Cone-rod dystrophy and hearing loss 1 is an autosomal recessive ciliopathy caused by biallelic CEP78 variants. It pairs a childhood- or adolescent-onset, cone-predominant cone-rod dystrophy with bilateral, postlingual, progressive sensorineural hearing loss, and in some affected males with sperm abnormalities causing infertility. The unifying mechanism is centriolar. CEP78 sits at the distal end of the mature centriole, recruited there by the CEP350-FOP scaffold, and it acts on CP110 through the EDD1-DYRK2-DDB1 ubiquitin ligase. Cells lacking CEP78 have elevated CP110 and disordered ciliogenesis, and patient fibroblasts and nasal brushings show elongated primary cilia. How CEP78 acts on that ligase is disputed, and the entry does not pick a side. The two papers that characterise it reach opposite conclusions - one has CEP78 inhibiting the ligase, which would make CEP78 loss increase CP110 ubiquitination, while the other has CEP78 recruiting it, which would make CEP78 loss decrease ubiquitination and so raise CP110. The elevated-CP110 observation is common ground and is what the pathograph rests on; the direction of the ubiquitination step is recorded as an open disagreement rather than resolved by picking the paper that fits. The three organs that fail are the three whose post-mitotic cells depend most on a centriole-derived structure: the photoreceptor connecting cilium, the cochlear hair cell, and the sperm flagellum. Why the eye is affected first and hardest has a partial anatomical answer - CEP78 labels cone inner segments more intensely than rods - which is unusually satisfying for a ciliopathy. It is deliberately not Usher syndrome, and the distinction is clinical as well as genetic: Usher syndrome is rod-first with congenital hearing loss, while this is cone-first with postlingual, progressive loss. Misdiagnosis as Usher syndrome is documented and the founding authors flag it. On scope. MONDO:0014980 "cone-rod dystrophy and hearing loss" xrefs OMIM phenotypic series OMIMPS:617236 and has exactly two descendants: this entry's term and MONDO:0020780 (CEP250), which dismech already curates as Cone-rod_Dystrophy_And_Hearing_Loss_2. Curating the series term would have duplicated that entry, so this is the CEP78 member, named to match its sibling. See notes.
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Conditions with similar clinical presentations that must be differentiated from Cone-rod dystrophy and hearing loss 1:
name: Cone-rod dystrophy and hearing loss 1
creation_date: "2026-09-11T11:40:00Z"
category: Mendelian
synonyms:
- CRDHL1
- CEP78-associated syndrome
- cone-rod dystrophy with hearing loss, CEP78-related
description: >-
Cone-rod dystrophy and hearing loss 1 is an autosomal recessive ciliopathy
caused by biallelic CEP78 variants. It pairs a childhood- or
adolescent-onset, cone-predominant cone-rod dystrophy with bilateral,
postlingual, progressive sensorineural hearing loss, and in some affected
males with sperm abnormalities causing infertility.
The unifying mechanism is centriolar. CEP78 sits at the distal end of the
mature centriole, recruited there by the CEP350-FOP scaffold, and it acts on
CP110 through the EDD1-DYRK2-DDB1 ubiquitin ligase. Cells lacking CEP78 have
elevated CP110 and disordered ciliogenesis, and patient fibroblasts and nasal
brushings show elongated primary cilia.
How CEP78 acts on that ligase is disputed, and the entry does not pick a side.
The two papers that characterise it reach opposite conclusions - one has CEP78
inhibiting the ligase, which would make CEP78 loss increase CP110
ubiquitination, while the other has CEP78 recruiting it, which would make
CEP78 loss decrease ubiquitination and so raise CP110. The elevated-CP110
observation is common ground and is what the pathograph rests on; the
direction of the ubiquitination step is recorded as an open disagreement
rather than resolved by picking the paper that fits. The three organs that fail
are the three whose post-mitotic cells depend most on a centriole-derived
structure: the photoreceptor connecting cilium, the cochlear hair cell, and
the sperm flagellum. Why the eye is affected first and hardest has a partial
anatomical answer - CEP78 labels cone inner segments more intensely than rods
- which is unusually satisfying for a ciliopathy.
It is deliberately not Usher syndrome, and the distinction is clinical as
well as genetic: Usher syndrome is rod-first with congenital hearing loss,
while this is cone-first with postlingual, progressive loss. Misdiagnosis as
Usher syndrome is documented and the founding authors flag it.
On scope. MONDO:0014980 "cone-rod dystrophy and hearing loss" xrefs OMIM
phenotypic series OMIMPS:617236 and has exactly two descendants: this entry's
term and MONDO:0020780 (CEP250), which dismech already curates as
Cone-rod_Dystrophy_And_Hearing_Loss_2. Curating the series term would have
duplicated that entry, so this is the CEP78 member, named to match its
sibling. See notes.
disease_term:
preferred_term: cone-rod dystrophy and hearing loss 1
term:
id: MONDO:0020778
label: cone-rod dystrophy and hearing loss 1
parents:
- Inherited retinal dystrophy
- Sensorineural hearing loss
- Ciliopathy
references:
- reference: PMID:27588452
title: "Bi-allelic Truncating Mutations in CEP78, Encoding Centrosomal Protein 78, Cause Cone-Rod Degeneration with Sensorineural Hearing Loss."
- reference: PMID:31999394
title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
- reference: PMID:28242748
title: Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1(Vpr)(BP).
- reference: PMID:34259627
title: CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels.
- reference: PMID:33968938
title: Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss.
- reference: PMID:38780195
title: "Exploring the diverse clinical and variant spectrum of CEP78-associated syndrome: Novel pathogenic variants identified in a case series."
- reference: PMID:22264887
title: "Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy."
- reference: PMID:28498263
title: Cochlear Implantation in Patients With Usher Syndrome Type IIa Increases Performance and Quality of Life.
- reference: PMID:29718797
title: CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family.
- reference: PMID:39747485
title: Cep78 knockout causes sterility and oligoasthenoteratozoospermia in male mice.
- reference: PMID:40064796
title: "Characterizing and expanding the neurological clinical spectrum of PHARC syndrome: a systematic review."
- reference: PMID:29198720
title: Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.
inheritance:
- name: Autosomal recessive inheritance
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Biallelic CEP78 variants, homozygous in founder settings and compound
heterozygous elsewhere. The allelic spectrum was initially all truncating
and has since widened to include a destabilising missense founder allele and
whole- or partial-gene deletions.
evidence:
- 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: >-
Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78, which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL.
explanation: >-
The founding report, with the recessive biallelic mechanism and the size of
the original cohort - six individuals.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: >-
No population estimate exists. The disorder was delineated in 2016 and the
literature is a series of small family reports. A practical consequence
noted by one group is that the count is probably an undercount: CEP78 was a
gene of uncertain significance before September 2016, so a disruptive
variant found by exome sequencing before then would not have been reported.
evidence:
- reference: PMID:38780195
reference_title: "Exploring the diverse clinical and variant spectrum of CEP78-associated syndrome: Novel pathogenic variants identified in a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Any pathogenic variant found in CEP78 before 2016 would have been categorized as a "clearly disruptive variant in a gene of uncertain significance (GUS)" and might not have been reported in the WES report.
explanation: >-
The ascertainment argument for why reported case counts understate the
true number.
pathophysiology:
- name: Biallelic CEP78 Loss-of-Function Variants
biological_scale: MOLECULAR
description: >-
Truncating variants, canonical splice variants causing exon skipping, a
destabilising missense founder allele p.(Leu150Ser), and structural variants
including a recurrent 15 kb partial-gene deletion and a 235 kb whole-gene
deletion. All converge on reduced functional CEP78; there is no reported
gain-of-function or dominant-negative allele.
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
genes:
- preferred_term: CEP78
term:
id: hgnc:25740
label: CEP78
downstream:
- target: Loss of CEP78 from the Distal End of the Mature Centriole
causal_link_type: DIRECT
evidence:
- 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: >-
RT-PCR analysis of CEP78 in blood leukocytes of affected individuals revealed that the c.893-1G>A mutation causes exon 7 skipping leading to deletion of 65bp, predicted to result in a frameshift and therefore a truncated protein
explanation: >-
Characterises the molecular consequence of the founder splice allele at
the RNA level rather than by prediction alone.
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Homology modeling revealed a detrimental effect of p.(Leu150Ser) on protein stability, which was corroborated in patients' fibroblasts.
explanation: >-
Shows the missense allele acts by destabilising the protein, which is why
it is grouped with the truncating alleles as loss of function rather than
treated as a separate mechanism.
- reference: PMID:33968938
reference_title: Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
two SVs affecting CEP78 were identified in three unrelated individuals with CRDHL: a heterozygous total gene deletion of 235 kb and a partial gene deletion of 15 kb in a heterozygous and homozygous state, respectively.
explanation: >-
Adds structural variants to the allelic spectrum, which matters
diagnostically because exome sequencing will not see them.
- name: Loss of CEP78 from the Distal End of the Mature Centriole
biological_scale: MOLECULAR
description: >-
CEP78 is recruited to the distal end of mature centrioles by the CEP350-FOP
scaffold and interacts with VprBP in the EDD1-DYRK2-DDB1 E3 ubiquitin ligase
complex. The disease-causing p.(Leu150Ser) substitution weakens the
CEP78-CEP350 interaction specifically, which is the cleanest available link
from a patient allele to a molecular interaction.
cellular_components:
- preferred_term: centriole
term:
id: GO:0005814
label: centriole
downstream:
- target: Elevated CP110 and Disordered Cilium Assembly
causal_link_type: DIRECT
evidence:
- reference: PMID:28242748
reference_title: Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1(Vpr)(BP).
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Here, we show that centrosomal protein of 78 kDa (Cep78) localizes to mature centrioles and directly interacts with viral protein R binding protein (VprBP).
explanation: >-
Establishes the localisation and the E3-ligase interaction this node
asserts.
- reference: PMID:34259627
reference_title: CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
identified a novel interaction between CEP78 and CEP350 that is weakened by the CEP78L150S mutation.
explanation: >-
Ties a specific patient allele to a specific lost interaction, which is
what makes this node a disease mechanism rather than cell biology.
- name: Elevated CP110 and Disordered Cilium Assembly
biological_scale: CELLULAR
conforms_to: "ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction"
description: >-
CP110 caps the distal end of the centriole and suppresses ciliogenesis;
CEP78 restrains it via EDD1. Without CEP78, CP110 rises and ciliogenesis is
disordered. The direction of the cellular phenotype is worth noting because
it is counterintuitive: patient cells grow cilia that are too long, not too
few, so this is a length-control and assembly defect rather than a simple
failure to ciliate.
biological_processes:
- preferred_term: cilium assembly
modifier: DECREASED
term:
id: GO:0060271
label: cilium assembly
- preferred_term: protein ubiquitination
term:
id: GO:0016567
label: protein ubiquitination
downstream:
- target: Photoreceptor Connecting Cilium Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Cochlear Hair Cell Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Sperm Flagellar Defect
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:34259627
reference_title: CEP78 functions downstream of CEP350 to control biogenesis of primary cilia by negatively regulating CP110 levels.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Consistently, cells lacking CEP78 display significantly increased cellular and centrosomal levels of CP110, and depletion of CP110 in CEP78-deficient cells restored ciliation frequency to normal.
explanation: >-
The rescue is what makes this causal rather than correlative: removing
CP110 in a CEP78-null cell restores ciliation.
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Elongated primary cilia without clear ultrastructural abnormalities in sperm or nasal brushes suggest impaired cilia assembly.
explanation: >-
The patient-derived cellular phenotype. Note the authors' own hedge
("suggest") and the absence of sperm ultrastructural abnormality, which is
why the organ nodes below are drawn with unknown intermediates.
- reference: PMID:28242748
reference_title: Cep78 controls centrosome homeostasis by inhibiting EDD-DYRK2-DDB1(Vpr)(BP).
supports: REFUTE
evidence_source: IN_VITRO
snippet: >-
Cep78 specifically impedes the transfer of ubiquitin from EDD to CP110
explanation: >-
Curated as REFUTE against the direction the other cited paper implies, not
against the node. If CEP78 impedes ubiquitin transfer to CP110, then
losing CEP78 should increase CP110 ubiquitination and lower CP110 - the
opposite of the recruitment model, and the opposite of the elevated CP110
that is actually observed. The two papers disagree, so the ubiquitination
process on this node carries no modifier. See the knowledge-gap
discussion.
- reference: PMID:36315013
reference_title: "The central scaffold protein CEP350 coordinates centriole length, stability, and maturation."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
recruiting the proteins CEP78 and OFD1 to the distal end of centrioles and promoting the assembly of subdistal appendages
explanation: >-
Independent support for the CEP350 scaffold recruiting CEP78 to the
centriole distal end, which is the step upstream of the disputed one and
is not itself in dispute.
- name: Photoreceptor Connecting Cilium Dysfunction
biological_scale: CELLULAR
conforms_to: "ciliopathy_dysfunction#Photoreceptor Connecting Cilium Degeneration"
description: >-
The connecting cilium is the sole conduit for the enormous daily flux of
protein and membrane from the photoreceptor inner segment to the outer
segment, and it is built on the mother centriole. A cone bias is not assumed
here: CEP78 labels cone inner segments more intensely than rods in human
retina, which is a direct anatomical reason for a cone-predominant dystrophy.
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
downstream:
- target: Cone/cone-rod dystrophy
causal_link_type: DIRECT
evidence:
- 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: IN_VITRO
snippet: >-
Immunohistochemistry studies in the human retina showed intense labeling of cone inner segments compared to rods.
explanation: >-
The anatomical basis for cone predominance, in human retina rather than a
model.
- 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
directness: INDIRECT
evidence_source: MODEL_ORGANISM
snippet: >-
relatively higher expression in S-cone-like photoreceptors of Nrl-knockout retina compared to rods
explanation: >-
A second, transcript-level line of support for the cone bias. Graded
MODEL_ORGANISM because the discriminating comparison is made in
Nrl-knockout mouse retina; the human-retina half of the original sentence
is a different measurement and is not quoted here. Indirect because the
cone-like surrogate is not a human cone.
- name: Cochlear Hair Cell Dysfunction
biological_scale: CELLULAR
description: >-
The hearing loss is sensorineural, bilateral, postlingual and progressive,
which places the lesion in the cochlea rather than in development of the ear.
The inference to the hair-cell kinocilium and its basal body follows the
ciliary logic of the other two organs and is not directly demonstrated: no
CEP78 cochlear tissue study has been reported. This node is drawn as
mechanism because the clinical phenotype requires one, and marked here as
inference.
cell_types:
- preferred_term: auditory hair cell
term:
id: CL:0000202
label: auditory hair cell
downstream:
- target: Progressive sensorineural hearing impairment
causal_link_type: DIRECT
evidence:
- 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
directness: INDIRECT
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: >-
Establishes auditory involvement as part of the CEP78 phenotype. Indirect
for this node specifically: it supports that the ear is affected, not that
the hair-cell cilium is the structure at fault.
- name: Sperm Flagellar Defect
biological_scale: CELLULAR
conforms_to: "ciliopathy_dysfunction#Motile Cilia Beat Dysfunction"
cell_types:
- preferred_term: sperm
term:
id: CL:0000019
label: sperm
description: >-
The sperm flagellum is a modified motile cilium built on the centriole, so
male infertility fits the centriolar mechanism. The evidence is two affected
males from different families, and the same report found no clear
ultrastructural abnormality in their sperm - so the connection is
phenotypic, not structural. One of the two also carried a complex allele in
SPAG17, a ciliary gene independently associated with male infertility, which
the authors themselves flag.
downstream:
- target: Male infertility
causal_link_type: DIRECT
evidence:
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Two affected males from different families displayed sperm abnormalities causing infertility.
explanation: >-
The primary observation, in two men from independent families.
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: NO_EVIDENCE
evidence_source: HUMAN_CLINICAL
snippet: >-
One of these is a heterozygous carrier of a complex allele in SPAG17, a ciliary gene previously associated with autosomal recessive male infertility.
explanation: >-
Graded NO_EVIDENCE against the CEP78-causes-infertility claim rather than
SUPPORT or REFUTE: this sentence neither supports nor contradicts it, it
records a confounder in one of the two men. With n=2, one confounded case
materially weakens the association, and dropping the sentence would make
the evidence look cleaner than the authors presented it.
- reference: PMID:39747485
reference_title: Cep78 knockout causes sterility and oligoasthenoteratozoospermia in male mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the CEP78 protein is essential for acrosomal biogenesis, sperm head shaping, and formation of flagella during spermiogenesis
explanation: >-
The structural lesion the human cohorts could not supply: a knockout mouse
shows CEP78 is required for flagellar formation during spermiogenesis.
This is the evidence that makes the infertility claim mechanistic rather
than an association in two men, and it is independent of the SPAG17
confounder in the human data.
phenotypes:
- name: Cone/cone-rod dystrophy
category: Ophthalmologic
diagnostic: true
description: >-
Cone-predominant, progressive, with onset in childhood or adolescence. This
is the feature that separates the disorder from Usher syndrome, where the
retinal disease is rod-first retinitis pigmentosa. The natural history of
cone-rod dystrophy as a class is severe: legal blindness at a mean age of 35
in a 19-year multicentre cohort.
phenotype_term:
preferred_term: Cone/cone-rod dystrophy
term:
id: HP:0000548
label: Cone/cone-rod dystrophy
clinical_course: PROGRESSIVE
evidence:
- 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: >-
The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL).
explanation: >-
States the retinal phenotype and its pairing with hearing loss as the
defining combination.
- reference: PMID:22264887
reference_title: "Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mean age of legal blindness was 48 (standard error [SE], 3.1) years in CD, and 35 (SE, 1.1; P<0.001) years in CRD.
explanation: >-
Supplies the visual prognosis. Indirect: this is a cohort of cone and
cone-rod dystrophy of all causes, predating the identification of CEP78,
so it describes the phenotype class rather than this genotype.
- name: Progressive sensorineural hearing impairment
category: Otologic
diagnostic: true
description: >-
Bilateral, postlingual and progressive. The postlingual onset is the
clinically consequential difference from Usher types 1 and 2: language is
acquired normally, and the loss then compounds a vision that is failing at
the same time. It is also variably expressed - two teenage siblings with
CEP78 cone-rod dystrophy had presumed normal hearing.
phenotype_term:
preferred_term: Progressive sensorineural hearing impairment
term:
id: HP:0000408
label: Progressive sensorineural hearing impairment
clinical_course: PROGRESSIVE
evidence:
- 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: >-
Establishes auditory involvement and its distinction from Usher syndrome.
- reference: PMID:38780195
reference_title: "Exploring the diverse clinical and variant spectrum of CEP78-associated syndrome: Novel pathogenic variants identified in a case series."
supports: REFUTE
evidence_source: HUMAN_CLINICAL
snippet: >-
Both teenagers have a clinical diagnosis of cone-rod dystrophy with presumed normal hearing.
explanation: >-
Graded REFUTE against the claim that hearing loss is an obligate feature,
not against the association. Two siblings with a homozygous pathogenic
CEP78 variant had normal hearing at the time of report, so absence of
hearing loss does not exclude the diagnosis - though these are teenagers
and the loss is postlingual and progressive, so it may yet appear.
- name: Male infertility
category: Reproductive
description: >-
Reported in two affected males from different families, attributed to sperm
abnormalities. Recorded as a phenotype of the disorder, with the caveat
about the SPAG17 confounder carried on the mechanism node.
phenotype_term:
preferred_term: Male infertility
term:
id: HP:0003251
label: Male infertility
evidence:
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interestingly, the CEP78 phenotype has been possibly expanded with male infertility.
explanation: >-
The authors' own framing, hedged with "possibly", which is the appropriate
strength for an observation in two men.
- name: Abnormal sperm morphology
category: Reproductive
description: >-
The sperm abnormality underlying the infertility. Notably, no clear
ultrastructural abnormality was found on examination of the sperm, so the
defect is functional or subtle rather than a visible axonemal lesion.
phenotype_term:
preferred_term: Abnormal sperm morphology
term:
id: HP:0012864
label: Abnormal sperm morphology
evidence:
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Two affected males from different families displayed sperm abnormalities causing infertility.
explanation: >-
Names the sperm abnormality as the basis of the infertility.
genetic:
- name: CEP78
association: Causal biallelic variant
gene_term:
preferred_term: CEP78
term:
id: hgnc:25740
label: CEP78
frequency: The gene of CRDHL1; CEP250 accounts for the sibling disorder CRDHL2.
notes: >-
Three points for anyone interpreting a CEP78 result.
The allelic spectrum is wider than sequencing alone will find. It began as
seven truncating variants, then added a destabilising missense founder
allele, then structural variants - a recurrent 15 kb partial-gene deletion
with a Belgian and British founder haplotype, and a 235 kb whole-gene
deletion. A negative exome does not exclude the gene.
Reported case counts are an undercount by construction. CEP78 became a
disease gene only in September 2016, so a disruptive variant found before
then would have been classified as being in a gene of uncertain significance
and might never have reached the report. One published family was solved
only when panel testing repeated what a 2015 exome had not returned.
Misdiagnosis runs in one particular direction. The founding authors and the
missense-allele authors both note that CEP78 loss-of-function may be
under-recognised in patients labelled as having Usher syndrome.
evidence:
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
explanation: >-
The under-ascertainment claim, in the authors' own words.
- reference: PMID:33968938
reference_title: Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A founder haplotype was demonstrated for the latter SV in cases of Belgian and British origin, respectively.
explanation: >-
Establishes the recurrent structural variant as a founder allele rather
than an isolated rearrangement, which makes targeted testing for it
worthwhile in those populations.
treatments:
- name: Cochlear implantation
description: >-
For severe-to-profound sensorineural loss. The case for it here is stronger
than for most ultra-rare disorders because the hearing loss is postlingual
and progressive, which is the profile in which implantation performs best,
and because concurrent progressive visual loss raises what hearing is worth.
The quantitative evidence, though, is borrowed from Usher type IIa, not
measured in this disorder.
therapeutic_modality: DEVICE
treatment_term:
preferred_term: cochlear device implantation
term:
id: NCIT:C15329
label: Surgical Procedure
qualifiers:
- predicate:
preferred_term: medical device
term:
id: NCIT:C16830
label: Medical Device
value:
preferred_term: cochlear implant
term:
id: NCIT:C157820
label: Cochlear Implant
target_phenotypes:
- preferred_term: Progressive sensorineural hearing impairment
term:
id: HP:0000408
label: Progressive sensorineural hearing impairment
evidence:
- reference: PMID:28498263
reference_title: Cochlear Implantation in Patients With Usher Syndrome Type IIa Increases Performance and Quality of Life.
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
The phoneme scores improved significantly from 41 to 87% in patients with USH2a (p = 0.02)
explanation: >-
The quantitative benefit. Indirect and it should be read as such: eight
adults with Usher syndrome type IIa, a different gene and a different
disorder, chosen because it shares the postlingual progressive profile.
No implantation outcome has been reported in a CEP78 patient.
- name: Low-vision rehabilitation
description: >-
Low-vision aids, mobility support and visual rehabilitation, planned against
a trajectory that in cone-rod dystrophy as a class reaches legal blindness in
the mid-thirties. Doing this alongside the hearing loss rather than after it
is the practical point, since each sense is the compensation for the other.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: Rehabilitation
term:
id: NCIT:C15315
label: Rehabilitation
target_phenotypes:
- preferred_term: Cone/cone-rod dystrophy
term:
id: HP:0000548
label: Cone/cone-rod dystrophy
evidence:
- reference: PMID:22264887
reference_title: "Clinical course, genetic etiology, and visual outcome in cone and cone-rod dystrophy."
supports: SUPPORT
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
The mean age onset for CD was 16 years (standard deviation, 11), and of CRD 12 years (standard deviation, 11; P = 0.02).
explanation: >-
Gives the onset age that rehabilitation planning works from. Indirect: a
mixed-aetiology cone-rod dystrophy cohort, not CEP78 patients.
diagnosis:
- name: Retinal dystrophy gene panel or exome sequencing, with dosage analysis
description: >-
Panel or exome sequencing finds most cases, but neither will see the
structural variants, and one reported family was solved by panel testing
after a 2015 exome had missed the variants entirely. Where the phenotype is
right and sequencing is negative, dosage or long-read analysis of the CEP78
region is the next step.
results: >-
Biallelic CEP78 truncating, splice, or destabilising missense variants; or a
partial or whole-gene deletion detectable only by dosage or long-read
methods.
evidence:
- reference: PMID:38780195
reference_title: "Exploring the diverse clinical and variant spectrum of CEP78-associated syndrome: Novel pathogenic variants identified in a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Intriguingly, neither of these variants was reported in an affected sibling's clinical whole-exome sequencing (WES) report when performed in 2015.
explanation: >-
The documented case of a negative exome preceding a positive panel, which
is the argument for re-testing rather than trusting an old negative.
- reference: PMID:33968938
reference_title: Long-Read Sequencing to Unravel Complex Structural Variants of CEP78 Leading to Cone-Rod Dystrophy and Hearing Loss.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Approaches used for the identification of the SVs are shallow whole-genome sequencing (sWGS) combined with quantitative polymerase chain reaction (PCR) and long-range PCR, or ExomeDepth analysis on whole-exome sequencing (WES) data.
explanation: >-
The methods that actually detect the structural variants, none of which is
standard exon sequencing.
- name: Electroretinography with multimodal retinal imaging
description: >-
Full-field ERG to establish the cone-worse-than-rod pattern that defines
cone-rod dystrophy and separates it from the rod-first disease of Usher
syndrome, with OCT and fundus autofluorescence.
results: >-
Cone responses reduced more than rod responses, with macular changes on
imaging.
evidence:
- 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
directness: INDIRECT
evidence_source: HUMAN_CLINICAL
snippet: >-
an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss
explanation: >-
Names the retinal pattern that electroretinography is performed to
establish. Indirect: the paper describes the phenotype rather than
evaluating the test.
- name: Pure-tone audiometry with longitudinal follow-up
description: >-
Audiometry at diagnosis and repeated, because the loss is postlingual and
progressive and because normal hearing at presentation does not exclude the
diagnosis - reported teenage siblings had presumed normal hearing.
results: >-
Bilateral sensorineural hearing loss, progressive on serial testing; may be
normal early.
evidence:
- reference: PMID:38780195
reference_title: "Exploring the diverse clinical and variant spectrum of CEP78-associated syndrome: Novel pathogenic variants identified in a case series."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both teenagers have a clinical diagnosis of cone-rod dystrophy with presumed normal hearing.
explanation: >-
The observation that makes repeated audiometry necessary rather than a
single baseline test.
differential_diagnoses:
- name: Cone-rod dystrophy and hearing loss 2
description: >-
The sibling disorder and the closest differential: biallelic CEP250, and
CEP250 binds CEP78 at the centriole, so the two are the same mechanism at
adjacent proteins. Reported CEP250 disease is milder on both axes. dismech
curates it as its own entry; the two share the MONDO phenotypic-series
parent MONDO:0014980.
disease_term:
preferred_term: cone-rod dystrophy and hearing loss 2
term:
id: MONDO:0020780
label: cone-rod dystrophy and hearing loss 2
distinguishing_features:
- Biallelic CEP250 rather than CEP78
- Milder cone-rod dystrophy and slighter hearing loss in reported cases
- No male infertility reported
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: >-
Our data indicate that mutations of CEP250 can cause mild CRD and SNHL in Japanese patients.
explanation: >-
Establishes CEP250 as a second locus for the same clinical combination,
and characterises it as mild.
- 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: >-
The physical interaction between the two gene products, which is why the
two disorders are mechanistically adjacent rather than merely similar.
- name: Usher syndrome
description: >-
The disorder this is most often mistaken for, and the mistake is documented
rather than theoretical. Usher syndrome is a disorder of the Usher protein
interactome that organises the hair-bundle; the hearing loss is congenital
and the retinal disease is rod-first retinitis pigmentosa. CEP78 disease is
cone-first with postlingual hearing loss.
disease_term:
preferred_term: Usher syndrome
term:
id: MONDO:0019501
label: Usher syndrome
distinguishing_features:
- Cone-predominant dystrophy rather than rod-first retinitis pigmentosa
- Postlingual progressive hearing loss rather than congenital impairment
- Centriolar CEP78 rather than a component of the Usher interactome
- Male infertility reported in CEP78 disease
evidence:
- 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 founding authors' explicit separation of this disorder from Usher
syndrome.
- reference: PMID:31999394
reference_title: "Functional characterization of the first missense variant in CEP78, a founder allele associated with cone-rod dystrophy, hearing loss, and reduced male fertility."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Finally, CEP78 loss-of-function variants may have an underestimated role in misdiagnosed Usher syndrome, with or without sperm abnormalities.
explanation: >-
Records that the confusion runs in a specific direction - CEP78 patients
labelled as Usher - which is what makes this differential actionable.
- name: PHARC syndrome
description: >-
Biallelic ABHD12. It shares retinal degeneration with hearing loss, but it
adds polyneuropathy, ataxia and cataract, and the full pentad is the
exception rather than the rule - which is what makes it a genuine
differential rather than an obviously different disease. Hearing loss is
most often the presenting symptom in both disorders, and PHARC carries a
mean diagnostic delay of twenty years, so an incomplete PHARC presenting
through the ear is exactly the case that could be mistaken for this
disorder.
disease_term:
preferred_term: PHARC syndrome
term:
id: MONDO:0012984
label: PHARC syndrome
distinguishing_features:
- Biallelic ABHD12 rather than CEP78
- Polyneuropathy, ataxia and cataract in addition to the retinal and auditory features
- Retinitis pigmentosa rather than a cone-predominant dystrophy
- A metabolic lipase defect rather than a centriolar one
evidence:
- reference: PMID:40064796
reference_title: "Characterizing and expanding the neurological clinical spectrum of PHARC syndrome: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PHARC syndrome is an autosomal recessive neurodegenerative disease caused by mutations in the ABHD12 gene and is characterized by five main clinical features: polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataracts.
explanation: >-
The full feature set, which is what separates PHARC from this disorder
when it is complete.
- reference: PMID:40064796
reference_title: "Characterizing and expanding the neurological clinical spectrum of PHARC syndrome: a systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The results showed that hearing loss was the most common initial symptom, with a complete syndrome observed in only 31.6% of reported cases.
explanation: >-
The reason this differential matters in practice rather than on paper:
two thirds of PHARC patients do not have the full pentad, and the usual
presenting symptom is the one this disorder shares.
- name: TUBB4B-related sensorineural disease
description: >-
Heterozygous TUBB4B variants at Arg391 cause an atypical association of
Leber congenital amaurosis with early-onset hearing loss. It is the other
dual-sensory disorder on this differential whose mechanism is
cytoskeletal - but microtubule rather than centriolar, and dominant rather
than recessive. The retinal disease is also far earlier and more severe:
blindness within the first year, against a childhood-to-adolescent onset
cone-rod dystrophy here.
disease_term:
preferred_term: Leber congenital amaurosis with early-onset deafness
term:
id: MONDO:0060650
label: Leber congenital amaurosis with early-onset deafness
distinguishing_features:
- Heterozygous dominant TUBB4B rather than biallelic recessive CEP78
- Leber congenital amaurosis with blindness in the first year rather than a later cone-rod dystrophy
- Microtubule dynamics rather than centriole distal-end function
evidence:
- reference: PMID:29198720
reference_title: Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two
heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding
(TUBB4B).
explanation: >-
The gene, the inheritance pattern and the dual-sensory phenotype that
makes this a differential.
animal_models:
- name: Cep78 knockout mouse
species: Mouse
genotype: Cep78 null, homozygous
publication: PMID:39747485
description: >-
The only in vivo model of the disorder, and it addresses the one organ
branch where the human evidence is weakest. Male knockouts are sterile with
an oligoasthenoteratozoospermia phenotype, and the defect is traced to
spermiogenesis - acrosomal biogenesis, sperm head shaping and flagellar
formation. Note that the reported phenotype is reproductive; the entry does
not claim it models the retinal or cochlear disease.
modeled_mechanisms:
- target: Sperm Flagellar Defect
relationship: RECAPITULATES
fidelity: MODERATE
model_scale: CELLULAR
description: >-
Cep78 loss produces sterility with oligoasthenoteratozoospermia and a
demonstrated failure of flagellar formation during spermiogenesis.
limitations: >-
A homozygous null, where the human disorder includes destabilising
missense and structural alleles that retain some protein. Male infertility
is also a variable feature in patients - two men from different families -
whereas the knockout male is sterile, so the model is more severe on this
axis than the disease. And the model speaks only to the reproductive
branch: no retinal or auditory phenotype is reported, so the two organs
that define the disorder clinically remain unmodelled.
readouts:
- name: Sperm morphology and motility
target: Sperm Flagellar Defect
direction: DECREASED
interpretation: >-
Oligoasthenoteratozoospermia as the measurable expression of the
flagellar defect.
evidence:
- reference: PMID:39747485
reference_title: Cep78 knockout causes sterility and oligoasthenoteratozoospermia in male mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the male Cep78-/- mice exhibited the OAT phenotype and sterility
explanation: >-
The phenotype measurement behind this readout.
evidence:
- reference: PMID:39747485
reference_title: Cep78 knockout causes sterility and oligoasthenoteratozoospermia in male mice.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
the CEP78 protein is essential for acrosomal biogenesis, sperm head shaping, and formation of flagella during spermiogenesis
explanation: >-
States what the model establishes about CEP78's role in spermiogenesis,
which is why it is treated as informative for this node.
notes: >-
An author correction to this paper exists (PMID:40075211). Its cache entry
has content_type unavailable, so the substance of the correction cannot be
inspected from the repository and has not been assessed here. Anyone
relying on the quantitative detail of this model should read the correction
directly.
discussions:
- discussion_id: gap_crdhl1_organ_selectivity_and_hearing_variability
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Why does loss of a ubiquitously expressed centriolar protein produce disease
in only three organs, and what decides whether a given patient has hearing
loss at all?
attaches_to:
- pathophysiology#Elevated CP110 and Disordered Cilium Assembly
- pathophysiology#Cochlear Hair Cell Dysfunction
- phenotypes#Progressive sensorineural hearing impairment
rationale: >-
CEP78 is expressed ubiquitously - the founding paper checked seventeen human
tissues - and the cellular phenotype, elongated primary cilia, is present in
fibroblasts and nasal epithelium that are clinically normal. So a cilium
defect that is detectable in a skin biopsy causes disease only in
photoreceptors, hair cells and sperm. For the retina there is a real partial
answer, in the cone-biased expression seen by immunohistochemistry. For the
ear there is none: no CEP78 cochlear study has been published, and the
hair-cell node in this entry is an inference from the ciliary logic rather
than an observation. The variability compounds it. Two teenage siblings
homozygous for a pathogenic variant had presumed normal hearing, while other
patients have early-onset loss, and nothing distinguishes them. Whether that
is age, allele, or a modifier is unknown, and it is the difference between
counselling a family to expect deafness and counselling them to watch for it.
- discussion_id: gap_crdhl1_cp110_ubiquitination_direction
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does CEP78 inhibit the EDD1-DYRK2-DDB1 ligase or recruit it? The two papers
that characterise the interaction predict opposite effects of CEP78 loss on
CP110 ubiquitination.
attaches_to:
- pathophysiology#Loss of CEP78 from the Distal End of the Mature Centriole
- pathophysiology#Elevated CP110 and Disordered Cilium Assembly
rationale: >-
Hossain et al. report that CEP78 binds EDD-DYRK2-DDB1(VprBP) and inhibits
it, specifically impeding transfer of ubiquitin from EDD to CP110, and that
depleting Cep78 enhances accumulation of ubiquitinated products. On that
model, losing CEP78 should increase CP110 ubiquitination and therefore lower
CP110. Nielsen et al. report that CEP350 recruits and stabilises CEP78 at
the centrosome, which in turn recruits EDD1 - on that model, losing CEP78
should reduce ligase recruitment and raise CP110, which is what they
observe.
Both cannot be right as stated, and the disease-relevant observation sits
with the second: CEP78-deficient cells have elevated CP110, and depleting
CP110 restores ciliation frequency. That is why the pathograph draws
elevated CP110 and why the node is named for it. But the entry does not
conclude from the downstream observation that the upstream direction is
settled, because the two are separable claims and only one of them has been
measured in both papers.
Resolving it matters for more than tidiness. If CEP78 inhibits the ligase,
then CP110 elevation in CEP78-null cells must come from somewhere else, and
the mechanism between the patient allele and the cilium is not the one this
entry draws. A single study measuring CP110 ubiquitination and CP110
abundance side by side, in the same cell system, with CEP78 depleted, would
settle it.
- discussion_id: gap_crdhl1_male_infertility_causal_attribution
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Is male infertility a genuine component of CEP78 disease, given that it
rests on two men and one of them carries a variant in a second infertility
gene?
attaches_to:
- pathophysiology#Sperm Flagellar Defect
- phenotypes#Male infertility
rationale: >-
The claim is mechanistically attractive - the sperm flagellum is a
centriole-derived cilium, so it belongs in the same story as the connecting
cilium and the kinocilium - and attraction is exactly the problem. The
observation is two affected males from different families. One of them is
also a heterozygous carrier of a complex allele in SPAG17, a ciliary gene
independently associated with recessive male infertility, which the authors
report rather than bury. No clear ultrastructural abnormality was found in
the sperm of those two men, so the human observation supplies no structural
lesion. The original authors themselves write that the phenotype has been
"possibly" expanded.
The Cep78 knockout mouse curated under animal_models does supply a
structural lesion, and it does so independently of the SPAG17 confounder,
since the mouse carries no second-gene variant. That changes what is open
here. It is no longer whether loss of CEP78 can cause a flagellar defect at
all - in mouse it demonstrably can - but whether these two men's infertility
is CEP78-attributable, what fraction of biallelic men are affected, and
whether allele class predicts it. The mouse is a null while the human
spectrum includes missense and structural alleles, and it is uniformly
sterile while the human report is of variable infertility, so it narrows the
question without closing it. What would settle it is systematic semen
analysis across a reported CEP78 cohort with second-gene variants excluded;
nothing of the kind has been done, and with a disorder this rare it may not
be.
notes: >-
On the entry's scope and its MONDO term.
The claim for this work was filed against MONDO:0014980, "cone-rod dystrophy
and hearing loss". That term xrefs OMIM phenotypic series OMIMPS:617236 and
has exactly two descendants - MONDO:0020778 (CEP78) and MONDO:0020780
(CEP250) - so it is a two-member series rather than a disease. dismech already
curates the CEP250 member as Cone-rod_Dystrophy_And_Hearing_Loss_2, merged in
PR #9998. Curating the series term would therefore have duplicated an existing
entry. This entry is the CEP78 member, named to match its sibling.
The queue stub argued the other way - it was a hand-authored lump replacing the
two numbered stubs, on the grounds that CEP78 and CEP250 are binding partners
and the phenotypes are the same syndrome. That is a real argument and the stub
itself anticipated being overridden: its note records that the CRDHL2 stub was
restored to the queue when claim issue #9981 took it, and that the claimant's
decision there would take precedence. It did - CRDHL2 shipped as a separate
entry - so the split is the repository's standing decision and this entry
follows it. The two entries cross-reference each other as differential
diagnoses, which preserves the lump argument's content without duplicating the
curation.
On the CP110 step, which is the one part of the mechanism where the sources
disagree. Two papers characterise how CEP78 acts on the EDD1-DYRK2-DDB1
ligase and they reach opposite conclusions: one has CEP78 inhibiting the
ligase and impeding ubiquitin transfer to CP110, which predicts that CEP78
loss raises CP110 ubiquitination and lowers CP110; the other has CEP350
recruiting CEP78 which in turn recruits the ligase, which predicts the
reverse. The observation both are trying to explain - CEP78-null cells have
elevated CP110, and depleting CP110 restores ciliation - is common ground and
is what the pathograph rests on. The ubiquitination process on that node
therefore carries no modifier, and the disagreement is curated as a REFUTE
evidence item plus a knowledge gap rather than resolved by preferring the
paper that fits the downstream observation.
On evidence. A large share of the quantitative claims in this entry are
borrowed and marked directness: INDIRECT - the visual prognosis comes from a
mixed-aetiology cone-rod dystrophy cohort assembled before CEP78 was known,
and the cochlear implantation benefit comes from eight adults with Usher
syndrome type IIa. Neither has been measured in a CEP78 patient. The one
NO_EVIDENCE item is deliberate: the SPAG17 confounder in one of the two
infertile men neither supports nor refutes the infertility claim, and with n=2
it was not something to leave out.