUPPORT Human Clinical
"Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea."
Electrophysiological and imaging confirmation of the cone-rod pattern.
PMID:34223797 SUPPORT Human Clinical
"Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms."
The onset range across the three CEP250 patients of the four-gene series, which places onset in adolescence to early adulthood.
Photophobia HP:0000613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photophobia (HP:0000613). HP:0000613 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30459346 SUPPORT Human Clinical
"Patient RP1973 suffered from bilateral moderate-severe progressive hearing loss manifested at 13 years old (Fig. 3b) and late-onset progressive diminution of vision in both eyes with photophobia (first ophthalmologic examination at 44 years old)."
Records photophobia alongside the progressive visual decline in a CEP250-biallelic patient.
Reduced visual acuity HP:0007663 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced visual acuity (HP:0007663). HP:0007663 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30459346 SUPPORT Human Clinical
"The BCVA was 0.6 in the right eye and 0.5 in the left eye (Snellen)."
The measured acuity in the CEP250-biallelic patient described in detail.
PMID:34223797 SUPPORT Human Clinical
"Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms."
The acuity range across the three CEP250 patients of the four-gene series, which is the severity spread behind the "generally mild" characterisation.
Spicular pigmentation of the retina HP:0007737 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spicular pigmentation of the retina (HP:0007737). HP:0007737 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30459346 SUPPORT Human Clinical
"The anterior segment findings were within normal limits, but fundus examination revealed migration of pigment in a bone-spicule pattern within a mid-peripheral annular zone of both eyes and narrowing of the peripheral retinal blood vessels (Fig. 3c)."
The fundus description in the CEP250-biallelic patient reported in detail.
PMID:34223797 REFUTE DIRECT Human Clinical
"Representative images of patients with CEP250 variants are shown in figure 2. Color fundus analysis revealed normal findings in all patients."
Bounds the claim rather than supporting it: colour fundus photography was normal in all three CEP250 patients of a later series, so bone-spicule pigmentation is a finding in some patients and not a characteristic feature of the disorder.
Constriction of peripheral visual field HP:0001133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constriction of peripheral visual field (HP:0001133). HP:0001133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30459346 SUPPORT Human Clinical
"Humphrey perimetry revealed peripheral visual field constriction with relative defects in the paracentral region in both eyes that has remained stable for the last five years."
Records the field defect and, unusually for this disorder, that it was stable over five years.
Abnormal electroretinogram HP:0000512 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal electroretinogram (HP:0000512). HP:0000512 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29718797 SUPPORT Human Clinical
"Electrophysiological analysis revealed a mild CRD in two family members."
Records that the retinal abnormality was established electrophysiologically.
Photoreceptor layer loss on macular OCT HP:0030609 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Photoreceptor layer loss on macular OCT (HP:0030609). HP:0030609 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34223797 SUPPORT Human Clinical
"OCT findings showed outer retinal atrophy in all three patients including thinning of the outer nuclear layer (ONL)"
Reports the finding in all three CEP250 patients of the series.
Abnormal fundus autofluorescence imaging HP:0030602 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal fundus autofluorescence imaging (HP:0030602). HP:0030602 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34223797 SUPPORT Human Clinical
"Color fundus analysis revealed normal findings in all patients. FAF demonstrated areas of subtle hyper-autofluorescence in the periphery"
Records abnormal autofluorescence against a normal colour fundus in the same patients.
🧬

Genetic Associations

1
CEP250 (Causal biallelic variant)
Gene: CEP250 hgnc:1859 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CEP250 (hgnc:1859). hgnc:1859 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:24780881 SUPPORT Human Clinical
"Patients who were double homozygotes had SNHL accompanied by early-onset and severe RP, while patients who were homozygous for the CEP250 mutation and carried a single mutant C2orf71 allele had SNHL with mild retinal degeneration."
The genotype-by-genotype breakdown that separates the CEP250-attributable phenotype from the two-gene one.
PMID:24780881 SUPPORT Human Clinical
"The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins."
The authors' own interpretation of the second locus as additive.
PMID:30998843 SUPPORT Human Clinical
"Here, we report the identification of a mutation (c.562C>T, p.R188*) in the CEP250 in a consanguineous family with nonsyndromic RP."
Documents an apparently non-syndromic retinal presentation of a CEP250 truncating allele that is also seen in the syndromic disorder.
💊

Medical Actions

1
Low-vision rehabilitation and hearing amplification
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Platform: Behavioral / lifestyle
No disease-modifying treatment exists. Management is supportive on both axes: low-vision support and monitoring for the retinal dystrophy, and amplification or other audiological management for the progressive hearing loss. Because either organ may present alone, the practical intervention with the clearest recommendation behind it is cross-referral - assessing the eyes of a patient who presents with hearing loss and vice versa.
Target Phenotypes: Cone/cone-rod dystrophy HP:0000548 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Cone/cone-rod dystrophy (HP:0000548). HP:0000548 is a phenotype from the Human Phenotype Ontology. Progressive sensorineural hearing impairment HP:0000408 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Progressive sensorineural hearing impairment (HP:0000408). HP:0000408 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39610034 SUPPORT Human Clinical
"We also recommend ophthalmological evaluation and follow-up in patients with isolated SNHL, and conversely."
The cross-referral recommendation that the supportive management rests on.
🔬

Diagnosis

3
Retinal assessment with electroretinography and high-resolution imaging
Full-field and macular electroretinography with optical coherence tomography and, where available, adaptive-optics imaging. Adaptive optics was needed to see the reduced foveal cone density in the Japanese family, and the authors recommended high-resolution imaging specifically because the ophthalmological phenotype can be so mild. Fundus appearance is unreliable: it was normal in all three CEP250 patients of one series.
retinal examination NCIT:C101217 NCI Thesaurus (NCIT)
Results: Cone-predominant electroretinographic abnormality, often with an absent macular response and only mild scotopic change; reduced foveal cone density on adaptive optics; outer retinal atrophy on optical coherence tomography.
Show evidence (2 references)
PMID:29718797 SUPPORT Human Clinical
"Because the ophthalmological phenotypes were very mild, high-resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease."
The authors' explicit recommendation for how to detect the retinal component.
PMID:30459346 SUPPORT Human Clinical
"Full-field electroretinography showed only mild alterations in the scotopic flash electroretinography (ERG), as the amplitudes of the b-wave were reduced in the right eye and absent in the left eye. Macular ERG showed an absence of response in both eyes, and Visual Evoked Potentials (VEP) were..."
Shows that the macular electroretinogram carried the abnormality while the full-field scotopic response was only mildly affected, which is why macular as well as full-field testing is specified here.
Audiometry
Pure-tone audiometry, which in this disorder is not a formality: the hearing loss may be the presenting or the only complaint, it is postlingual and progressive, and it may be slight enough that it is found only on formal testing. Vestibular assessment is normal, which is one of the findings that separates this disorder from Usher syndrome type 1.
audiometric test NCIT:C38036 NCI Thesaurus (NCIT)
Results: Postlingual, progressive, bilateral sensorineural hearing loss with normal vestibular function.
Show evidence (3 references)
PMID:30459346 SUPPORT Human Clinical
"Patient RP1973 suffered from bilateral moderate-severe progressive hearing loss manifested at 13 years old (Fig. 3b) and late-onset progressive diminution of vision in both eyes with photophobia (first ophthalmologic examination at 44 years old)."
A patient in whom the audiometric abnormality preceded the ophthalmic one by three decades, which is why audiometry is curated as its own diagnostic step.
PMID:39610034 SUPPORT Human Clinical
"Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors dysfunction without vestibular signs."
Records the absence of vestibular signs that the assessment is looking for.
PMID:34223797 SUPPORT Human Clinical
"Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms."
A third independent human-clinical source for vestibular sparing, which is one of the grounds for separating this disorder from Usher syndrome type 1.
CEP250 sequencing within an Usher-gene panel
Molecular confirmation by targeted panel, exome or genome sequencing. CEP250 entered Usher-syndrome diagnostic panels as an uncertainly associated gene and was consolidated as causative by panel screening, so the practical advice is to include atypical as well as classical Usher genes when either sensory system is affected.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Results: Biallelic truncating CEP250 variants.
Show evidence (2 references)
PMID:30459346 SUPPORT Human Clinical
"Therefore, this approach proved reliable results for the molecular diagnosis of the disease and also allowed the consolidation of the CEP250 gene as disease causative for an Usher-like phenotype."
Documents panel sequencing as the route by which CEP250 disease is identified.
PMID:39610034 SUPPORT Human Clinical
"We strongly recommend genetic analysis of classical and atypical Usher related-genes, in patients with isolated retinal dystrophy or SNHL."
The recommendation to include atypical Usher genes such as CEP250 in the panel.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population estimate exists. A 2025 series counted 19 previously reported descriptions and added 7 unrelated individuals of its own.
Show evidence (1 reference)
PMID:39610034 SUPPORT Human Clinical
"To date, only 19 scattered descriptions have been reported. In this study, we present detailed clinical and genetic description of 7 unrelated individuals with CEP250 related disease, along with a literature review to provide new insight on the severity and course of the disease."
The published case count, standing in for a population estimate that has never been made.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Cone-rod dystrophy and hearing loss 2:

Usher syndrome Not Yet Curated MONDO:0019501
Overlapping Features The disorder this one is repeatedly compared with, and the reason the literature calls it atypical Usher syndrome. Usher syndrome is caused by disruption of the Usher protein interactome, which organises the stereocilia hair bundle and the photoreceptor periciliary region; C-Nap1 is not part of that network. Clinically, Usher types 1 and 2 have congenital hearing loss and rod-first retinitis pigmentosa, with vestibular areflexia in type 1.
Distinguishing Features
  • Postlingual progressive hearing loss rather than congenital deafness
  • Cone-predominant retinal dystrophy rather than rod-cone retinitis pigmentosa
  • Vestibular function spared
  • Centriolar cohesion protein rather than a component of the Usher interactome
Show evidence (2 references)
PMID:39610034 SUPPORT Human Clinical
"Classically, Usher syndrome is characterized by the association of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP) and possible vestibular dysfunction. Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and..."
Contrasts the classical syndrome with the CEP250 phenotype, including the absence of vestibular signs.
PMID:27588452 SUPPORT Human Clinical
"We conclude that truncating mutations in CEP78 result in a phenotype involving both the visual and auditory systems but different from typical Usher syndrome."
The same conclusion drawn for the sibling centrosomal disorder, that the phenotype is distinct from typical Usher syndrome.
Cone-rod dystrophy and hearing loss 1 MONDO:0020778
Overlapping Features The CEP78-related disorder, and the closest relative of this one: the two proteins interact, both are centrosomal, and both give cone-rod degeneration with sensorineural hearing loss. Reported CEP78 retinal disease is phenotypically broader, with vascular attenuation, optic disc pallor, intraretinal pigment and macular change, where CEP250 retinal disease is typically mild.
Distinguishing Features
  • Biallelic CEP78 rather than CEP250 variants
  • Broader and generally more severe retinal phenotype
Show evidence (1 reference)
PMID:34223797 SUPPORT Human Clinical
"CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer..."
The CEP78-specific findings from the same series, showing the broader retinal spectrum of the sibling disorder.
Non-syndromic autosomal recessive hearing loss MONDO:0019497
Overlapping Features A CEP250 nonsense variant has been reported in a family with progressive moderate sensorineural hearing loss and no retinal degeneration, so non-syndromic deafness is a differential that resolves to the same gene. Whether those individuals will develop retinal disease later is not known, which is why ophthalmological follow-up is recommended.
Distinguishing Features
  • No retinal degeneration at the time of report
  • Same gene and same class of truncating allele
Show evidence (1 reference)
PMID:37759551 SUPPORT Human Clinical
"Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration."
Documents the non-syndromic hearing-loss presentation of the same gene.
🐁

Animal Models

5
Cep250 knockout mouse (exon 6-7 deletion)
The mouse made specifically to model the disorder, by the group that reported the original patients. It is the useful one, and the reason is a negative fact about the field: most Usher-syndrome mouse models have normal retinal function and structure, so a mouse that loses both vision and hearing is unusual. The catch is timing - the electroretinogram is normal at 6 months and the deficits are documented at 20 months, which is near the end of a mouse lifespan.
Species
Mouse
Genotype
Cep250 null, homozygous (knockout-first construct deleting exons 6 and 7, converted with Cre)
Publication
PMID:36857066
Pathograph links
Progressive Cone-Predominant Photoreceptor Degeneration recapitulates fidelity: moderate Full-field electroretinography declines gradually with age and histology confirms late-onset retinal degeneration.
Limitations: The retinal decline is not cone-predominant in the way the human disease is: photopic and scotopic responses both fall. Onset is very late, so the model cannot address why patients present in childhood or early adulthood, and it gives no read on the mildness that characterises the human retinal phenotype.
Readouts
Full-field electroretinogram amplitude
Direction: DECREASED
Interpretation: Functional confirmation of progressive photoreceptor loss in the model.
Show evidence (1 reference)
PMID:36857066 SUPPORT Model Organism
"At 6 months, the ffERG was normal, but it decreased gradually with age. For both photopic and scotopic ffERG responses, very low amplitudes were evident at 20 months. Histological analysis confirmed late-onset retinal degeneration."
The electroretinographic and histological measurement of the retinal phenotype, including its timing.
Show evidence (1 reference)
PMID:36857066 SUPPORT Model Organism
"Although most USH animal models have normal retinal function and structure, the Cep250 KO mouse model shows both retinal degeneration and hearing loss with a relatively late age of onset."
States what makes this model informative relative to the alternatives, and states the timing caveat in the same sentence.
Progressive Postlingual Sensorineural Hearing Loss recapitulates fidelity: moderate Auditory brainstem response thresholds rise significantly by 20 months, giving an adult-onset progressive hearing loss like the patients'.
Limitations: Hearing was tested only at 20 months, so the model establishes that the deficit exists but not its time course, and the human hearing loss is already present in childhood in several reported patients.
Readouts
Auditory brainstem response threshold
Direction: INCREASED
Interpretation: A raised threshold is reduced hearing sensitivity, the model counterpart of the patients' sensorineural loss.
Show evidence (1 reference)
PMID:36857066 SUPPORT Model Organism
"ABR tests illustrated that hearing threshold significantly increased at the age of 20 months."
The auditory measurement in the model.
Show evidence (1 reference)
PMID:36857066 SUPPORT Model Organism
"Hearing thresholds were detected using auditory brainstem response (ABR) at the age of 20 months."
Establishes how and when hearing was assessed in this model.
Cep250 p.R188* knock-in mouse
A knock-in carrying an actual patient allele - the same c.562C>T, p.R188* nonsense variant found both in the Japanese cone-rod-dystrophy family and in a consanguineous family with non-syndromic retinitis pigmentosa. Among the models curated here it is the one that tests a specific human variant rather than a null; the other three are knockouts.
Species
Mouse
Genotype
Cep250 p.R188* knock-in, homozygous
Publication
PMID:30998843
Pathograph links
Progressive Cone-Predominant Photoreceptor Degeneration recapitulates fidelity: moderate Homozygous knock-in mice show significantly reduced retinal thickness and reduced electroretinographic responses.
Limitations: The retinal impairment is described as severe, whereas the human phenotype associated with this same allele is mild, so the model overstates severity. It was made to characterise a non-syndromic retinitis pigmentosa presentation and its hearing was not reported, so it says nothing about the auditory branch.
Readouts
Retinal thickness and electroretinogram response
Direction: DECREASED
Interpretation: Structural and functional confirmation that a patient truncating allele is sufficient to cause photoreceptor disease.
Show evidence (1 reference)
PMID:30998843 SUPPORT Model Organism
"The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses."
The two retinal measurements made in this model.
Show evidence (1 reference)
PMID:30998843 SUPPORT Model Organism
"Remarkably, the disruption of Cep250 resulted in severe impairment of retinal function and significant retinal morphological alterations."
Establishes that the model reproduces retinal disease, and in the authors' own word, severely.
Cep250 knockout mouse (cochlear characterisation)
A Cep250-null line phenotyped for the ear rather than the eye, alongside a human family with non-syndromic hearing loss. It is the source of the hair-cell mechanism for the auditory branch of this disorder.
Species
Mouse
Genotype
Cep250 null, homozygous
Publication
PMID:37759551
Pathograph links
Cochlear Hair Cell Degeneration recapitulates fidelity: moderate Cep250 is expressed in mouse inner and outer hair cells, and the null mice lose them, with progressive hearing loss on auditory brainstem response.
Limitations: Hair-cell degeneration has not been demonstrated in human cochlea, so the cellular mechanism of the human hearing loss rests on this model. The accompanying human family had no retinal disease, so the model as published addresses the auditory branch only.
Readouts
Cochlear hair cell survival
Direction: DECREASED
Interpretation: The cellular lesion proposed to underlie the sensorineural hearing loss.
Show evidence (1 reference)
PMID:37759551 SUPPORT Model Organism
"Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response."
The hair-cell measurement and the hearing deficit that accompanies it.
Show evidence (1 reference)
PMID:37759551 SUPPORT Model Organism
"In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells."
Establishes that the cell type this model reads out is one that expresses the gene.
Cep250 CRISPR knockout mouse (cochlear morphology line)
A CRISPR-generated Cep250-null line phenotyped specifically for the inner ear, with auditory brainstem responses, a swimming test for vestibular function, and hair-cell counts by immunofluorescence. It is the model that speaks most directly to what separates this disorder from classical Usher syndrome, because it tests hearing and balance in the same animals. It is a Research Square preprint and has not been peer reviewed; that is recorded here rather than treated as equivalent to the published models.
Species
Mouse
Genotype
Cep250 homozygous null, generated by CRISPR/Cas9
Publication
DOI:10.21203/rs.3.rs-4515679/v1
Pathograph links
Cochlear Hair Cell Degeneration recapitulates fidelity: moderate Homozygous nulls lose cochlear hair cells and lose hearing, with the deficit concentrated in the high frequencies, while vestibular function is spared and heterozygotes are unaffected.
Limitations: Preprint, not peer reviewed, so the measurements have not been through external scrutiny. The mouse is a complete null while patients carry truncating alleles in a large protein, and hearing was assessed only over P30 to P60, which does not test the progressive course seen in patients.
Readouts
Cochlear hair cell number
Direction: DECREASED
Interpretation: Independent confirmation, in a second knockout line, of the hair-cell lesion proposed to underlie the human hearing loss.
Show evidence (1 reference)
DOI:10.21203/rs.3.rs-4515679/v1 Preprint · not peer-reviewed SUPPORT Model Organism
"Immunofluorescence staining reveals a significant reduction in the number of cochlear hair cells in Cep250−/− mice, confirming the association between Cep250 gene mutation and hearing function loss."
The hair-cell count in this model.
Auditory brainstem response threshold by frequency
Direction: INCREASED
Interpretation: A raised threshold is reduced hearing sensitivity, so INCREASED here is a hearing deficit. The high-frequency predominance matches the sloping loss reported in patients.
Show evidence (1 reference)
DOI:10.21203/rs.3.rs-4515679/v1 Preprint · not peer-reviewed SUPPORT Model Organism
"We demonstrate that Cep250−/− mice exhibit impaired hearing function, particularly in high-frequency ranges, whereas their vestibular function remains unaffected."
The auditory measurement, and in the same sentence the preserved vestibular function that distinguishes this disorder from Usher type 1.
Show evidence (1 reference)
DOI:10.21203/rs.3.rs-4515679/v1 Preprint · not peer-reviewed SUPPORT Model Organism
"Heterozygous mice show no significant changes in hearing, indicating that a single allele mutation in Cep250 is insufficient to affect normal Cep250 expression levels."
The heterozygote result, which matches the recessive inheritance in patients and shows the model is dose-appropriate for this disorder.
Cep250 global knockout mouse (retinal transcriptome and metabolome line)
A global Cep250-null line phenotyped from P90 to P180 with optical coherence tomography, electroretinography, TUNEL, RNA sequencing and untargeted metabolomics. It is where the candidate downstream death pathways come from - cGMP-PKG and MAPK signalling from the transcriptomics, dysregulated arginine metabolism from the companion metabolomic study on a global knockout from the same centre.
Species
Mouse
Genotype
Cep250 null, homozygous (global knockout)
Publication
PMID:37240188
Pathograph links
Progressive Cone-Predominant Photoreceptor Degeneration measures fidelity: moderate Reads out the transcriptional and metabolic consequences of Cep250 loss in the retina, implicating cGMP-PKG and MAPK signalling and arginine metabolism.
Limitations: Pathway enrichment from bulk retinal RNA sequencing at a single timepoint is hypothesis-generating; neither implicated pathway has been tested by intervention, and neither has been examined in human retina. The a-wave falls more than the b-wave here, a photoreceptor-level signature, but the model does not separate cones from rods the way the human phenotype does.
Readouts
Retinal cGMP-PKG and MAPK pathway transcript enrichment
Direction: INCREASED
Interpretation: The candidate signalling route from ciliary defect to photoreceptor death.
Show evidence (1 reference)
PMID:37240188 SUPPORT Model Organism
"A KEGG enrichment analysis indicated that cGMP-PKG signalling pathways, MAPK signalling pathways, edn2-fgf2 axis pathways, and thyroid hormone synthesis were upregulated, whereas protein processing in the endoplasmic reticulum was downregulated in Cep250 KO eyes."
The enrichment result behind the proposed pathway.
Outer nuclear layer and whole-retina thickness
Direction: DECREASED
Interpretation: Structural confirmation of photoreceptor loss in the line the transcriptomics was run on.
Show evidence (1 reference)
PMID:37240188 SUPPORT Model Organism
"Compared with WT mice, the thickness of the ONL, IS/OS, and whole retina of Cep250 mice was significantly reduced."
The structural measurement in this model.
Show evidence (1 reference)
PMID:37656476 SUPPORT Model Organism
"We used Cep250 KO mice and untargeted metabolomics to uncover potential mechanisms underlying retinal degeneration."
The companion metabolomic study on a global Cep250 knockout from the same centre, establishing what this model is used for.
{ }

Source YAML

click to show 
name: Cone-rod dystrophy and hearing loss 2
creation_date: "2026-08-29T00:00:00Z"
category: Mendelian
synonyms:
- CRDHL2
- CEP250-related retinal dystrophy and hearing loss
- atypical Usher syndrome, CEP250-related
description: >-
  Cone-rod dystrophy and hearing loss 2 is a rare autosomal recessive
  dual-sensory disorder caused by biallelic truncating variants in CEP250, which
  encodes C-Nap1. C-Nap1 sits at the proximal ends of the two parent centrioles
  and, with rootletin and NEK2, holds them together; in photoreceptors the
  mother centriole is the basal body of the connecting cilium, and C-Nap1 is
  expressed in that cilium and interacts with CEP78, the protein mutated in the
  sibling disorder cone-rod dystrophy and hearing loss 1.

  The disorder is repeatedly described in the literature as atypical Usher
  syndrome, and it is worth being precise about what that means. It is
  Usher-like in combining retinal degeneration with sensorineural hearing loss.
  It is not Usher syndrome in mechanism - C-Nap1 is not a component of the Usher
  protein interactome that organises the stereocilia hair bundle - and it
  differs clinically in ways that matter: the hearing loss is postlingual and
  progressive rather than congenital, vestibular function is spared, and the
  retinal disease is cone-predominant and often mild rather than the rod-first
  retinitis pigmentosa of classical Usher syndrome.

  The presentation is asymmetric between the two organs and between patients.
  Some individuals come to attention through vision, some through hearing, and
  in reported series a minority have appeared to have only one of the two.
  Because the ophthalmological changes can be very subtle, high-resolution
  retinal imaging has been recommended to detect them.
disease_term:
  preferred_term: cone-rod dystrophy and hearing loss 2
  term:
    id: MONDO:0020780
    label: cone-rod dystrophy and hearing loss 2
parents:
- Inherited retinal dystrophy
- Sensorineural hearing loss
- Ciliopathy
references:
- reference: PMID:24780881
  title: A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.
- reference: PMID:29718797
  title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
- reference: PMID:30459346
  title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
- reference: PMID:39610034
  title: The phenotypic spectrum of CEP250 gene variants.
- reference: PMID:34223797
  title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
- reference: PMID:37759551
  title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
- reference: PMID:30998843
  title: Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa.
- reference: PMID:36857066
  title: Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice.
- reference: PMID:37240188
  title: RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency.
- reference: PMID:37656476
  title: Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice.
- reference: PMID:27588452
  title: "Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss."
- reference: DOI:10.21203/rs.3.rs-4515679/v1
  title: "The cochlear morphology alteration and hearing loss in Cep250 knockout mice"
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic CEP250 variants, homozygous in consanguineous families and
    compound heterozygous elsewhere. Every reported patient in the largest
    series carried truncating alleles only.
  evidence:
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors dysfunction without vestibular signs.
    explanation: >-
      States the recessive biallelic mechanism and the defining sensory
      combination without vestibular involvement.
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All patients harbored isolated truncating variants.
    explanation: >-
      Records that the reported allelic spectrum in this series is truncating.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists. A 2025 series counted 19 previously reported
    descriptions and added 7 unrelated individuals of its own.
  evidence:
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, only 19 scattered descriptions have been reported. In this study, we present detailed clinical and genetic description of 7 unrelated individuals with CEP250 related disease, along with a literature review to provide new insight on the severity and course of the disease.
    explanation: >-
      The published case count, standing in for a population estimate that has
      never been made.
pathophysiology:
- name: Biallelic CEP250 Truncating Variants
  biological_scale: MOLECULAR
  description: >-
    Nonsense, frameshift and splice variants on both CEP250 alleles. The
    truncated products lose the C-terminal region of C-Nap1: the allele in the
    original family removes the NEK2-phosphorylation region, and a nonsense
    allele reported in a deafness family produces a protein that no longer
    reaches the centrosome at all.
  genes:
  - preferred_term: CEP250
    term:
      id: hgnc:1859
      label: CEP250
  evidence:
  - reference: PMID:24780881
    reference_title: A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CEP250 expression analysis of the mutant allele revealed the generation of a truncated protein lacking the NEK2-phosphorylation region.
    explanation: >-
      Characterises the molecular consequence of the founder allele.
  - reference: PMID:29718797
    reference_title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      WES of the proband identified compound heterozygous variants c.361C>T, p.R121*, and c.562C>T, p.R188* in CEP250. The variants were found to co-segregate with the disease in five members of the family.
    explanation: >-
      Documents biallelic truncating variants segregating with the
      cone-rod-dystrophy-plus-hearing-loss phenotype.
  downstream:
  - target: Loss of C-Nap1 from the Centriole
    description: >-
      A truncated C-Nap1 does not occupy its normal position at the proximal
      centriole.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37759551
      reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        The nonsense variant in CEP250 led to the early truncating protein of C-Nap1, which hindered centrosome localization; heterologous expression of CEP250 (c.3511C>T) in NIH3T3 cells within cilia expression condition revealed that the truncating C-Nap1 (p.Gln1171Ter) was not localized at the centrosome but was dispersed in the cytosol.
      explanation: >-
        Direct demonstration that a patient truncating allele mislocalises the
        protein away from the centrosome.
- name: Loss of C-Nap1 from the Centriole
  biological_scale: MOLECULAR
  description: >-
    C-Nap1 docks at the proximal ends of both parent centrioles and anchors the
    rootletin fibres that hold them together; NEK2 phosphorylation of C-Nap1 is
    what releases that linkage at mitosis. Losing the protein from the centriole
    therefore removes the anchor for centriole-centriole cohesion. Because the
    mother centriole is also the basal body from which a primary cilium is
    built, the same lesion is felt at the ciliary base.
  cellular_components:
  - preferred_term: centriole
    term:
      id: GO:0005814
      label: centriole
  biological_processes:
  - preferred_term: centriole-centriole cohesion
    modifier: DECREASED
    term:
      id: GO:0010457
      label: centriole-centriole cohesion
  evidence:
  - reference: PMID:37759551
    reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      C-Nap1 is expressed in photoreceptor cilia and interacts with other ciliary proteins, including Rootletin and NEK2 [9].
    explanation: >-
      Establishes the protein's ciliary localisation and its rootletin and NEK2
      partners, the components of the centriole linker.
  downstream:
  - target: Photoreceptor Connecting Cilium Dysfunction
    description: >-
      The photoreceptor connecting cilium is built on the mother centriole that
      C-Nap1 anchors, and C-Nap1 is itself expressed there.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:29718797
      reference_title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        C-Nap1 has been reported to be expressed in the photoreceptor cilia and is known to interact with other ciliary proteins.
      explanation: >-
        Places the protein in the photoreceptor cilium, the structure this edge
        runs to.
  - target: Cochlear Hair Cell Degeneration
    description: >-
      Cep250 is expressed in cochlear hair cells, which degenerate when it is
      lost. This is a parallel branch from the same molecular lesion, not a
      consequence of the retinal branch.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37759551
      reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells. Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response.
      explanation: >-
        Establishes hair-cell expression and hair-cell degeneration on loss of
        the gene.
- name: Photoreceptor Connecting Cilium Dysfunction
  biological_scale: CELLULAR
  description: >-
    The connecting cilium is the only conduit between the photoreceptor inner
    segment, where outer-segment proteins are made, and the outer segment, where
    they work. Disorders of the photoreceptor cilium are a recognised cause of
    retinal degeneration for this reason. What C-Nap1 contributes at that
    structure is not established in detail; that it is present there and
    interacts with ciliary partners including CEP78 is what links the gene to
    the retinal phenotype.
  cellular_components:
  - preferred_term: photoreceptor connecting cilium
    term:
      id: GO:0032391
      label: photoreceptor connecting cilium
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  - preferred_term: retinal rod cell
    term:
      id: CL:0000604
      label: retinal rod cell
  evidence:
  - reference: PMID:37656476
    reference_title: Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Degeneration of retinal photoreceptors is frequently observed in diverse ciliopathy disorders, and photoreceptor cilium gates the molecular trafficking between the inner and the outer segment (OS).
    explanation: >-
      States the general role of the photoreceptor cilium that makes this node
      the link between the centriolar lesion and photoreceptor loss.
  - reference: PMID:27588452
    reference_title: "Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CEP78 was reported previously to interact with c-nap1, encoded by CEP250 that we reported earlier to cause atypical Usher syndrome.
    explanation: >-
      Establishes the CEP78-C-Nap1 interaction that ties this disorder to its
      sibling disorder at the same subcellular site.
  downstream:
  - target: Progressive Cone-Predominant Photoreceptor Degeneration
    description: >-
      Photoreceptors with a defective connecting cilium degenerate
      progressively.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:37240188
      reference_title: RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Cep250 KO mice experience a late-stage retinal degeneration that manifests as the atypical USH phenotype. The dysregulation of the cGMP-PKG-MAPK pathways may contribute to the pathogenesis of cilia-related retinal degeneration.
      explanation: >-
        The only mechanistic account of how the ciliary defect kills
        photoreceptors, and its authors state it as a possible contribution
        rather than a demonstrated pathway, which is why this edge is indirect
        with unknown intermediates.
- name: Progressive Cone-Predominant Photoreceptor Degeneration
  biological_scale: TISSUE
  description: >-
    Progressive photoreceptor dysfunction that in most reported patients affects
    cones earlier or more than rods, producing a cone-rod rather than a rod-cone
    pattern. Severity is variable and often mild: in the Japanese family the
    electrophysiological abnormality was slight and reduced foveal cone density
    was visible only on adaptive-optics imaging. Reduced retinal thickness and
    photoreceptor loss are reproduced in Cep250-null mice.
  cell_types:
  - preferred_term: retinal cone cell
    term:
      id: CL:0000573
      label: retinal cone cell
  evidence:
  - reference: PMID:29718797
    reference_title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea.
    explanation: >-
      Documents the cone-predominant retinal phenotype and its mildness.
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction.
    explanation: >-
      Records that the photoreceptor dysfunction is usually progressive.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      ffERG was obtained on one of the three patients (CEP250–1) which showed a mild cone dystrophy with normal rod function (table 1).
    explanation: >-
      A CEP250-labelled patient in whom the cone system was affected and rod
      function was normal, which is the cone-predominant pattern this node
      describes.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OCT findings showed outer retinal atrophy in all three patients including thinning of the outer nuclear layer (ONL) (CEP250–1) and subtle disruption of the EZ and interdigitation zone (IZ) (CEP250–3).
    explanation: >-
      Structural confirmation of photoreceptor loss in all three CEP250 patients
      of that series, despite normal colour fundus findings.
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Full-field electroretinography showed only mild alterations in the scotopic flash electroretinography (ERG), as the amplitudes of the b-wave were reduced in the right eye and absent in the left eye. Macular ERG showed an absence of response in both eyes, and Visual Evoked Potentials (VEP) were altered (Supplemental Fig. S1).
    explanation: >-
      In a CEP250-biallelic patient the macular response was absent while the
      rod-driven scotopic response was only mildly abnormal, which is the
      cone-predominant pattern this node asserts, measured in one patient.
- name: Cochlear Hair Cell Degeneration
  biological_scale: TISSUE
  description: >-
    Loss of cochlear inner and outer hair cells. This is the auditory branch of
    the same molecular lesion; it is demonstrated in Cep250-null mice, where
    hair-cell degeneration accompanies a rising auditory brainstem response
    threshold, and it is the proposed basis of the hearing loss in patients.
  cell_types:
  - preferred_term: cochlea auditory hair cell
    term:
      id: CL:4023120
      label: cochlea auditory hair cell
  evidence:
  - reference: PMID:37759551
    reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In conclusion, a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea, which is associated with the progression of hearing loss in humans and mice.
    explanation: >-
      States the hair-cell mechanism and its correspondence with the human
      hearing loss.
  downstream:
  - target: Progressive Postlingual Sensorineural Hearing Loss
    description: >-
      Hair-cell loss produces a sensorineural hearing loss that worsens with
      age, matching the postlingual progressive pattern seen in patients.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:37759551
      reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response.
      explanation: >-
        Pairs the hair-cell loss with the measured progressive hearing deficit
        in the model.
- name: Progressive Postlingual Sensorineural Hearing Loss
  biological_scale: ORGANISM
  description: >-
    Sensorineural hearing loss that begins after speech acquisition and worsens.
    The distinction from classical Usher syndrome is not cosmetic: congenital
    profound deafness is the presenting feature of Usher type 1, whereas here
    the hearing loss may be slight enough to be found only on formal audiometry
    and may be the only complaint the patient has.
  evidence:
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL.
    explanation: >-
      The CEP250-specific finding from a series that also covered three other
      genes; it records both the mild retinal disease and the progressive
      non-congenital hearing loss.
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient RP1973 suffered from bilateral moderate-severe progressive hearing loss manifested at 13 years old (Fig. 3b) and late-onset progressive diminution of vision in both eyes with photophobia (first ophthalmologic examination at 44 years old).
    explanation: >-
      A single CEP250-biallelic patient in whom the hearing loss declared itself
      at 13 and the visual decline three decades later, which is the postlingual
      progressive pattern with hearing-first presentation.
phenotypes:
- name: Cone-rod dystrophy
  category: Ophthalmologic
  diagnostic: true
  description: >-
    Cone-predominant retinal dystrophy, often mild, with reduced foveal cone
    density. It is the feature that names the disorder and the one that
    separates it from classical Usher syndrome, where the retinal disease is
    rod-first retinitis pigmentosa. Across the three CEP250 patients of the
    four-gene series that reports per-patient ophthalmic detail, the age of
    onset ranged from 13 to 30 years, so this is an adolescent-to-adult onset
    dystrophy rather than a congenital one.
  phenotype_term:
    preferred_term: Cone/cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, we detected two novel nonsense mutations in CEP250 in a patient with a disease mimicking Usher syndrome that associates visual impairment due to cone-rod dystrophy and progressive hearing loss.
    explanation: >-
      Documents cone-rod dystrophy as the retinal phenotype in a
      CEP250-biallelic patient.
  - reference: PMID:29718797
    reference_title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea.
    explanation: >-
      Electrophysiological and imaging confirmation of the cone-rod pattern.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms.
    explanation: >-
      The onset range across the three CEP250 patients of the four-gene
      series, which places onset in adolescence to early adulthood.
- name: Progressive sensorineural hearing impairment
  category: Otologic
  diagnostic: true
  description: >-
    Postlingual, progressive sensorineural hearing loss without vestibular
    involvement. In the Japanese family it was slight; in a Korean family a
    CEP250 nonsense variant produced moderate progressive hearing loss with no
    ocular findings at all. All three CEP250 patients of the four-gene series
    that reports per-patient detail were affected, with an age of onset from
    under 10 to 24 years - typically before the retinal disease declares
    itself.
  phenotype_term:
    preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL.
    explanation: >-
      The CEP250-specific statement of the hearing phenotype.
  - reference: PMID:37759551
    reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration.
    explanation: >-
      Documents progressive sensorineural hearing loss as the sole feature in
      one family.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms.
    explanation: >-
      Progressive SNHL in all three CEP250 patients of the four-gene series,
      with the age-of-onset range.
- name: Postlingual sensorineural hearing impairment
  category: Otologic
  description: >-
    Hearing loss with onset after speech acquisition, in contrast to the
    congenital deafness of Usher syndrome types 1 and 2.
  phenotype_term:
    preferred_term: Postlingual sensorineural hearing impairment
    term:
      id: HP:0008596
      label: Postlingual sensorineural hearing impairment
  evidence:
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CEP250 pathogenic variants are associated with post-lingual SNHL, and most often progressive photoreceptor dysfunction.
    explanation: >-
      States that the hearing loss is postlingual.
- name: Photophobia
  category: Ophthalmologic
  description: >-
    Light sensitivity accompanying the visual decline, reported in a
    CEP250-biallelic patient and consistent with the cone-predominant pattern.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
  evidence:
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient RP1973 suffered from bilateral moderate-severe progressive hearing loss manifested at 13 years old (Fig. 3b) and late-onset progressive diminution of vision in both eyes with photophobia (first ophthalmologic examination at 44 years old).
    explanation: >-
      Records photophobia alongside the progressive visual decline in a
      CEP250-biallelic patient.
- name: Reduced visual acuity
  category: Ophthalmologic
  description: >-
    Reduced best-corrected visual acuity from the retinal dystrophy. It is
    generally mild relative to classical Usher syndrome; in the one patient
    reported in detail it was 0.6 and 0.5 Snellen in the fourth decade, and
    across the three CEP250 patients of the four-gene series that reports
    per-patient acuity the most recent values ranged from 20/60 to 20/200. That
    range, rather than the single patient, is what the "generally mild"
    characterisation rests on.
  phenotype_term:
    preferred_term: Reduced visual acuity
    term:
      id: HP:0007663
      label: Reduced visual acuity
  evidence:
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The BCVA was 0.6 in the right eye and 0.5 in the left eye (Snellen).
    explanation: >-
      The measured acuity in the CEP250-biallelic patient described in detail.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms.
    explanation: >-
      The acuity range across the three CEP250 patients of the four-gene
      series, which is the severity spread behind the "generally mild"
      characterisation.
- name: Spicular pigmentation of the retina
  category: Ophthalmologic
  description: >-
    Bone-spicule pigment migration in a mid-peripheral annular zone with
    narrowing of the peripheral retinal vessels, in the one CEP250 patient whose
    fundus is described in detail. Fundus appearance is not uniform in this
    disorder: colour fundus photography was normal in all three CEP250 patients
    of a later series.
  phenotype_term:
    preferred_term: Spicular pigmentation of the retina
    term:
      id: HP:0007737
      label: Spicular pigmentation of the retina
  evidence:
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The anterior segment findings were within normal limits, but fundus examination revealed migration of pigment in a bone-spicule pattern within a mid-peripheral annular zone of both eyes and narrowing of the peripheral retinal blood vessels (Fig. 3c).
    explanation: >-
      The fundus description in the CEP250-biallelic patient reported in detail.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: REFUTE
    directness: DIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Representative images of patients with CEP250 variants are shown in figure 2. Color fundus analysis revealed normal findings in all patients.
    explanation: >-
      Bounds the claim rather than supporting it: colour fundus photography was
      normal in all three CEP250 patients of a later series, so bone-spicule
      pigmentation is a finding in some patients and not a characteristic
      feature of the disorder.
- name: Constriction of peripheral visual field
  category: Ophthalmologic
  description: >-
    Peripheral visual field constriction, stable over five years of follow-up in
    the one patient in whom serial perimetry is reported.
  phenotype_term:
    preferred_term: Constriction of peripheral visual field
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Humphrey perimetry revealed peripheral visual field constriction with relative defects in the paracentral region in both eyes that has remained stable for the last five years.
    explanation: >-
      Records the field defect and, unusually for this disorder, that it was
      stable over five years.
- name: Abnormal electroretinogram
  category: Ophthalmologic
  diagnostic: true
  description: >-
    Electroretinography is how the retinal involvement is detected and graded,
    and it may be the only abnormality in a patient whose fundus looks normal.
  phenotype_term:
    preferred_term: Abnormal electroretinogram
    term:
      id: HP:0000512
      label: Abnormal electroretinogram
  evidence:
  - reference: PMID:29718797
    reference_title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiological analysis revealed a mild CRD in two family members.
    explanation: >-
      Records that the retinal abnormality was established
      electrophysiologically.
- name: Photoreceptor layer loss on macular OCT
  category: Ophthalmologic
  description: >-
    Outer retinal atrophy with thinning of the outer nuclear layer, present in
    all three CEP250 patients of the four-gene series. It is the
    structural counterpart of the electrophysiological cone-rod pattern, and it
    is present even where colour fundus photography is normal.
  phenotype_term:
    preferred_term: Photoreceptor layer loss on macular OCT
    term:
      id: HP:0030609
      label: Photoreceptor layer loss on macular OCT
  evidence:
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      OCT findings showed outer retinal atrophy in all three patients including thinning of the outer nuclear layer (ONL)
    explanation: >-
      Reports the finding in all three CEP250 patients of the series.
- name: Abnormal fundus autofluorescence imaging
  category: Ophthalmologic
  description: >-
    Subtle hyper-autofluorescence peripherally or peripapillary in two of the
    three CEP250 patients of the four-gene series, against normal
    colour fundus photography in all three. Autofluorescence detects retinal
    involvement that ophthalmoscopy misses, which is what makes a normal fundus
    examination uninformative in this disorder.
  phenotype_term:
    preferred_term: Abnormal fundus autofluorescence imaging
    term:
      id: HP:0030602
      label: Abnormal fundus autofluorescence imaging
  evidence:
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Color fundus analysis revealed normal findings in all patients. FAF demonstrated areas of subtle hyper-autofluorescence in the periphery
    explanation: >-
      Records abnormal autofluorescence against a normal colour fundus in the
      same patients.
biochemical: []
genetic:
- name: CEP250
  association: Causal biallelic variant
  gene_term:
    preferred_term: CEP250
    term:
      id: hgnc:1859
      label: CEP250
  notes: >-
    Two cautions attach to the reported allelic spectrum. First, the original
    family that established the gene segregated a second ciliary-gene allele:
    the individuals homozygous for the CEP250 nonsense variant who also carried
    a single C2orf71 nonsense allele had mild retinal degeneration, while the
    double homozygotes had early-onset severe retinitis pigmentosa, which the
    authors read as an additive effect. Severe early retinal disease in that
    family therefore should not be attributed to CEP250 alone. Second, the
    same class of truncating allele has been reported with apparently isolated
    hearing loss and with non-syndromic retinitis pigmentosa, so a biallelic
    truncating genotype does not predict which organ presents.

    A second, independent CEP250-biallelic patient also carried a monoallelic
    rare variant in another Usher gene - a heterozygous USH2A missense change
    with no second USH2A hit found. Two of the small number of reported patients
    therefore carry an unexplained single allele in a second retinal gene, which
    is why the second-locus question is recorded as an open gap rather than
    treated as settled.
  evidence:
  - reference: PMID:24780881
    reference_title: A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patients who were double homozygotes had SNHL accompanied by early-onset and severe RP, while patients who were homozygous for the CEP250 mutation and carried a single mutant C2orf71 allele had SNHL with mild retinal degeneration.
    explanation: >-
      The genotype-by-genotype breakdown that separates the CEP250-attributable
      phenotype from the two-gene one.
  - reference: PMID:24780881
    reference_title: A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins.
    explanation: >-
      The authors' own interpretation of the second locus as additive.
  - reference: PMID:30998843
    reference_title: Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we report the identification of a mutation (c.562C>T, p.R188*) in the CEP250 in a consanguineous family with nonsyndromic RP.
    explanation: >-
      Documents an apparently non-syndromic retinal presentation of a CEP250
      truncating allele that is also seen in the syndromic disorder.
environmental: []
treatments:
- name: Low-vision rehabilitation and hearing amplification
  description: >-
    No disease-modifying treatment exists. Management is supportive on both
    axes: low-vision support and monitoring for the retinal dystrophy, and
    amplification or other audiological management for the progressive hearing
    loss. Because either organ may present alone, the practical intervention
    with the clearest recommendation behind it is cross-referral - assessing the
    eyes of a patient who presents with hearing loss and vice versa.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Cone/cone-rod dystrophy
    term:
      id: HP:0000548
      label: Cone/cone-rod dystrophy
  - preferred_term: Progressive sensorineural hearing impairment
    term:
      id: HP:0000408
      label: Progressive sensorineural hearing impairment
  evidence:
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also recommend ophthalmological evaluation and follow-up in patients with isolated SNHL, and conversely.
    explanation: >-
      The cross-referral recommendation that the supportive management rests on.
diagnosis:
- name: Retinal assessment with electroretinography and high-resolution imaging
  description: >-
    Full-field and macular electroretinography with optical coherence tomography
    and, where available, adaptive-optics imaging. Adaptive optics was needed to
    see the reduced foveal cone density in the Japanese family, and the authors
    recommended high-resolution imaging specifically because the
    ophthalmological phenotype can be so mild. Fundus appearance is unreliable:
    it was normal in all three CEP250 patients of one series.
  results: >-
    Cone-predominant electroretinographic abnormality, often with an absent
    macular response and only mild scotopic change; reduced foveal cone density
    on adaptive optics; outer retinal atrophy on optical coherence tomography.
  diagnosis_term:
    preferred_term: retinal examination
    term:
      id: NCIT:C101217
      label: Retinal Examination
  evidence:
  - reference: PMID:29718797
    reference_title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Because the ophthalmological phenotypes were very mild, high-resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease.
    explanation: >-
      The authors' explicit recommendation for how to detect the retinal
      component.
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Full-field electroretinography showed only mild alterations in the scotopic flash electroretinography (ERG), as the amplitudes of the b-wave were reduced in the right eye and absent in the left eye. Macular ERG showed an absence of response in both eyes, and Visual Evoked Potentials (VEP) were altered (Supplemental Fig. S1).
    explanation: >-
      Shows that the macular electroretinogram carried the abnormality while the
      full-field scotopic response was only mildly affected, which is why macular
      as well as full-field testing is specified here.
- name: Audiometry
  description: >-
    Pure-tone audiometry, which in this disorder is not a formality: the hearing
    loss may be the presenting or the only complaint, it is postlingual and
    progressive, and it may be slight enough that it is found only on formal
    testing. Vestibular assessment is normal, which is one of the findings that
    separates this disorder from Usher syndrome type 1.
  results: >-
    Postlingual, progressive, bilateral sensorineural hearing loss with normal
    vestibular function.
  diagnosis_term:
    preferred_term: audiometric test
    term:
      id: NCIT:C38036
      label: Audiometric Test
  evidence:
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient RP1973 suffered from bilateral moderate-severe progressive hearing loss manifested at 13 years old (Fig. 3b) and late-onset progressive diminution of vision in both eyes with photophobia (first ophthalmologic examination at 44 years old).
    explanation: >-
      A patient in whom the audiometric abnormality preceded the ophthalmic one
      by three decades, which is why audiometry is curated as its own diagnostic
      step.
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors dysfunction without vestibular signs.
    explanation: >-
      Records the absence of vestibular signs that the assessment is looking
      for.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Age of onset ranged from 13 to 30 years. BCVA at the most recent visit ranged from 20/60 to 20/200. All patients demonstrated progressive SNHL with an age of onset from <10 to 24 years. There were no reports of vestibular symptoms.
    explanation: >-
      A third independent human-clinical source for vestibular sparing, which
      is one of the grounds for separating this disorder from Usher syndrome
      type 1.
- name: CEP250 sequencing within an Usher-gene panel
  description: >-
    Molecular confirmation by targeted panel, exome or genome sequencing. CEP250
    entered Usher-syndrome diagnostic panels as an uncertainly associated gene
    and was consolidated as causative by panel screening, so the practical
    advice is to include atypical as well as classical Usher genes when either
    sensory system is affected.
  results: Biallelic truncating CEP250 variants.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Therefore, this approach proved reliable results for the molecular diagnosis of the disease and also allowed the consolidation of the CEP250 gene as disease causative for an Usher-like phenotype.
    explanation: >-
      Documents panel sequencing as the route by which CEP250 disease is
      identified.
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We strongly recommend genetic analysis of classical and atypical Usher related-genes, in patients with isolated retinal dystrophy or SNHL.
    explanation: >-
      The recommendation to include atypical Usher genes such as CEP250 in the
      panel.
differential_diagnoses:
- name: Usher syndrome
  description: >-
    The disorder this one is repeatedly compared with, and the reason the
    literature calls it atypical Usher syndrome. Usher syndrome is caused by
    disruption of the Usher protein interactome, which organises the stereocilia
    hair bundle and the photoreceptor periciliary region; C-Nap1 is not part of
    that network. Clinically, Usher types 1 and 2 have congenital hearing loss
    and rod-first retinitis pigmentosa, with vestibular areflexia in type 1.
  disease_term:
    preferred_term: Usher syndrome
    term:
      id: MONDO:0019501
      label: Usher syndrome
  distinguishing_features:
  - Postlingual progressive hearing loss rather than congenital deafness
  - Cone-predominant retinal dystrophy rather than rod-cone retinitis pigmentosa
  - Vestibular function spared
  - Centriolar cohesion protein rather than a component of the Usher interactome
  evidence:
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Classically, Usher syndrome is characterized by the association of sensorineural hearing loss (SNHL), retinitis pigmentosa (RP) and possible vestibular dysfunction. Pathogenic bi-allelic variants in CEP250 cause atypical autosomal recessive Usher syndrome, which is associated with SNHL and photoreceptors dysfunction without vestibular signs.
    explanation: >-
      Contrasts the classical syndrome with the CEP250 phenotype, including the
      absence of vestibular signs.
  - reference: PMID:27588452
    reference_title: "Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that truncating mutations in CEP78 result in a phenotype involving both the visual and auditory systems but different from typical Usher syndrome.
    explanation: >-
      The same conclusion drawn for the sibling centrosomal disorder, that the
      phenotype is distinct from typical Usher syndrome.
- name: Cone-rod dystrophy and hearing loss 1
  description: >-
    The CEP78-related disorder, and the closest relative of this one: the two
    proteins interact, both are centrosomal, and both give cone-rod degeneration
    with sensorineural hearing loss. Reported CEP78 retinal disease is
    phenotypically broader, with vascular attenuation, optic disc pallor,
    intraretinal pigment and macular change, where CEP250 retinal disease is
    typically mild.
  disease_term:
    preferred_term: cone-rod dystrophy and hearing loss 1
    term:
      id: MONDO:0020778
      label: cone-rod dystrophy and hearing loss 1
  distinguishing_features:
  - Biallelic CEP78 rather than CEP250 variants
  - Broader and generally more severe retinal phenotype
  evidence:
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CEP78-related disease included sensorineural hearing loss (SNHL) in 6/7 patients and demonstrated a broad phenotypic spectrum including: vascular attenuation, pallor of the optic disc, intraretinal pigment, retinal pigment epithelium mottling, areas of mid-peripheral hypo-autofluorescence, outer retinal atrophy, mild pigmentary changes in the macula, foveal hypo-autofluorescence, and granularity of the ellipsoid zone.
    explanation: >-
      The CEP78-specific findings from the same series, showing the broader
      retinal spectrum of the sibling disorder.
- name: Non-syndromic autosomal recessive hearing loss
  description: >-
    A CEP250 nonsense variant has been reported in a family with progressive
    moderate sensorineural hearing loss and no retinal degeneration, so
    non-syndromic deafness is a differential that resolves to the same gene.
    Whether those individuals will develop retinal disease later is not known,
    which is why ophthalmological follow-up is recommended.
  disease_term:
    preferred_term: nonsyndromic genetic hearing loss
    term:
      id: MONDO:0019497
      label: nonsyndromic genetic hearing loss
  distinguishing_features:
  - No retinal degeneration at the time of report
  - Same gene and same class of truncating allele
  evidence:
  - reference: PMID:37759551
    reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Herein, we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter) among the family members with progressive moderate sensorineural hearing loss in nonsyndromic autosomal recessive type but without retinal degeneration.
    explanation: >-
      Documents the non-syndromic hearing-loss presentation of the same gene.
animal_models:
- name: Cep250 knockout mouse (exon 6-7 deletion)
  species: Mouse
  genotype: Cep250 null, homozygous (knockout-first construct deleting exons 6 and 7, converted with Cre)
  publication: PMID:36857066
  description: >-
    The mouse made specifically to model the disorder, by the group that
    reported the original patients. It is the useful one, and the reason is a
    negative fact about the field: most Usher-syndrome mouse models have normal
    retinal function and structure, so a mouse that loses both vision and
    hearing is unusual. The catch is timing - the electroretinogram is normal at
    6 months and the deficits are documented at 20 months, which is near the end
    of a mouse lifespan.
  modeled_mechanisms:
  - target: Progressive Cone-Predominant Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Full-field electroretinography declines gradually with age and histology
      confirms late-onset retinal degeneration.
    limitations: >-
      The retinal decline is not cone-predominant in the way the human disease
      is: photopic and scotopic responses both fall. Onset is very late, so the
      model cannot address why patients present in childhood or early
      adulthood, and it gives no read on the mildness that characterises the
      human retinal phenotype.
    readouts:
    - name: Full-field electroretinogram amplitude
      target: Progressive Cone-Predominant Photoreceptor Degeneration
      direction: DECREASED
      interpretation: >-
        Functional confirmation of progressive photoreceptor loss in the model.
      evidence:
      - reference: PMID:36857066
        reference_title: Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          At 6 months, the ffERG was normal, but it decreased gradually with age. For both photopic and scotopic ffERG responses, very low amplitudes were evident at 20 months. Histological analysis confirmed late-onset retinal degeneration.
        explanation: >-
          The electroretinographic and histological measurement of the retinal
          phenotype, including its timing.
    evidence:
    - reference: PMID:36857066
      reference_title: Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Although most USH animal models have normal retinal function and structure, the Cep250 KO mouse model shows both retinal degeneration and hearing loss with a relatively late age of onset.
      explanation: >-
        States what makes this model informative relative to the alternatives,
        and states the timing caveat in the same sentence.
  - target: Progressive Postlingual Sensorineural Hearing Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Auditory brainstem response thresholds rise significantly by 20 months,
      giving an adult-onset progressive hearing loss like the patients'.
    limitations: >-
      Hearing was tested only at 20 months, so the model establishes that the
      deficit exists but not its time course, and the human hearing loss is
      already present in childhood in several reported patients.
    readouts:
    - name: Auditory brainstem response threshold
      target: Progressive Postlingual Sensorineural Hearing Loss
      direction: INCREASED
      interpretation: >-
        A raised threshold is reduced hearing sensitivity, the model counterpart
        of the patients' sensorineural loss.
      evidence:
      - reference: PMID:36857066
        reference_title: Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          ABR tests illustrated that hearing threshold significantly increased at the age of 20 months.
        explanation: >-
          The auditory measurement in the model.
    evidence:
    - reference: PMID:36857066
      reference_title: Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Hearing thresholds were detected using auditory brainstem response (ABR) at the age of 20 months.
      explanation: >-
        Establishes how and when hearing was assessed in this model.
- name: Cep250 p.R188* knock-in mouse
  species: Mouse
  genotype: Cep250 p.R188* knock-in, homozygous
  publication: PMID:30998843
  description: >-
    A knock-in carrying an actual patient allele - the same c.562C>T, p.R188*
    nonsense variant found both in the Japanese cone-rod-dystrophy family and in
    a consanguineous family with non-syndromic retinitis pigmentosa. Among the
    models curated here it is the one that tests a specific human variant rather
    than a null; the other three are knockouts.
  modeled_mechanisms:
  - target: Progressive Cone-Predominant Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygous knock-in mice show significantly reduced retinal thickness and
      reduced electroretinographic responses.
    limitations: >-
      The retinal impairment is described as severe, whereas the human
      phenotype associated with this same allele is mild, so the model
      overstates severity. It was made to characterise a non-syndromic retinitis
      pigmentosa presentation and its hearing was not reported, so it says
      nothing about the auditory branch.
    readouts:
    - name: Retinal thickness and electroretinogram response
      target: Progressive Cone-Predominant Photoreceptor Degeneration
      direction: DECREASED
      interpretation: >-
        Structural and functional confirmation that a patient truncating allele
        is sufficient to cause photoreceptor disease.
      evidence:
      - reference: PMID:30998843
        reference_title: Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses.
        explanation: >-
          The two retinal measurements made in this model.
    evidence:
    - reference: PMID:30998843
      reference_title: Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Remarkably, the disruption of Cep250 resulted in severe impairment of retinal function and significant retinal morphological alterations.
      explanation: >-
        Establishes that the model reproduces retinal disease, and in the
        authors' own word, severely.
- name: Cep250 knockout mouse (cochlear characterisation)
  species: Mouse
  genotype: Cep250 null, homozygous
  publication: PMID:37759551
  description: >-
    A Cep250-null line phenotyped for the ear rather than the eye, alongside a
    human family with non-syndromic hearing loss. It is the source of the
    hair-cell mechanism for the auditory branch of this disorder.
  modeled_mechanisms:
  - target: Cochlear Hair Cell Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cep250 is expressed in mouse inner and outer hair cells, and the null mice
      lose them, with progressive hearing loss on auditory brainstem response.
    limitations: >-
      Hair-cell degeneration has not been demonstrated in human cochlea, so the
      cellular mechanism of the human hearing loss rests on this model. The
      accompanying human family had no retinal disease, so the model as
      published addresses the auditory branch only.
    readouts:
    - name: Cochlear hair cell survival
      target: Cochlear Hair Cell Degeneration
      direction: DECREASED
      interpretation: >-
        The cellular lesion proposed to underlie the sensorineural hearing loss.
      evidence:
      - reference: PMID:37759551
        reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Knockout mice of Cep250 showed significant hair cell degeneration and progressive hearing loss in auditory brainstem response.
        explanation: >-
          The hair-cell measurement and the hearing deficit that accompanies it.
    evidence:
    - reference: PMID:37759551
      reference_title: Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In the murine adult cochlea, Cep250 was expressed in the inner and outer hair cells.
      explanation: >-
        Establishes that the cell type this model reads out is one that
        expresses the gene.
- name: Cep250 CRISPR knockout mouse (cochlear morphology line)
  species: Mouse
  genotype: Cep250 homozygous null, generated by CRISPR/Cas9
  publication: DOI:10.21203/rs.3.rs-4515679/v1
  description: >-
    A CRISPR-generated Cep250-null line phenotyped specifically for the inner
    ear, with auditory brainstem responses, a swimming test for vestibular
    function, and hair-cell counts by immunofluorescence. It is the model that
    speaks most directly to what separates this disorder from classical Usher
    syndrome, because it tests hearing and balance in the same animals. It is a
    Research Square preprint and has not been peer reviewed; that is recorded
    here rather than treated as equivalent to the published models.
  modeled_mechanisms:
  - target: Cochlear Hair Cell Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygous nulls lose cochlear hair cells and lose hearing, with the
      deficit concentrated in the high frequencies, while vestibular function is
      spared and heterozygotes are unaffected.
    limitations: >-
      Preprint, not peer reviewed, so the measurements have not been through
      external scrutiny. The mouse is a complete null while patients carry
      truncating alleles in a large protein, and hearing was assessed only over
      P30 to P60, which does not test the progressive course seen in patients.
    readouts:
    - name: Cochlear hair cell number
      target: Cochlear Hair Cell Degeneration
      direction: DECREASED
      interpretation: >-
        Independent confirmation, in a second knockout line, of the hair-cell
        lesion proposed to underlie the human hearing loss.
      evidence:
      - reference: DOI:10.21203/rs.3.rs-4515679/v1
        reference_title: "The cochlear morphology alteration and hearing loss in Cep250 knockout mice"
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Immunofluorescence staining reveals a significant reduction in the number of cochlear hair cells in Cep250−/− mice, confirming the association between Cep250 gene mutation and hearing function loss.
        explanation: >-
          The hair-cell count in this model.
    - name: Auditory brainstem response threshold by frequency
      target: Cochlear Hair Cell Degeneration
      direction: INCREASED
      interpretation: >-
        A raised threshold is reduced hearing sensitivity, so INCREASED here is
        a hearing deficit. The high-frequency predominance matches the sloping
        loss reported in patients.
      evidence:
      - reference: DOI:10.21203/rs.3.rs-4515679/v1
        reference_title: "The cochlear morphology alteration and hearing loss in Cep250 knockout mice"
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          We demonstrate that Cep250−/− mice exhibit impaired hearing function, particularly in high-frequency ranges, whereas their vestibular function remains unaffected.
        explanation: >-
          The auditory measurement, and in the same sentence the preserved
          vestibular function that distinguishes this disorder from Usher type 1.
    evidence:
    - reference: DOI:10.21203/rs.3.rs-4515679/v1
      reference_title: "The cochlear morphology alteration and hearing loss in Cep250 knockout mice"
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Heterozygous mice show no significant changes in hearing, indicating that a single allele mutation in Cep250 is insufficient to affect normal Cep250 expression levels.
      explanation: >-
        The heterozygote result, which matches the recessive inheritance in
        patients and shows the model is dose-appropriate for this disorder.
- name: Cep250 global knockout mouse (retinal transcriptome and metabolome line)
  species: Mouse
  genotype: Cep250 null, homozygous (global knockout)
  publication: PMID:37240188
  description: >-
    A global Cep250-null line phenotyped from P90 to P180 with optical coherence
    tomography, electroretinography, TUNEL, RNA sequencing and untargeted
    metabolomics. It is where the candidate downstream death pathways come from
    - cGMP-PKG and MAPK signalling from the transcriptomics, dysregulated
    arginine metabolism from the companion metabolomic study on a global
    knockout from the same centre.
  modeled_mechanisms:
  - target: Progressive Cone-Predominant Photoreceptor Degeneration
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Reads out the transcriptional and metabolic consequences of Cep250 loss in
      the retina, implicating cGMP-PKG and MAPK signalling and arginine
      metabolism.
    limitations: >-
      Pathway enrichment from bulk retinal RNA sequencing at a single timepoint
      is hypothesis-generating; neither implicated pathway has been tested by
      intervention, and neither has been examined in human retina. The a-wave
      falls more than the b-wave here, a photoreceptor-level signature, but the
      model does not separate cones from rods the way the human phenotype does.
    readouts:
    - name: Retinal cGMP-PKG and MAPK pathway transcript enrichment
      target: Progressive Cone-Predominant Photoreceptor Degeneration
      direction: INCREASED
      interpretation: >-
        The candidate signalling route from ciliary defect to photoreceptor
        death.
      evidence:
      - reference: PMID:37240188
        reference_title: RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          A KEGG enrichment analysis indicated that cGMP-PKG signalling pathways, MAPK signalling pathways, edn2-fgf2 axis pathways, and thyroid hormone synthesis were upregulated, whereas protein processing in the endoplasmic reticulum was downregulated in Cep250 KO eyes.
        explanation: >-
          The enrichment result behind the proposed pathway.
    - name: Outer nuclear layer and whole-retina thickness
      target: Progressive Cone-Predominant Photoreceptor Degeneration
      direction: DECREASED
      interpretation: >-
        Structural confirmation of photoreceptor loss in the line the
        transcriptomics was run on.
      evidence:
      - reference: PMID:37240188
        reference_title: RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Compared with WT mice, the thickness of the ONL, IS/OS, and whole retina of Cep250 mice was significantly reduced.
        explanation: >-
          The structural measurement in this model.
    evidence:
    - reference: PMID:37656476
      reference_title: Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We used Cep250 KO mice and untargeted metabolomics to uncover potential mechanisms underlying retinal degeneration.
      explanation: >-
        The companion metabolomic study on a global Cep250 knockout from the
        same centre, establishing what this model is used for.
discussions:
- discussion_id: gap_crdhl2_organ_selectivity_and_presentation
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does loss of a ubiquitously expressed centriole-linker protein produce
    disease confined to photoreceptors and cochlear hair cells, and what decides
    whether a given patient presents through the eye, through the ear, or with
    only one of the two?
  attaches_to:
  - pathophysiology#Loss of C-Nap1 from the Centriole
  - pathophysiology#Photoreceptor Connecting Cilium Dysfunction
  - genetic#CEP250
  rationale: >-
    C-Nap1 is a general centrosomal protein and centriole cohesion is a general
    cell-cycle process, yet the disease is restricted to two post-mitotic
    sensory cell types. The obvious hypothesis is the ciliary one - the mother
    centriole is the basal body of the photoreceptor connecting cilium and
    C-Nap1 is expressed there - but what C-Nap1 does at that structure has not
    been established, and it does not by itself explain the hair cell. The
    variability is at least as unexplained. Reported patients with the same
    class of truncating allele have had a cone-rod dystrophy with hearing loss,
    apparently isolated hearing loss with a normal retina, or apparently
    non-syndromic retinitis pigmentosa. In the largest series the dual-sensory
    presentation was the majority but not the whole of it - five of seven
    patients - and the largest series raised the
    possibility that loss- and gain-of-function effects coexist, which it noted
    would complicate gene therapy. Nothing currently predicts which
    presentation a genotype will produce.
  evidence:
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The coexistence of loss- and gain-of-function effects may exist, complicating the development of gene therapy.
    explanation: >-
      The authors' statement that the variant mechanism itself is unresolved,
      and its therapeutic consequence.
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two patients appear to present either isolated hearing loss or visual impairment, but further investigations are needed to confirm a possible non-syndromic presentation.
    explanation: >-
      Records the single-organ presentations that the gap asks about, with the
      authors' own caveat.
  - reference: PMID:39610034
    reference_title: The phenotypic spectrum of CEP250 gene variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most patients (5/7) exhibit both retinal dystrophy and SNHL.
    explanation: >-
      Quantifies how often the dual-sensory presentation actually occurs in the
      largest series, which is what makes the single-organ cases a minority
      rather than an anomaly.
- discussion_id: gap_crdhl2_second_locus_attribution
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    How much of the retinal phenotype in the family that established CEP250 is
    attributable to CEP250, given that a second ciliary-gene nonsense allele
    segregated in the same pedigree?
  attaches_to:
  - genetic#CEP250
  - pathophysiology#Progressive Cone-Predominant Photoreceptor Degeneration
  rationale: >-
    The discovery family carried nonsense variants in two ciliary genes, CEP250
    and C2orf71. Individuals homozygous for both had early-onset severe
    retinitis pigmentosa; individuals homozygous for CEP250 with a single mutant
    C2orf71 allele had only mild retinal degeneration. The authors read this as
    an additive effect. That reading has since been supported indirectly, in
    that CEP250 families without a second locus also show mild retinal disease -
    but the contribution of a heterozygous C2orf71 allele to even the mild
    phenotype has not been separately assessed, and no series has been powered
    to test digenic contribution. The practical consequence is that severe
    early-onset retinal disease should not be quoted as part of the CEP250
    phenotype on the strength of that pedigree.
  evidence:
  - reference: PMID:24780881
    reference_title: A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severe retinal involvement in the double homozygotes indicates an additive effect caused by nonsense mutations in genes encoding ciliary proteins.
    explanation: >-
      The authors' own attribution of the severe phenotype to two loci acting
      together.
  - reference: PMID:34223797
    reference_title: Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our patients with CEP250 variants exhibited nonsense and frameshift variants suggesting that this phenotype of mild RP with progressive SNHL may be specific for biallelic CEP250 nonsense or frameshift variants that lead to defective proteins in the absence of pathogenic variants in other genes.
    explanation: >-
      A later series proposing exactly this reading - that mild retinal disease
      with progressive hearing loss is what CEP250 alone produces - stated as a
      suggestion rather than a demonstration, which is why the gap remains
      open.
  - reference: PMID:30459346
    reference_title: "High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The analysis of the targeted panel and WES results showed no additional putative pathogenic mutations, except for one heterozygous missense variant in USH2A (rs773526991: c.4561C > T/p.Arg1521Cys), presenting an allele frequency of 0.00002 in ExAC and for which the in silico tools implied a deleterious effect.
    explanation: >-
      A second independent CEP250 patient carrying an unexplained monoallelic
      variant in another retinal gene, which broadens the gap beyond the
      C2orf71 finding in the discovery family.
clinical_trials: []
datasets: []
notes: >-
  Lump/split decision. Curated as a standalone Disease rather than as a subtype
  of an Usher entity, on three grounds. MONDO places MONDO:0020780 under
  cone-rod dystrophy and hearing loss, not under Usher syndrome. The mechanism is
  not an Usher one: C-Nap1 is a centriole-linker protein, belonging to neither
  the upper tip-link density complex of Usher syndrome type 1 nor the ankle-link
  complex of type 2, which is why the sibling CEP78 disorder was also described
  as different from typical Usher syndrome. And the clinical pattern differs on
  each of the three axes that define the Usher types - onset and character of the
  hearing loss, cone-first rather than rod-first retinal disease, and preserved
  vestibular function.

  Updated 2026-09-24: this paragraph previously argued against subtyping under a
  single lumped `Usher_Syndrome` entry and described that entry's pathograph as
  built on "loss of an Usher protein complex component". That entry no longer
  exists - it was split into four mechanism entities plus
  kb/groupings/Usher_Syndrome.yaml (issue #10822) precisely because there is no
  single Usher protein complex. The conclusion is unchanged and is if anything
  better supported: there is now no umbrella Usher Disease entry to be a subtype
  of, and no one of the four entities this disorder's mechanism fits.

  Evidence-source convention: patient clinical and genetic findings are graded
  HUMAN_CLINICAL; mouse work MODEL_ORGANISM; the NIH3T3 localisation experiment
  IN_VITRO; background statements of established cell biology drawn from
  introductions rather than from the citing paper's own data are graded OTHER.

  One source here is a preprint. The cochlear-morphology mouse
  (DOI:10.21203/rs.3.rs-4515679/v1) is a Research Square deposit that has not
  been peer reviewed. It is cited because it is the only study that tests
  hearing and vestibular function in the same Cep250-null animals, which is the
  distinction that separates this disorder from Usher type 1, and its preprint
  status is stated in the model description and limitations. Its three snippets
  are checked against the cached abstract by the reference validator.
📚

References & Deep Research

References

12
PMID:24780881
A homozygous nonsense CEP250 mutation combined with a heterozygous nonsense C2orf71 mutation is associated with atypical Usher syndrome.
No top-level findings curated for this source.
PMID:29718797
CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
No top-level findings curated for this source.
PMID:30459346
High-throughput sequencing for the molecular diagnosis of Usher syndrome reveals 42 novel mutations and consolidates CEP250 as Usher-like disease causative.
No top-level findings curated for this source.
PMID:39610034
The phenotypic spectrum of CEP250 gene variants.
No top-level findings curated for this source.
PMID:34223797
Expanding the clinical phenotype in patients with disease causing variants associated with atypical Usher syndrome.
No top-level findings curated for this source.
PMID:37759551
Novel Variant in CEP250 Causes Protein Mislocalization and Leads to Nonsyndromic Autosomal Recessive Type of Progressive Hearing Loss.
No top-level findings curated for this source.
PMID:30998843
Functional characterization of CEP250 variant identified in nonsyndromic retinitis pigmentosa.
No top-level findings curated for this source.
PMID:36857066
Homozygous Knockout of Cep250 Leads to a Relatively Late-Onset Retinal Degeneration and Sensorineural Hearing Loss in Mice.
No top-level findings curated for this source.
PMID:37240188
RNA-Seq Analysis Reveals an Essential Role of the cGMP-PKG-MAPK Pathways in Retinal Degeneration Caused by Cep250 Deficiency.
No top-level findings curated for this source.
PMID:37656476
Dysregulated Arginine Metabolism Is Linked to Retinal Degeneration in Cep250 Knockout Mice.
No top-level findings curated for this source.
PMID:27588452
Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss.
No top-level findings curated for this source.
DOI:10.21203/rs.3.rs-4515679/v1
The cochlear morphology alteration and hearing loss in Cep250 knockout mice
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Cone-rod dystrophy and hearing loss 2 (MONDO:0020780) · 2026-08-29T02:57:13Z · View source

New de novo Disease entry for cone-rod dystrophy and hearing loss 2 (MONDO:0020780, CEP250, hgnc:1859). entry_type decided as DISEASE (standalone), not a has_subtypes entry on Usher_Syndrome. Three grounds, recorded in the entry notes: MONDO places MONDO:0020780 under cone-rod dystrophy and hearing loss rather than under Usher syndrome; the mechanism is centriole cohesion rather than the Usher protein interactome that the existing Usher pathograph is built on, which is why the sibling CEP78 disorder was likewise described as different from typical Usher syndrome; and the clinical pattern differs on each of the three axes that define the Usher types - postlingual progressive rather than congenital hearing loss, cone-first rather than rod-first retinal disease, and preserved vestibular function. Named Entity Confusion: preflight-dr PASS (CEP250 mentioned 80 times, OMIM 618358 matching MONDO). The gene-keyed check cannot see the two real confusion risks here, which were handled by re-reading: 1. Two-gene discovery family. PMID:24780881 segregated nonsense alleles in both CEP250 and C2orf71. Double homozygotes had early-onset severe RP; CEP250 homozygotes carrying a single C2orf71 allele had mild retinal degeneration. Severe early retinal disease is therefore NOT curated as part of the CEP250 phenotype; the genotype-by-genotype breakdown is quoted in genetic.notes and a KNOWLEDGE_GAP records the unresolved second-locus contribution. 2. Four-gene cohort paper. PMID:34223797 covers CEP78, CEP250, ARSG and ABHD12. Only sentences explicitly labelled CEP250 were used. A block of numbers in the full text (age of onset 13-30 years, BCVA 20/60-20/200, hearing onset under 10 to 24 years) sits immediately after the CEP78 paragraph with no gene-labelled heading in the cached extraction, so its attribution is ambiguous and it was NOT used, even though the falcon deep-research report attributed it to CEP250. Deep-research defect noted: the falcon report cites nan2024thecochlearmorphology three times for a claim about basal-turn hair-cell loss in Cep250 mice. That citation key has no bibliographic entry in the sidecar and no matching PubMed record was found, so the claim was dropped. Four animal models curated, kept separate because they are distinct lines from distinct groups: the exon 6-7 knockout (PMID:36857066, retina and hearing, late onset), the p.R188* patient-allele knock-in (PMID:30998843), a cochlea-phenotyped knockout (PMID:37759551), and a global knockout used for retinal transcriptomics and metabolomics (PMID:37240188 with PMID:37656476). Evidence-source convention stated in the entry notes: patient findings HUMAN_CLINICAL, mouse MODEL_ORGANISM, the NIH3T3 localisation experiment IN_VITRO, established cell biology quoted from introductions OTHER. Validation: just validate exit 0 (52/52 snippets verified), validate-terms exit 0, check-duplicate-keys, check-entity-refs, check-folded-hyphens, check-snippet-length, check-title-snippets, check-snippet-grading, check-environmental-evidence all exit 0.

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 33 citations 2026-08-28T19:12:05.411098

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: cone-rod dystrophy and hearing loss 2 (CRDHL2, biallelic CEP250)
  • MONDO ID: MONDO:0020780 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on cone-rod dystrophy and hearing loss 2 (CRDHL2, biallelic CEP250) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Cone-rod dystrophy and hearing loss 2 (CRDHL2; biallelic CEP250): disease-characteristics report

Executive summary

CRDHL2 is an exceptionally rare, autosomal-recessive, progressive oto-retinal disorder caused by biallelic pathogenic variants in CEP250, which encodes the centrosome-linker protein C-Nap1. The best-supported clinical pattern is progressive, usually noncongenital sensorineural hearing loss (SNHL), followed by or accompanied by a relatively mild, cone-predominant retinal dystrophy. It is frequently called CEP250-related atypical Usher syndrome or an Usher-like disorder, although it does not consistently fit classic Usher types 1–3. Published human evidence remains limited to a small number of families and retrospective cases; consequently, prevalence, penetrance, phenotype frequencies, and long-term prognosis cannot yet be estimated reliably. A 2021 multicenter series included only three CEP250-affected individuals. Their ocular onset ranged from 13–30 years, hearing-loss onset from under 10–24 years, and best-corrected visual acuity (BCVA) from 20/60–20/200; all had progressive SNHL and none reported vestibular symptoms. (igelman2021expandingtheclinical pages 5-7)

The most important 2023–2024 developments are mouse studies reproducing retinal degeneration and hearing loss, identification of photoreceptor apoptosis and candidate cGMP–PKG–MAPK/EDN2–FGF2 responses, and demonstration that cochlear hair-cell loss is concentrated in the basal/high-frequency region. These establish useful preclinical platforms but have not yet produced a CEP250-specific clinical trial or disease-modifying treatment. (chen2023rnaseqanalysisreveals pages 1-2, nan2024thecochlearmorphology pages 5-8, abudiab2023homozygousknockoutof pages 1-2)

1. Disease information

Definition and identifiers

  • Preferred name: cone-rod dystrophy and hearing loss 2.
  • Abbreviation: CRDHL2.
  • MONDO: MONDO:0020780 (identifier supplied in the target specification; users should verify the current MONDO release).
  • OMIM phenotype: 618358.
  • Causal gene: CEP250, OMIM 609689; approved gene symbol CEP250; protein name centrosomal protein 250/C-Nap1.
  • Common synonyms: CEP250-related cone-rod dystrophy with hearing loss; CEP250-related retinal dystrophy and hearing loss; CEP250-associated atypical Usher syndrome; CEP250-associated Usher-like disease.
  • Orphanet/MeSH: no disease-specific Orphanet or MeSH descriptor was identified in the retrieved evidence. Broader descriptors such as cone-rod dystrophy, hereditary retinal dystrophy, sensorineural hearing loss, and Usher syndrome may be used for retrieval but should not replace the molecular diagnosis.
  • ICD-10/ICD-11: no unique CRDHL2 code was identified. In practice, component manifestations are coded under inherited retinal dystrophy/cone-rod dystrophy and sensorineural hearing loss. A specific CEP250 molecular annotation should therefore accompany clinical coding.

The disease definition comes from aggregated disease-level literature and small research cohorts, not population-scale EHR evidence. The 2018 diagnostic study analyzed 77 unrelated suspected Usher cases and identified two CEP250 nonsense variants in one individual; its overall panel detection rate was 82.8%, but that statistic applies to the full Usher cohort—not CRDHL2. (fustergarcia2018highthroughputsequencingfor pages 1-2)

A central classification caveat is allelic heterogeneity: CEP250 variants have also been reported with nonsyndromic retinitis pigmentosa (RP) and with progressive nonsyndromic hearing loss. Consequently, “biallelic CEP250 disease” is broader than CRDHL2, and a molecular result alone does not establish that both sensory phenotypes are already present. (kang2023novelvariantin pages 9-11, kang2023novelvariantin pages 1-2, huang2019functionalcharacterizationof pages 1-2)

2. Etiology, risk, and protective factors

Primary cause

CRDHL2 is caused by germline biallelic CEP250 variants, most convincingly truncating nonsense or frameshift alleles, inherited in an autosomal-recessive pattern. In the 2021 atypical-Usher cohort, all CEP250 variants were novel nonsense or frameshift variants. Compound-heterozygous and homozygous families have been reported. (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5)

The causal model is loss of normal C-Nap1 function or localization rather than environmental injury. A 2023 functional study showed that p.Gln1171Ter was translated but failed to localize to centrosomes, dispersing in the cytosol; the investigators found no dominant-negative effect on wild-type CEP250. (kang2023novelvariantin pages 6-9, kang2023novelvariantin pages 11-12)

Risk factors and modifiers

  • Established risk: two pathogenic CEP250 alleles in trans.
  • Family history/consanguinity: increase the prior probability of recessive disease but are not required. The founding report involved a consanguineous Iranian-Jewish family; other cases were compound heterozygotes. (chen2023rnaseqanalysisreveals pages 1-2, fustergarcia2018highthroughputsequencingfor pages 10-10)
  • Possible modifier: the original Iranian-Jewish family also carried a heterozygous nonsense variant in C2orf71/PCARE, creating uncertainty about a digenic or modifying contribution. Later independent CEP250-only families strengthened CEP250 causality, but the modifying role of C2orf71 remains unresolved. (huang2019functionalcharacterizationof pages 4-6, chen2023rnaseqanalysisreveals pages 1-2)
  • Age: not an etiologic risk factor, but expression is age-dependent; retinal and auditory abnormalities can emerge or worsen over decades.
  • Sex: no sex effect is established.
  • Protective variants: none established.
  • Environmental, occupational, infectious, dietary, smoking, alcohol, or exercise effects: none demonstrated specifically for CRDHL2.
  • Gene–environment interactions: no CRDHL2-specific evidence.

Ordinary retinal and hearing health measures may be prudent, but they must not be represented as proven disease-modifying interventions.

3. Phenotypes

Core human phenotype

Manifestation Character and timing Available frequency evidence Suggested HPO term
Sensorineural hearing impairment Bilateral, progressive, mild-to-moderate or moderate-severe; onset reported from <10 to 24 years in the three-patient series 3/3 in that selected CEP250 cohort; not a population estimate HP:0000407; progressive hearing impairment HP:0001731
Cone/cone-rod retinal dystrophy Usually mild and progressive; ocular onset 13–30 years in the series; one ffERG showed mild cone dysfunction with normal rods 3/3 had retinal disease by study design; one had reported ffERG Cone-rod dystrophy HP:0000548; cone dystrophy HP:0000547
Reduced visual acuity Progressive; latest BCVA 20/60–20/200 in the three cases Reported in the small case series Reduced visual acuity HP:0007663
Photophobia Prominent in some patients; RP1973 developed photophobia with late progressive visual decline Case-level, frequency unknown HP:0000613
Outer retinal atrophy OCT: ONL thinning and/or subtle ellipsoid/interdigitation-zone disruption All three CEP250 cases had some outer retinal atrophy Suggested: outer retinal atrophy; retinal degeneration HP:0000546
Abnormal fundus autofluorescence May be subtle peripheral or peripapillary hyper-autofluorescence; FAF may also be normal Variable among three cases Abnormal fundus autofluorescence HP:0030636
Visual-field constriction Variable, from approximately 100° to approximately 20° horizontally with a V4e target in reported siblings 2 tested siblings Visual-field defect HP:0001123; constricted visual fields HP:0001133
RP-like fundus changes Mid-peripheral bone-spicule pigment and vessel attenuation in RP1973; other cases can have a normal-appearing color fundus Variable Retinitis pigmentosa HP:0000510; bone-spicule pigmentation HP:0007703
Vestibular dysfunction Not reported in the three CEP250 cases; mouse swimming behavior also normal 0/3 reported, but sample is inadequate to exclude rare involvement Abnormal vestibular function HP:0001751, marked absent when appropriate

The multicenter study explicitly reported: “Age of onset ranged from 13 to 30 years,” “All patients demonstrated progressive SNHL,” and “There were no reports of vestibular symptoms.” Color fundus findings were normal in all three, illustrating that OCT/FAF/ERG can detect disease despite subtle ophthalmoscopy. (igelman2021expandingtheclinical pages 5-7)

A deeply characterized 2018 patient, RP1973, developed bilateral moderate-severe progressive hearing loss at 13 years and underwent the first reported ophthalmic examination at 44 years after late progressive visual decline and photophobia. BCVA was 0.6 right and 0.5 left; examination showed mid-peripheral bone-spicule pigment and peripheral vessel narrowing. (fustergarcia2018highthroughputsequencingfor pages 4-5)

Quality-of-life impact

No CEP250-specific EQ-5D, SF-36, PROMIS, educational, mobility, or employment study was found. Nevertheless, combined progressive hearing and visual impairment plausibly compromises communication, reading, driving, orientation, and independent mobility. These are clinical inferences—not measured CRDHL2 outcomes. Dual-sensory rehabilitation should begin before severe loss because one sensory system becomes progressively less able to compensate for the other.

4. Genetic and molecular information

Gene and variant spectrum

CEP250 encodes a large coiled-coil centrosomal protein, C-Nap1, which anchors linker proteins including rootletin at proximal centriole ends and contributes to interphase centrosome cohesion. CEP250 also localizes in photoreceptor ciliary/basal-body contexts and interacts with rootletin, NEK2, and CEP78. (kang2023novelvariantin pages 1-2, huang2019functionalcharacterizationof pages 1-2)

Reported alleles relevant to the phenotypic spectrum include:

  • c.3463C>T, p.Arg1155Ter: homozygous in the original atypical-Usher family, alongside heterozygous C2orf71/PCARE p.Gln1097Ter. (huang2019functionalcharacterizationof pages 4-6, chen2023rnaseqanalysisreveals pages 1-2)
  • c.361C>T, p.Arg121Ter and c.562C>T, p.Arg188Ter: compound heterozygous in a Japanese family with mild cone-rod dystrophy and SNHL. (huang2019functionalcharacterizationof pages 4-6)
  • p.Lys1113Ter and p.Arg1336Ter: compound heterozygous in a later case with progressive hearing loss and late-onset CRD. (abudiab2023homozygousknockoutof pages 1-2)
  • c.562C>T, p.Arg188Ter: also reported homozygously with nonsyndromic RP during follow-up to age 28, demonstrating phenotype overlap rather than a one-variant/one-phenotype rule. A knock-in mouse carrying the corresponding allele had severe retinal dysfunction. (abudiab2023homozygousknockoutof pages 1-2, huang2019functionalcharacterizationof pages 1-2)
  • c.1826C>T, p.Ala609Val: reported with nonsyndromic RP; its relatively high Ashkenazi-Jewish frequency (>1/600 alleles in the cited report) warrants especially careful contemporary ClinVar/gnomAD and segregation review before classification. (huang2019functionalcharacterizationof pages 4-6)
  • c.3511C>T, p.Gln1171Ter: homozygous progressive nonsyndromic SNHL without retinal degeneration at the time of study; affected adults were only in their late 30s/early 40s, so delayed retinal disease was not excluded. (kang2023novelvariantin pages 9-11, kang2023novelvariantin pages 1-2)

Additional novel nonsense/frameshift variants were present in the 2021 series, but exact table-level HGVS data were not recoverable from the retrieved text. Every variant should be assessed independently under current ACMG/AMP criteria; historical labels such as “UV4” are not equivalent to a current ClinVar consensus. Current gnomAD frequencies and ClinVar review status were not available in the retrieved evidence and should not be inferred.

All reported disease alleles are germline. No somatic CEP250 mechanism, recurrent pathogenic chromosomal rearrangement, repeat expansion, mitochondrial variant, or disease-specific epigenetic abnormality is established. No validated modifier gene beyond the unresolved C2orf71/PCARE observation is known.

Pathogenic consequence

The strongest direct functional example is p.Gln1171Ter: a roughly 150-kDa truncated product was made but failed centrosomal localization. In murine cochlea, Cep250 is expressed in inner and outer hair cells; knockout produced hair-cell degeneration and progressive hearing loss. The authors’ abstract states: “a nonsense variant in CEP250 results in a deficit of centrosome localization and hair cell degeneration in the cochlea.” Published 21 September 2023; DOI: https://doi.org/10.3390/cells12182328. (kang2023novelvariantin pages 1-2)

5. Environmental information

No toxin, radiation, pollution, occupational exposure, infection, medication, diet, exercise pattern, tobacco exposure, or alcohol exposure is known to cause or trigger CRDHL2. Likewise, no preventive drug, nutrient, antioxidant, or exposure avoidance strategy has demonstrated CEP250-specific benefit. The disorder should therefore be represented as genetic, with environmental fields marked “no disease-specific evidence,” rather than populated from generic retinal-degeneration associations.

6. Mechanism and pathophysiology

Proposed causal chain

  1. Upstream genetic lesion: biallelic damaging CEP250 variants reduce functional C-Nap1 or prevent its centrosomal localization.
  2. Organelle-level defect: impaired proximal-centriole linker/centrosome cohesion and disturbed specialized ciliary-rootlet or basal-body homeostasis.
  3. Cell-specific vulnerability: photoreceptors depend on continuous protein transport and structural maintenance across the connecting cilium; cochlear hair cells depend on highly polarized cytoskeletal/centrosomal organization.
  4. Downstream injury: mislocalization of photoreceptor outer-segment proteins, photoreceptor dysfunction and apoptosis; degeneration of cochlear hair cells, particularly basal-turn outer hair cells.
  5. Clinical expression: cone-predominant or cone-rod dystrophy with photophobia and progressive visual loss, plus progressive high-frequency-predominant SNHL. (kang2023novelvariantin pages 6-9, nan2024thecochlearmorphology pages 5-8, huang2019functionalcharacterizationof pages 1-2, chen2023rnaseqanalysisreveals pages 1-2)

This chain is biologically coherent but only the genotype-to-phenotype association is directly demonstrated in humans. Intermediate mechanisms derive predominantly from cultured cells and mice.

Molecular profiling

In a 2023 Cep250-knockout retina study, OCT/ERG and histology at P90 and P180 showed reduced outer nuclear layer (ONL), inner/outer segment, and whole-retinal thickness; reduced scotopic and photopic a- and b-waves; fewer photoreceptors; and increased TUNEL labeling. RNA-seq at P90 found 298 differentially expressed genes: 149 upregulated and 149 downregulated. cGMP–PKG, MAPK, EDN2–FGF2, and thyroid-hormone synthesis pathways were enriched upward, whereas endoplasmic-reticulum protein processing was downregulated. Increased Pde3a, Pde3b, Gfap, Edn2, Fgf2, and Tyr expression was validated. These changes may represent downstream stress/reactive responses rather than the initiating lesion. Published 16 May 2023; DOI: https://doi.org/10.3390/ijms24108843. (chen2023rnaseqanalysisreveals pages 1-2, chen2023rnaseqanalysisreveals pages 5-7)

No validated human CRDHL2 transcriptomic, proteomic, metabolomic, lipidomic, epigenomic, spatial-transcriptomic, patient-iPSC, retinal-organoid, or multi-omics signature was identified. A 2024 mouse preprint mined cochlear single-cell RNA-seq across P1–P100 and found increasing Cep250 expression in auditory hair cells but little expression in vestibular hair cells; this provides a possible explanation for auditory disease without vestibular dysfunction but is not human proof. (nan2024thecochlearmorphology pages 5-8, nan2024thecochlearmorphology pages 8-16)

Suggested mechanism ontologies

  • GO cellular component: centrosome GO:0005813; centriole GO:0005814; basal body GO:0005932; cilium GO:0005929; photoreceptor connecting cilium; cytosol GO:0005829.
  • GO biological process: cilium organization GO:0044782; centrosome cycle; microtubule cytoskeleton organization; photoreceptor-cell maintenance; sensory perception of sound; visual perception; apoptotic process GO:0006915; MAPK cascade GO:0000165.
  • Cell Ontology: photoreceptor cell CL:0000679; rod photoreceptor CL:0000604; cone photoreceptor CL:0000710; auditory hair cell CL:0000589; inner and outer hair-cell child terms where supported.

7. Anatomical structures affected

The primary organs are bilateral retina and inner ear/cochlea. Retinal injury is concentrated in photoreceptors and the outer retina—ONL, inner/outer segments, ellipsoid zone, and interdigitation zone—with secondary retinal pigment epithelial/fundus changes in some cases. Cochlear evidence implicates inner and outer hair cells, especially outer hair cells of the basal, high-frequency turn. Spiral-ganglion expression occurs in mice, but direct neuronal degeneration has not been established. (kang2023novelvariantin pages 6-9, nan2024thecochlearmorphology pages 5-8, igelman2021expandingtheclinical pages 5-7)

Suggested anatomical terms include retina UBERON:0000966, eye UBERON:0000970, inner ear UBERON:0001844, cochlea UBERON:0001853, organ of Corti, retinal photoreceptor layer, and retinal outer nuclear layer. Disease is generally bilateral. No consistent brain, kidney, skeletal, cardiac, respiratory, gastrointestinal, immune, endocrine, or metabolic organ involvement has been demonstrated in humans.

8. Temporal development

CRDHL2 is chronic, lifelong, insidious, and progressive. Hearing loss often begins in childhood or adolescence and may precede recognized retinal disease by decades. Ocular onset in the available multicenter cases was 13–30 years; RP1973’s first documented ophthalmic evaluation was at 44 years. Progression rates vary and formal stages have not been validated. (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5)

A pragmatic—not validated—clinical staging framework is:

  • Presymptomatic molecular stage: biallelic CEP250 variants; normal or near-normal functional testing.
  • Early auditory stage: high-frequency or moderate SNHL, potentially before visual complaints.
  • Early retinal stage: photophobia, declining acuity, mild cone-predominant ffERG abnormality, subtle OCT/FAF change.
  • Established dual-sensory stage: progressive SNHL plus cone/cone-rod dystrophy and visual-field loss.
  • Advanced stage: severe dual-sensory disability; frequency and timing unknown.

There is no evidence of spontaneous remission, relapsing-remitting disease, or treatment-induced reversal. The likely therapeutic window is before irreversible photoreceptor and hair-cell loss, but no human biomarker-defined window has been established.

9. Inheritance and population

Inheritance is autosomal recessive. For two heterozygous carrier parents, each pregnancy has a theoretical 25% affected, 50% carrier, and 25% noncarrier probability. Heterozygous mice showed no significant auditory phenotype in the 2024 study, consistent with recessive inheritance, although this does not prove complete absence of subtle effects in human carriers. (nan2024thecochlearmorphology pages 1-5)

Disease-specific prevalence, incidence, carrier frequency, sex ratio, penetrance, age-specific penetrance, and geographic distribution are unknown. Published families include Iranian-Jewish, Japanese, European/Spanish, Chinese, and Korean ascertainments, but these do not establish population enrichment. No validated founder allele for CRDHL2 was identified. The approximately 1/4,000 RP prevalence and general Usher estimates sometimes cited in source papers must not be assigned to CRDHL2. (abudiab2023homozygousknockoutof pages 1-2, nan2024thecochlearmorphology pages 1-5)

Expressivity is clearly variable: biallelic CEP250 variants can yield dual-sensory disease, retinal-only disease, or hearing-only disease at the age examined. Anticipation is not expected and has not been reported. Germline mosaicism has not been documented but cannot be excluded as a general reproductive possibility.

10. Diagnostics

Clinical evaluation

There are no validated disease-specific diagnostic criteria. Diagnosis requires concordance of phenotype, molecular findings, segregation, and exclusion of more common causes.

Ophthalmic assessment: BCVA and refraction; slit-lamp examination; dilated fundus examination; color photography; spectral-domain OCT; fundus autofluorescence; kinetic/static perimetry; and full-field ERG. A normal-looking fundus does not exclude early CEP250 retinal disease. (igelman2021expandingtheclinical pages 5-7)

Audiovestibular assessment: pure-tone air and bone-conduction audiometry, speech audiometry, tympanometry as indicated, otoacoustic emissions, and ABR when behavioral testing is unreliable. The 2023 human study measured air thresholds at 250–8,000 Hz and bone thresholds at 250–4,000 Hz. Vestibular history/examination should be documented despite its apparent sparing. (kang2023novelvariantin pages 1-2)

Routine blood chemistry, enzyme assays, biopsy, MRI, CT, or systemic imaging have no disease-specific diagnostic role unless another diagnosis is suspected.

Genetic testing strategy

  1. Use an inherited-retinal-disease, hearing-loss, or comprehensive Usher/dual-sensory panel that includes CEP250, with sequencing and exon-level deletion/duplication analysis.
  2. If negative or only one allele is found, proceed to trio WES or preferably WGS, including CNV, splice-region, and structural-variant analysis.
  3. Confirm candidate variants by orthogonal testing and parental segregation to establish trans configuration.
  4. Reanalyze periodically because phenotype assignment and variant classification are evolving.
  5. RNA/minigene analysis is appropriate for suspected splice variants, although the minigene-positive variants in the 2018 paper were in other Usher genes, not CEP250. (fustergarcia2018highthroughputsequencingfor pages 3-4, fustergarcia2018highthroughputsequencingfor pages 4-5)

The 2018 panel covered all 32 CEP250 coding exons using transcript NM_007186.4 and achieved 100% designed target coverage for CEP250. WES was used in RP1973 to search for competing causes. The authors concluded that thorough clinical examination—particularly of cone involvement—is needed because different CEP250 alleles produce overlapping phenotypes. (fustergarcia2018highthroughputsequencingfor pages 3-4, fustergarcia2018highthroughputsequencingfor pages 10-10)

CMA, karyotyping, FISH, mitochondrial testing, and repeat-expansion testing are not first-line unless the broader presentation suggests another disorder.

Differential diagnosis

Important alternatives include classic Usher syndrome (MYO7A, USH1C, CDH23, PCDH15, USH1G, CIB2, USH2A, ADGRV1, WHRN, CLRN1), CEP78-related CRDHL1, and atypical Usher-like disease due to ARSG or ABHD12. Other considerations include Alström syndrome, peroxisomal/mitochondrial disease, isolated inherited retinal dystrophy with unrelated hearing loss, and nonsyndromic CEP250-associated RP or deafness. Genotype-first classification is especially valuable because the retinal phenotype may be cone-predominant and the hearing loss noncongenital. (igelman2021expandingtheclinical pages 3-5, igelman2021expandingtheclinical pages 5-7)

11. Outcome and prognosis

No survival curve, mortality rate, life-expectancy estimate, or disease-specific cause of death has been published. Available evidence suggests that CRDHL2 affects sensory function rather than lifespan. Morbidity is driven by progressive visual and auditory disability; individual endpoints such as legal blindness, cochlear implantation, loss of independent mobility, or employment outcomes have not been quantified.

Prognosis is difficult to predict from genotype alone. Truncating variants are enriched in reported dual-sensory cases, but truncating alleles can also appear hearing-only or retinal-only at a particular age. Baseline OCT/ERG, visual fields, audiometric configuration, and longitudinal rates of change are therefore more defensible prognostic measures than variant class alone. (kang2023novelvariantin pages 9-11, abudiab2023homozygousknockoutof pages 1-2, igelman2021expandingtheclinical pages 5-7)

12. Treatment and current implementation

No CEP250-specific pharmacotherapy, gene therapy, cell therapy, RNA therapy, gene editing, or approved disease-modifying treatment was identified. No relevant CEP250/CRDHL2 interventional ClinicalTrials.gov study was found in the tool search. Mouse models are described as platforms for future treatment or gene-therapy development, not evidence of human efficacy. (abudiab2023homozygousknockoutof pages 1-2)

Current real-world management is multidisciplinary:

  • Hearing: hearing aids; remote microphone and communication systems; speech/auditory rehabilitation; cochlear-implant evaluation when conventional amplification no longer provides adequate benefit. CEP250-specific implant outcomes are unavailable.
  • Vision: correction of refractive error; tinted lenses for photophobia; low-vision rehabilitation; magnification, screen readers, orientation/mobility training; management of cataract or epiretinal membrane when clinically indicated.
  • Surveillance: periodic audiograms and ophthalmic examination with OCT, FAF, visual fields, and ERG according to age and findings.
  • Communication planning: introduce accessible communication and dual-sensory supports early rather than waiting for advanced visual loss.
  • Genetic care: molecular confirmation, cascade testing, and reproductive counseling.

Suggested NCIT intervention concepts include Genetic Testing, Genetic Counseling, Electroretinography, Optical Coherence Tomography, Pure Tone Audiometry, Hearing Aid Device, Cochlear Implantation, Low Vision Rehabilitation, Assistive Device, and Gene Therapy—the last marked experimental. No CEP250 pharmacogenomic association or treatment-response statistic is available.

13. Prevention

Primary prevention through lifestyle modification, immunization, medication, or environmental control is not available. Vaccination and infectious prophylaxis are not disease-specific. Reproductive options after identifying familial variants include carrier testing of relatives/partners, prenatal diagnosis, and preimplantation genetic testing for monogenic disease, undertaken with nondirective genetic counseling.

Secondary prevention consists of cascade testing and anticipatory surveillance. At-risk siblings with biallelic variants should receive baseline audiology and retinal evaluation even if asymptomatic because hearing or retinal manifestations may be delayed. Tertiary prevention includes prompt amplification, accessible communication, low-vision rehabilitation, fall and mobility assessment, and educational/workplace accommodations. Population newborn screening for CEP250 is not established; standard newborn hearing screening may miss later-progressive loss.

14. Other species and natural disease

The orthologous Cep250 gene has been studied in laboratory mouse (Mus musculus, NCBI Taxonomy 10090). C-Nap1/CEP250 is evolutionarily conserved in vertebrate centrosome-linker biology. No well-validated naturally occurring veterinary syndrome exactly equivalent to human CRDHL2, breed-specific risk, VBO annotation, zoonotic transmission, or cross-species infectious susceptibility was identified. The condition is genetic and noncommunicable.

15. Model organisms and experimental systems

Mouse models

  1. p.Arg188Ter-corresponding knock-in mouse (2019): homozygotes showed reduced retinal thickness and ERG responses, with ciliary/outer-segment protein mislocalization. It models retinal disease but hearing was not initially evaluated. The human-study abstract states: “The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses.” DOI: https://doi.org/10.1002/humu.23759; accepted 2 April 2019. (huang2019functionalcharacterizationof pages 1-2)

  2. Exon 6–7 knockout (2023): ffERG was normal at six months but declined progressively; by 20 months photopic and scotopic amplitudes were very low, histology confirmed retinal degeneration, and ABR thresholds were significantly increased. This late-onset dual-sensory phenotype is unusually faithful relative to many Usher mouse models. Published 1 March 2023; DOI: https://doi.org/10.1167/tvst.12.3.3. (abudiab2023homozygousknockoutof pages 1-2)

  3. CRISPR deletion of exons 3–12/8,593 bp (2023 retinal study): at P90/P180, mice exhibited retinal thinning, reduced ERG responses, photoreceptor loss/apoptosis, and the 298-gene RNA-seq signature described above. (chen2023rnaseqanalysisreveals pages 1-2, chen2023rnaseqanalysisreveals pages 5-7)

  4. Same/similar exons 3–12 knockout, cochlear analysis (2023–2024): hearing thresholds were elevated particularly at 20–30 kHz; basal-turn hair-cell loss was highly significant (reported p<0.0001), while heterozygotes and swimming behavior were normal. The June 2024 report is a preprint, so its conclusions require peer-reviewed confirmation. DOI: https://doi.org/10.21203/rs.3.rs-4515679/v1. (nan2024thecochlearmorphology pages 1-5, nan2024thecochlearmorphology pages 5-8)

Cellular systems

NIH3T3 heterologous expression demonstrated cytosolic mislocalization of p.Gln1171Ter C-Nap1. CEP250-disrupted retinal/RPE-derived cellular systems have also supported ciliary involvement. Limitations include overexpression, nonhuman cell context, and the observation that general primary cilia can form normally after C-Nap1 loss; specialized photoreceptor and hair-cell maintenance may therefore be more relevant than universal ciliogenesis failure. (kang2023novelvariantin pages 6-9, kang2023novelvariantin pages 11-12)

No validated CEP250 patient-derived iPSC retinal organoid, cochlear organoid, zebrafish CRDHL2 model, Drosophila model, or therapeutic rescue study was identified in the retrieved evidence.

Knowledge-base ontology crosswalk

The following crosswalk distinguishes direct human observations from model-derived suggestions.

Domain Item Suggested ontology mapping(s) Key details for KB entry Evidence level Citations
Disease identifiers Cone-rod dystrophy and hearing loss 2 MONDO:0020780; OMIM: 618358 Rare Mendelian oto-retinal disorder linked to biallelic CEP250; often described as atypical Usher-like disease rather than classic Usher subtype Direct human disease-level resource and case-series context (abudiab2023homozygousknockoutof pages 1-2, igelman2021expandingtheclinical pages 3-5, fustergarcia2018highthroughputsequencingfor pages 10-10)
Synonyms CEP250-related CRDHL2; atypical Usher syndrome; Usher-like disease; cone-rod dystrophy with sensorineural hearing loss Suggested synonym set only Literature uses overlapping labels; disease boundaries remain somewhat fluid because CEP250 alleles can also present as nonsyndromic RP or nonsyndromic hearing loss Direct human, with nomenclature caveat (kang2023novelvariantin pages 1-2, fustergarcia2018highthroughputsequencingfor pages 10-10)
Core phenotype Progressive sensorineural hearing loss Suggested HPO: Sensorineural hearing impairment HP:0000407; Progressive hearing impairment HP:0001731 Human CEP250 series: onset reported from <10 to 24 years; RP1973 had bilateral moderate-severe progressive hearing loss starting at age 13; no vestibular symptoms reported in the 2021 series Direct human (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5)
Core phenotype Mild cone-predominant retinal dysfunction / cone-rod dystrophy spectrum Suggested HPO: Cone-rod dystrophy HP:0000548; Cone dystrophy HP:0000547; Abnormality of electroretinogram HP:0001311 Age of ocular onset in CEP250 cases ranged 13-30 years in multicenter series; one tested patient showed mild cone dystrophy with normal rod function on ffERG; literature also includes late-onset cone-rod dystrophy Direct human (igelman2021expandingtheclinical pages 5-7, abudiab2023homozygousknockoutof pages 1-2, fustergarcia2018highthroughputsequencingfor pages 10-10)
Core phenotype Photophobia and reduced visual acuity Suggested HPO: Photophobia HP:0000613; Reduced visual acuity HP:0007663 RP1973 had late-onset progressive visual decline with photophobia; BCVA in CEP250 series ranged about 20/60 to 20/200 Direct human (fustergarcia2018highthroughputsequencingfor pages 4-5, igelman2021expandingtheclinical pages 5-7)
Core phenotype Subtle to mild retinal structural abnormality Suggested HPO: Outer retinal atrophy HP:0030498; Thinning of outer nuclear layer HP:0033667; Abnormal fundus autofluorescence HP:0030636 Color fundus may be normal or mildly abnormal; FAF showed subtle peripheral/peripapillary changes; OCT showed outer retinal atrophy, ONL thinning, and subtle EZ/IZ disruption Direct human (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5)
Core phenotype Retinitis pigmentosa-like fundus changes in some cases Suggested HPO: Retinitis pigmentosa HP:0000510; Bone spicule pigmentation of the retina HP:0007703; Attenuated retinal blood vessels HP:0007763 RP1973 showed mid-peripheral bone-spicule pigment migration and narrowed peripheral vessels, supporting overlap with RP/Usher-like phenotypes Direct human (fustergarcia2018highthroughputsequencingfor pages 4-5)
Core phenotype Vestibular involvement Suggested HPO: Abnormal vestibular function HP:0001751 No vestibular symptoms were reported in the CEP250 patients of the 2021 multicenter series; vestibular dysfunction therefore appears absent or uncommon in currently described CRDHL2 cases Direct human negative finding (igelman2021expandingtheclinical pages 5-7)
Gene / protein CEP250 / C-Nap1 HGNC gene symbol: CEP250; OMIM gene: 609689 Encodes centrosome-associated C-Nap1, a centrosome linker/cohesion protein also localized in photoreceptor/basal-body contexts Human molecular + broader cell biology (kang2023novelvariantin pages 1-2, huang2019functionalcharacterizationof pages 1-2)
Inheritance Autosomal recessive Suggested HPO: Autosomal recessive inheritance HP:0000007 Disease is associated with biallelic CEP250 variants; reported affected individuals include homozygous and compound-heterozygous cases Direct human (abudiab2023homozygousknockoutof pages 1-2, igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5)
Variant spectrum relevant to CRDHL2 Truncating alleles predominate Suggested sequence ontology classes: nonsense_variant, frameshift_variant All CEP250 variants in the 2021 atypical Usher cohort were novel nonsense or frameshift variants; reported syndromic examples include p.R1155, p.K1113, p.R1336*, and Japanese family compound heterozygous nonsense variants Direct human, partially summarized across studies (igelman2021expandingtheclinical pages 5-7, abudiab2023homozygousknockoutof pages 1-2, fustergarcia2018highthroughputsequencingfor pages 10-10, huang2019functionalcharacterizationof pages 4-6)
Allelic heterogeneity caveat Nonsyndromic RP or nonsyndromic hearing loss can also result from CEP250 variants Suggested note, not ontology assertion Missense and some nonsense alleles have been reported in nonsyndromic RP or progressive hearing loss without retinal degeneration at time of report; genotype-phenotype correlation remains incomplete Direct human with caution (kang2023novelvariantin pages 1-2, huang2019functionalcharacterizationof pages 1-2, kang2023novelvariantin pages 9-11)
Organ / system Eye / retina Suggested UBERON: retina UBERON:0000966; eye UBERON:0000970 Primary visual tissue affected; human imaging points to outer retina involvement Direct human (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5)
Organ / system Inner ear / cochlea Suggested UBERON: inner ear UBERON:0001844; cochlea UBERON:0001853 Primary auditory tissue affected; progressive SNHL is a core disease manifestation Direct human; mouse supports tissue localization (igelman2021expandingtheclinical pages 5-7, kang2023novelvariantin pages 1-2, nan2024thecochlearmorphology pages 1-5)
Tissue / cell type Photoreceptors Suggested CL: photoreceptor cell CL:0000679; rod photoreceptor cell CL:0000604; cone photoreceptor cell CL:0000710 Human ffERG and OCT support photoreceptor dysfunction, with cone involvement possibly greater in some cases Direct human; mouse mechanistic support (igelman2021expandingtheclinical pages 5-7, chen2023rnaseqanalysisreveals pages 1-2)
Tissue / cell type Cochlear hair cells Suggested CL: auditory hair cell CL:0000589; inner hair cell / outer hair cell suggested Cep250 is expressed in murine inner and outer hair cells; knockout models show hair-cell degeneration and high-frequency hearing loss Mouse/in vitro inference supporting human auditory phenotype (kang2023novelvariantin pages 1-2, nan2024thecochlearmorphology pages 1-5)
Subcellular compartment Centrosome / centriole proximal end / basal body / ciliary region Suggested GO CC: centrosome GO:0005813; centriole GO:0005814; basal body GO:0005932; ciliary basal body suggested C-Nap1 is a centrosomal linker protein; human variant p.Gln1171Ter mislocalized from centrosome to cytosol in NIH3T3 cells; literature places CEP250 in photoreceptor ciliary/basal-body contexts In vitro + broader biology; indirect for CRDHL2 (kang2023novelvariantin pages 1-2, huang2019functionalcharacterizationof pages 1-2, kang2023novelvariantin pages 6-9)
Biological process Centrosome cohesion / ciliogenesis / cilium organization Suggested GO BP: centrosome cycle / centrosome cohesion suggested; cilium organization GO:0044782; ciliogenesis suggested Mechanistic model: loss of C-Nap1 disrupts centrosome localization/cohesion and ciliary homeostasis, impairing photoreceptor and hair-cell maintenance In vitro + mouse inference (kang2023novelvariantin pages 1-2, huang2019functionalcharacterizationof pages 1-2, kang2023novelvariantin pages 6-9)
Biological process Photoreceptor degeneration and apoptosis Suggested GO BP: photoreceptor cell maintenance suggested; apoptotic process GO:0006915 Cep250-deficient retina shows reduced photoreceptors and increased TUNEL positivity in mice Mouse inference (chen2023rnaseqanalysisreveals pages 1-2)
Biological process Stress/signaling dysregulation in retina Suggested GO/Pathway terms: MAPK cascade GO:0000165; cyclic nucleotide signaling suggested RNA-seq in Cep250 KO retina found 149 upregulated and 149 downregulated genes; enriched pathways included cGMP-PKG, MAPK, edn2-fgf2 axis, thyroid hormone synthesis; ER protein processing downregulated Mouse inference (chen2023rnaseqanalysisreveals pages 1-2, chen2023rnaseqanalysisreveals pages 5-7)
Diagnostics Molecular diagnosis Suggested NCIT: Genetic Testing; Whole Exome Sequencing; Targeted Next-Generation Sequencing Panel WES and targeted high-throughput panels have identified causal biallelic CEP250 variants; useful especially in atypical Usher/dual sensory phenotypes Direct human real-world implementation (kang2023novelvariantin pages 1-2, fustergarcia2018highthroughputsequencingfor pages 10-10, igelman2021expandingtheclinical pages 3-5)
Diagnostics Ophthalmic functional testing Suggested NCIT: Electroretinography ffERG can show mild cone dystrophy with normal rod function in some human CEP250 cases; useful for disease characterization Direct human (igelman2021expandingtheclinical pages 5-7)
Diagnostics Retinal imaging Suggested NCIT: Optical Coherence Tomography; Fundus Autofluorescence Imaging; Fundus Photography; Visual Field Examination Human cases showed OCT outer retinal atrophy/ONL thinning/EZ-IZ disruption and subtle FAF abnormalities; visual fields may range from near-normal wide fields to marked constriction Direct human (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5, igelman2021expandingtheclinical pages 3-5)
Diagnostics Audiologic testing Suggested NCIT: Pure Tone Audiometry; Auditory Brainstem Response Progressive SNHL is central; pure-tone audiograms used clinically in human hearing studies; ABR is established in mouse models and can support translational studies Human + mouse (kang2023novelvariantin pages 1-2, abudiab2023homozygousknockoutof pages 1-2, nan2024thecochlearmorphology pages 1-5)
Differential diagnosis Classic Usher syndrome types 1-3; CEP78-, ARSG-, ABHD12-related atypical Usher; nonsyndromic RP; nonsyndromic AR hearing loss Suggested note Clinical overlap is substantial; genotype-first evaluation is recommended in atypical presentations combining retinal disease with progressive SNHL Direct human (igelman2021expandingtheclinical pages 3-5, igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 10-10)
Management Sensory surveillance and supportive care Suggested NCIT: Ophthalmologic Examination; Audiologic Monitoring; Genetic Counseling No CEP250-specific disease-modifying therapy identified; current care centers on longitudinal eye/hearing follow-up and counseling Direct evidence for absence of targeted therapy; standard-of-care inference (fustergarcia2018highthroughputsequencingfor pages 10-10)
Management Hearing rehabilitation Suggested NCIT: Hearing Aid Device; Cochlear Implantation Disease-specific CEP250 outcome data not identified, but progressive SNHL makes standard hearing rehabilitation relevant in practice Indirect clinical inference (fustergarcia2018highthroughputsequencingfor pages 10-10, kang2023novelvariantin pages 1-2)
Management Low-vision and disability support Suggested NCIT: Low Vision Rehabilitation; Assistive Device Disease-specific studies absent, but visual acuity loss, photophobia, and retinal degeneration support standard low-vision measures Indirect clinical inference (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 4-5)
Advanced therapeutics Gene therapy / RNA therapy / trials Suggested NCIT: Gene Therapy No CEP250-specific interventional trial or approved therapy was identified in gathered evidence; mouse models were proposed as platforms for future therapy development Negative evidence + preclinical rationale (abudiab2023homozygousknockoutof pages 1-2, fustergarcia2018highthroughputsequencingfor pages 10-10)
Evidence caveat Human evidence base is very small Suggested note Current phenotype definition relies on a small number of families/cases, plus retrospective multicenter aggregation of only three CEP250 patients in one series Direct human caveat (igelman2021expandingtheclinical pages 5-7, fustergarcia2018highthroughputsequencingfor pages 10-10)
Evidence caveat Variant-phenotype correlation remains unresolved Suggested note Truncating alleles are enriched in syndromic cases, but CEP250 can also underlie nonsyndromic retinal or auditory disease; penetrance and age dependence are not yet well quantified Direct human caveat (kang2023novelvariantin pages 1-2, huang2019functionalcharacterizationof pages 1-2, kang2023novelvariantin pages 9-11)
Evidence caveat Epidemiology and modifiers largely unavailable Suggested note No robust disease-specific prevalence, incidence, penetrance, sex ratio, environmental modifiers, or protective factors were identified in the gathered literature Absence of evidence (fustergarcia2018highthroughputsequencingfor pages 10-10)

Table: This table condenses the gathered evidence into a compact knowledge-base crosswalk for CEP250-associated CRDHL2, linking phenotype, anatomy, mechanism, diagnostics, and management to suggested ontology terms. It also flags where statements are supported directly by human data versus mouse or in-vitro inference.

Key primary sources and exact abstract quotations

  1. Fuster-García et al., Scientific Reports, published November 2018. DOI: https://doi.org/10.1038/s41598-018-35085-0. Abstract: “we detected two novel nonsense mutations in CEP250 in a patient with a disease mimicking Usher syndrome that associates visual impairment due to cone-rod dystrophy and progressive hearing loss.” The study’s 82.8% detection ratio concerns the complete 77-person Usher cohort. (fustergarcia2018highthroughputsequencingfor pages 1-2)

  2. Huang et al., Human Mutation, accepted 2 April 2019. DOI: https://doi.org/10.1002/humu.23759. Abstract: “we report the identification of a mutation (c.562C>T, p.R188*) in the CEP250 in a consanguineous family with nonsyndromic RP” and “The homozygous knockin mice showed significantly reduced retinal thickness and ERG responses.” (huang2019functionalcharacterizationof pages 1-2)

  3. Igelman et al., Ophthalmic Genetics, 2021. DOI: https://doi.org/10.1080/13816810.2021.1946704. Abstract: “Nonsense and frameshift variants in CEP250 showed mild retinal disease with progressive, non-congenital SNHL.” This is the best comparative human phenotype series, but it included only three CEP250 patients. (igelman2021expandingtheclinical pages 5-7)

  4. Abu-Diab et al., Translational Vision Science & Technology, published 1 March 2023. DOI: https://doi.org/10.1167/tvst.12.3.3. Abstract: “At 6 months, the ffERG was normal, but it decreased gradually with age” and “ABR tests illustrated that hearing threshold significantly increased at the age of 20 months.” (abudiab2023homozygousknockoutof pages 1-2)

  5. Chen et al., International Journal of Molecular Sciences, published 16 May 2023. DOI: https://doi.org/10.3390/ijms24108843. Abstract: “An RNA-seq analysis showed that 149 genes were upregulated and another 149 genes were downregulated” and “The dysregulation of the cGMP-PKG-MAPK pathways may contribute to the pathogenesis of cilia-related retinal degeneration.” (chen2023rnaseqanalysisreveals pages 1-2)

  6. Kang et al., Cells, published 21 September 2023. DOI: https://doi.org/10.3390/cells12182328. Abstract: “we identified a novel nonsense homozygous variant in CEP250 (c.3511C>T; p.Gln1171Ter)” in progressive nonsyndromic SNHL and found that the truncated protein “was not localized at the centrosome but was dispersed in the cytosol.” (kang2023novelvariantin pages 1-2)

  7. Nan et al., preprint posted 19 June 2024. DOI: https://doi.org/10.21203/rs.3.rs-4515679/v1. Abstract: Cep250-null mice had high-frequency hearing impairment, reduced cochlear hair-cell numbers, unaffected swimming behavior, and no significant heterozygous hearing change. This is recent but not equivalent to peer-reviewed clinical evidence. (nan2024thecochlearmorphology pages 1-5)

Evidence limitations and expert interpretation

The principal limitation is extreme data scarcity. Percentages from cohorts selected for retinal disease or atypical Usher syndrome are subject to ascertainment bias and must not be treated as penetrance estimates. Genotype–phenotype correlations are provisional: truncating alleles predominate in CRDHL2, yet apparently similar alleles can present as retinal-only or hearing-only disease, possibly because of age, residual protein function, background modifiers, or incomplete phenotyping. The most defensible current practice is therefore a genotype-informed but phenotype-led longitudinal diagnosis: any person with biallelic CEP250 variants and one sensory manifestation should undergo repeated assessment of the other sensory system. The 2018 investigators similarly recommended “thorough clinical examinations,” particularly for cone involvement. (kang2023novelvariantin pages 9-11, fustergarcia2018highthroughputsequencingfor pages 10-10)

No disease-specific epidemiology, validated clinical criteria, prognostic biomarker, environmental modifier, quality-of-life statistic, approved targeted treatment, or human therapeutic trial was identified. Those fields should be marked unavailable rather than extrapolated from general Usher syndrome or inherited-retinal-disease data.

References

  1. (igelman2021expandingtheclinical pages 5-7): Austin D. Igelman, Cristy Ku, Mariana Matioli da Palma, Michalis Georgiou, Elena R. Schiff, Byron L. Lam, Eeva-Marja Sankila, Jeeyun Ahn, Lindsey Pyers, Ajoy Vincent, Juliana Maria Ferraz Sallum, Wadih M. Zein, Jin Kyun Oh, Ramiro S. Maldonado, Joseph Ryu, Stephen H. Tsang, Michael B. Gorin, Andrew R. Webster, Michel Michaelides, Paul Yang, and Mark E. Pennesi. Expanding the clinical phenotype in patients with disease causing variants associated with atypical usher syndrome. Ophthalmic Genetics, 42:664-673, Jul 2021. URL: https://doi.org/10.1080/13816810.2021.1946704, doi:10.1080/13816810.2021.1946704. This article has 35 citations and is from a peer-reviewed journal.

  2. (chen2023rnaseqanalysisreveals pages 1-2): Chong Chen, Yu Rong, Youyuan Zhuang, Cheng Tang, Qian Liu, Peng Lin, Dandan Li, Xinyi Zhao, Fan Lu, Jia Qu, and Xinting Liu. Rna-seq analysis reveals an essential role of the cgmp-pkg-mapk pathways in retinal degeneration caused by cep250 deficiency. International Journal of Molecular Sciences, 24:8843, May 2023. URL: https://doi.org/10.3390/ijms24108843, doi:10.3390/ijms24108843. This article has 3 citations.

  3. (nan2024thecochlearmorphology pages 5-8): Benyu Nan, Xi Gu, Xinlei Wu, Keyang Chen, Chuqin Zhang, Qijun Fan, Yingying Chen, Bobei Chen, and Xiufeng Huang. The cochlear morphology alteration and hearing loss in cep250 knockout mice. Jun 2024. URL: https://doi.org/10.21203/rs.3.rs-4515679/v1, doi:10.21203/rs.3.rs-4515679/v1.

  4. (abudiab2023homozygousknockoutof pages 1-2): Alaa Abu-Diab, Prakadeeswari Gopalakrishnan, Chen Matsevich, Marije de Jong, Alexey Obolensky, Ayat Khalaileh, Manar Salameh, Ayala Ejzenberg, Menachem Gross, Eyal Banin, Dror Sharon, and Samer Khateb. Homozygous knockout of cep250 leads to a relatively late-onset retinal degeneration and sensorineural hearing loss in mice. Translational Vision Science & Technology, 12:3, Mar 2023. URL: https://doi.org/10.1167/tvst.12.3.3, doi:10.1167/tvst.12.3.3. This article has 6 citations and is from a peer-reviewed journal.

  5. (fustergarcia2018highthroughputsequencingfor pages 1-2): Carla Fuster-García, Gema García-García, Teresa Jaijo, Neus Fornés, Carmen Ayuso, Miguel Fernández-Burriel, Ana Sánchez-De la Morena, Elena Aller, and José M. Millán. High-throughput sequencing for the molecular diagnosis of usher syndrome reveals 42 novel mutations and consolidates cep250 as usher-like disease causative. Scientific Reports, Nov 2018. URL: https://doi.org/10.1038/s41598-018-35085-0, doi:10.1038/s41598-018-35085-0. This article has 55 citations and is from a peer-reviewed journal.

  6. (kang2023novelvariantin pages 9-11): Minjin Kang, Jung Ah Kim, Mee Hyun Song, Sun Young Joo, Se Jin Kim, Seung Hyun Jang, Ho Lee, Je Kyung Seong, Jae Young Choi, Heon Yung Gee, and Jinsei Jung. Novel variant in cep250 causes protein mislocalization and leads to nonsyndromic autosomal recessive type of progressive hearing loss. Cells, 12:2328, Sep 2023. URL: https://doi.org/10.3390/cells12182328, doi:10.3390/cells12182328. This article has 8 citations.

  7. (kang2023novelvariantin pages 1-2): Minjin Kang, Jung Ah Kim, Mee Hyun Song, Sun Young Joo, Se Jin Kim, Seung Hyun Jang, Ho Lee, Je Kyung Seong, Jae Young Choi, Heon Yung Gee, and Jinsei Jung. Novel variant in cep250 causes protein mislocalization and leads to nonsyndromic autosomal recessive type of progressive hearing loss. Cells, 12:2328, Sep 2023. URL: https://doi.org/10.3390/cells12182328, doi:10.3390/cells12182328. This article has 8 citations.

  8. (huang2019functionalcharacterizationof pages 1-2): Xiu‐Feng Huang, Lue Xiang, Xiao‐Long Fang, Wei‐Qin Liu, You‐Yuan Zhuang, Zhen‐Ji Chen, Ren‐Juan Shen, Wan Cheng, Ru‐Yi Han, Si‐Si Zheng, Xue‐Jiao Chen, Xiaoling Liu, and Zi‐Bing Jin. Functional characterization of cep250 variant identified in nonsyndromic retinitis pigmentosa. Apr 2019. URL: https://doi.org/10.1002/humu.23759, doi:10.1002/humu.23759. This article has 27 citations and is from a domain leading peer-reviewed journal.

  9. (fustergarcia2018highthroughputsequencingfor pages 4-5): Carla Fuster-García, Gema García-García, Teresa Jaijo, Neus Fornés, Carmen Ayuso, Miguel Fernández-Burriel, Ana Sánchez-De la Morena, Elena Aller, and José M. Millán. High-throughput sequencing for the molecular diagnosis of usher syndrome reveals 42 novel mutations and consolidates cep250 as usher-like disease causative. Scientific Reports, Nov 2018. URL: https://doi.org/10.1038/s41598-018-35085-0, doi:10.1038/s41598-018-35085-0. This article has 55 citations and is from a peer-reviewed journal.

  10. (kang2023novelvariantin pages 6-9): Minjin Kang, Jung Ah Kim, Mee Hyun Song, Sun Young Joo, Se Jin Kim, Seung Hyun Jang, Ho Lee, Je Kyung Seong, Jae Young Choi, Heon Yung Gee, and Jinsei Jung. Novel variant in cep250 causes protein mislocalization and leads to nonsyndromic autosomal recessive type of progressive hearing loss. Cells, 12:2328, Sep 2023. URL: https://doi.org/10.3390/cells12182328, doi:10.3390/cells12182328. This article has 8 citations.

  11. (kang2023novelvariantin pages 11-12): Minjin Kang, Jung Ah Kim, Mee Hyun Song, Sun Young Joo, Se Jin Kim, Seung Hyun Jang, Ho Lee, Je Kyung Seong, Jae Young Choi, Heon Yung Gee, and Jinsei Jung. Novel variant in cep250 causes protein mislocalization and leads to nonsyndromic autosomal recessive type of progressive hearing loss. Cells, 12:2328, Sep 2023. URL: https://doi.org/10.3390/cells12182328, doi:10.3390/cells12182328. This article has 8 citations.

  12. (fustergarcia2018highthroughputsequencingfor pages 10-10): Carla Fuster-García, Gema García-García, Teresa Jaijo, Neus Fornés, Carmen Ayuso, Miguel Fernández-Burriel, Ana Sánchez-De la Morena, Elena Aller, and José M. Millán. High-throughput sequencing for the molecular diagnosis of usher syndrome reveals 42 novel mutations and consolidates cep250 as usher-like disease causative. Scientific Reports, Nov 2018. URL: https://doi.org/10.1038/s41598-018-35085-0, doi:10.1038/s41598-018-35085-0. This article has 55 citations and is from a peer-reviewed journal.

  13. (huang2019functionalcharacterizationof pages 4-6): Xiu‐Feng Huang, Lue Xiang, Xiao‐Long Fang, Wei‐Qin Liu, You‐Yuan Zhuang, Zhen‐Ji Chen, Ren‐Juan Shen, Wan Cheng, Ru‐Yi Han, Si‐Si Zheng, Xue‐Jiao Chen, Xiaoling Liu, and Zi‐Bing Jin. Functional characterization of cep250 variant identified in nonsyndromic retinitis pigmentosa. Apr 2019. URL: https://doi.org/10.1002/humu.23759, doi:10.1002/humu.23759. This article has 27 citations and is from a domain leading peer-reviewed journal.

  14. (chen2023rnaseqanalysisreveals pages 5-7): Chong Chen, Yu Rong, Youyuan Zhuang, Cheng Tang, Qian Liu, Peng Lin, Dandan Li, Xinyi Zhao, Fan Lu, Jia Qu, and Xinting Liu. Rna-seq analysis reveals an essential role of the cgmp-pkg-mapk pathways in retinal degeneration caused by cep250 deficiency. International Journal of Molecular Sciences, 24:8843, May 2023. URL: https://doi.org/10.3390/ijms24108843, doi:10.3390/ijms24108843. This article has 3 citations.

  15. (nan2024thecochlearmorphology pages 8-16): Benyu Nan, Xi Gu, Xinlei Wu, Keyang Chen, Chuqin Zhang, Qijun Fan, Yingying Chen, Bobei Chen, and Xiufeng Huang. The cochlear morphology alteration and hearing loss in cep250 knockout mice. Jun 2024. URL: https://doi.org/10.21203/rs.3.rs-4515679/v1, doi:10.21203/rs.3.rs-4515679/v1.

  16. (nan2024thecochlearmorphology pages 1-5): Benyu Nan, Xi Gu, Xinlei Wu, Keyang Chen, Chuqin Zhang, Qijun Fan, Yingying Chen, Bobei Chen, and Xiufeng Huang. The cochlear morphology alteration and hearing loss in cep250 knockout mice. Jun 2024. URL: https://doi.org/10.21203/rs.3.rs-4515679/v1, doi:10.21203/rs.3.rs-4515679/v1.

  17. (fustergarcia2018highthroughputsequencingfor pages 3-4): Carla Fuster-García, Gema García-García, Teresa Jaijo, Neus Fornés, Carmen Ayuso, Miguel Fernández-Burriel, Ana Sánchez-De la Morena, Elena Aller, and José M. Millán. High-throughput sequencing for the molecular diagnosis of usher syndrome reveals 42 novel mutations and consolidates cep250 as usher-like disease causative. Scientific Reports, Nov 2018. URL: https://doi.org/10.1038/s41598-018-35085-0, doi:10.1038/s41598-018-35085-0. This article has 55 citations and is from a peer-reviewed journal.

  18. (igelman2021expandingtheclinical pages 3-5): Austin D. Igelman, Cristy Ku, Mariana Matioli da Palma, Michalis Georgiou, Elena R. Schiff, Byron L. Lam, Eeva-Marja Sankila, Jeeyun Ahn, Lindsey Pyers, Ajoy Vincent, Juliana Maria Ferraz Sallum, Wadih M. Zein, Jin Kyun Oh, Ramiro S. Maldonado, Joseph Ryu, Stephen H. Tsang, Michael B. Gorin, Andrew R. Webster, Michel Michaelides, Paul Yang, and Mark E. Pennesi. Expanding the clinical phenotype in patients with disease causing variants associated with atypical usher syndrome. Ophthalmic Genetics, 42:664-673, Jul 2021. URL: https://doi.org/10.1080/13816810.2021.1946704, doi:10.1080/13816810.2021.1946704. This article has 35 citations and is from a peer-reviewed journal.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 7
On topic 4
Off topic 0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 35
Resolved 32
Unresolved (possible confabulation) 1
Obsolete 2
Unverifiable 0
Terms whose name was checked 2
Terms named correctly 0
Terms named as a different term 2

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0020780 (3 mentions) - the report calls it "if available"; MONDO calls it cone-rod dystrophy and hearing loss 2
  • HP:0000613 (2 mentions) - the report calls it "Case-level, frequency unknown"; HP calls it Photophobia

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

  • HP:0001731 (2 mentions) - HP does not contain this term

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • HP:0000547 (obsolete Tapetoretinal degeneration) (2 mentions) - replaced by HP:0000510
  • GO:0005932 (GO_0005932) (2 mentions) - replaced by GO:0036064