CWC27-Related Retinitis Pigmentosa With or Without Skeletal Anomalies

Mendelian MONDO:0009598 Pathograph 22 Show in embeddings browser Ophthalmological Disease Retinal Dystrophy Inherited retinal dystrophy Skeletal Dysplasia Spliceosomopathy

CWC27-related retinitis pigmentosa with or without skeletal anomalies (RPSKA) is an autosomal recessive spliceosomopathy caused by biallelic protein-truncating or splice-disrupting variants in CWC27, a spliceosome-associated cyclophilin-like protein that joins the activated (Bact) spliceosome together with its partner CWC22. Its N-terminal cyclophilin domain has lost the catalytic residue and is thought to bind proline rather than isomerize it. The disease spans isolated retinal degeneration (retinitis pigmentosa, or Leber congenital amaurosis in one child) to a syndrome adding brachydactyly, craniofacial anomalies, short stature, developmental delay with intellectual disability, and ectodermal features such as sparse hair, eyebrows and eyelashes and dental anomalies. Night blindness typically begins near age ten and is followed by constriction of the visual fields. Severity tracks allele position: C-terminal truncations give the retina-restricted form, earlier truncations the syndrome, and the same split is reproduced by a hypomorphic C-terminal frameshift mouse (late-onset retinal degeneration) versus Cwc27 knockout mice (embryonic lethality with growth, craniofacial and limb defects). CWC27 is unusual among spliceosome genes in causing both the retinal and the craniofacial-skeletal spliceosomopathy phenotypes.

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Inheritance

1
Autosomal recessive inheritance HP:0000007
Homozygous or compound heterozygous truncating and splice-site variants; heterozygous parents and heterozygous mice are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:28285769 SUPPORT Human clinical
"By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes"
Recessive truncating variants in seven families.
CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z SUPPORT Other
"The variants segregated fully with disease, and were not found in the heterozygous state."
ClinGen summary of segregation across the curated probands.
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Discussions and Knowledge Gaps

1
Would AAV gene augmentation of CWC27 in photoreceptors, which reduces degeneration in the hypomorphic K338fs mouse, help patients with the retina-restricted or syndromic disease?
HUMAN MODEL MISMATCH OPEN cwc27_gene_augmentation_human_translation
Attached to
pathophysiology#Photoreceptor Degeneration
The rescue was shown only in a hypomorphic mouse allele with late-onset degeneration, while most patients carry earlier truncations and many have systemic disease. Whether human photoreceptors are still present at the age of diagnosis, and whether the truncated proteins interfere with the transgene, are untested.
Show evidence (1 reference)
PMID:37479075 SUPPORT Model organism
"In this study, we demonstrated that subretinal injection of AAV8-GRK-Cwc27-FLAG in mutant mice can improve the functionality and morphology of the retina."
The mouse rescue result whose human relevance is open.
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Pathophysiology

5
Biallelic CWC27 Loss-of-Function Variants
Biallelic nonsense, frameshift and canonical splice-site variants truncate CWC27. Patient blood RNA and mouse retina show that the mutant transcripts escape complete nonsense-mediated decay, so truncated protein may persist. CWC27 binds CWC22 directly through its C-terminal region, forming a heterodimer that sits in the Bact spliceosome and stabilizes eIF4A3 binding; the protein binding term records that shown interaction. No peptidyl-prolyl isomerase activity term is bound, because the human cyclophilin domain lacks a conserved active-site residue and is described as catalytically inactive. Allele position predicts severity: C-terminal truncations such as p.Val335Serfs*13 cause retina-restricted disease, while earlier truncations cause the syndromic form.
CWC27 hgnc:10664 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CWC27 (hgnc:10664). hgnc:10664 is a gene from the HUGO Gene Nomenclature Committee.
CWC22 binding GO:0005515 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves CWC22 binding, annotated with protein binding (GO:0005515). GO:0005515 is a molecular function from the Gene Ontology.
spliceosomal complex GO:0005681 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves spliceosomal complex (GO:0005681). GO:0005681 is a cellular component from the Gene Ontology.
Downstream
Retinal Mis-Splicing With Intron Retention
Impaired Embryonic Growth and Craniofacial-Limb Development
Show evidence (6 references)
CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z SUPPORT Other
"This curation includes ten variants (five nonsense, three frameshift, and two disrupting splicing) that have collectively been reported in ten probands in four publications"
The variant spectrum across reported probands.
PMID:28285769 SUPPORT Human clinical
"Similarly, the affected individuals in families 3 and 7 with a frameshift mutation (p.Val335Serfs∗13) in the C-terminal part of the protein have a milder phenotype, whereas affected individuals with earlier CWC27 protein truncations have craniofacial defects, brachydactyly, short stature, and..."
Genotype-phenotype correlation by truncation position.
PMID:28285769 SUPPORT In vitro / ex vivo
"Furthermore, qRT-PCR on the RNA of the two affected individuals from family 4 showed that the CWC27 mRNA quantity was reduced by only 33%–43% compared with a control subject"
In patient fibroblasts, mutant CWC27 transcripts are only partly degraded.
+ 3 more references
Retinal Mis-Splicing With Intron Retention
Evidence comes from the Cwc27 K338fs/K338fs mouse retina, where bulk and single-cell RNA sequencing found altered splice-site usage and intron retention alongside gene expression changes, the first in vivo evidence that CWC27 acts as a splicing factor. In a human RPE cell line (hTERT RPE-1), CWC27 knock-down changed expression of many of the same genes as CWC22 knock-down. Which mis-spliced transcripts explain photoreceptor loss is not established.
mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal mRNA splicing, via spliceosome (GO:0000398). GO:0000398 is a biological process from the Gene Ontology.
Animal models
Cwc27 K338fs hypomorphic mouse Mouse measures Retinal bulk and single-cell RNA sequencing reports splicing changes in this model.
Downstream
Retinal Endoplasmic Reticulum Stress
Photoreceptor Degeneration
Show evidence (2 references)
PMID:34726245 SUPPORT Model organism
"Bulk RNA and single cell RNA-sequencing of the mouse retina showed that there were gene expression and splicing pattern changes, including alternative splice site usage and intron retention."
Mis-splicing in the hypomorphic mouse retina.
PMID:32329775 SUPPORT In vitro / ex vivo
"Knock-down of either CWC27 or CWC22 in immortalized retinal pigment epithelial cells affects numerous common genes, indicating that these proteins cooperate, targeting the same pathways."
Gene expression changes after CWC27 depletion in human RPE cells.
Retinal Endoplasmic Reticulum Stress
CHOP staining in the Cwc27 K338fs/K338fs mouse retina suggests ER stress follows the splicing changes. The authors propose it as a likely contributor; it has not been tested by blocking ER stress.
response to endoplasmic reticulum stress GO:0034976 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to endoplasmic reticulum stress (GO:0034976). GO:0034976 is a biological process from the Gene Ontology.
Downstream
Photoreceptor Degeneration
Show evidence (1 reference)
PMID:34726245 SUPPORT Model organism
"Positive staining for CHOP suggests that ER stress may be activated in response to the splicing pattern changes and is a likely contributor to the disease mechanism."
Proposed ER stress downstream of mis-splicing in mouse retina.
Photoreceptor Degeneration
Photoreceptors degenerate, with loss of the outer nuclear layer and outer segments in patients. In mice the evidence comes from the hypomorphic K338fs model, whose degeneration is driven mainly by photoreceptor death, includes cones, and is reduced by AAV8 delivery of Cwc27 to photoreceptors. Whether the retinal pigment epithelium fails independently has not been studied.
rod photoreceptor CL:0000604 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves rod photoreceptor, annotated with retinal rod cell (CL:0000604). CL:0000604 is a cell type from the Cell Ontology. cone photoreceptor CL:0000573 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cone photoreceptor, annotated with retinal cone cell (CL:0000573). CL:0000573 is a cell type from the Cell Ontology.
photoreceptor cell maintenance GO:0045494 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased photoreceptor cell maintenance (GO:0045494). GO:0045494 is a biological process from the Gene Ontology.
Animal models
Cwc27 K338fs hypomorphic mouse Mouse recapitulates Reproduces retinal dysfunction and outer retinal thinning, and its degeneration is reduced by AAV8 Cwc27 augmentation.
Downstream
Rod-cone dystrophy
Nyctalopia
Constriction of peripheral visual field
Attenuation of retinal blood vessels
Chorioretinal atrophy
Show evidence (3 references)
PMID:28285769 SUPPORT Human clinical
"OCT through the retinal fovea shows a loss of volume of the outer nuclear layer (photoreceptor nuclei) and complete absence of the photoreceptor outer segments throughout the field of view."
Photoreceptor loss on OCT in a patient.
PMID:37479075 SUPPORT Model organism
"By 6 months of age, Cwc27 mutant mice show a retinal degenerative phenotype, including morphological and functional abnormalities, primarily driven by the death of photoreceptors."
Photoreceptor death drives the mouse retinal phenotype.
PMID:37479075 SUPPORT Model organism
"Immunostaining analyses revealed a notable decrease in photoreceptor degeneration, including cone cell degeneration, in the AAV-injected eyes compared to the PBS-injected eyes."
Restoring Cwc27 in photoreceptors reduces rod and cone degeneration.
Impaired Embryonic Growth and Craniofacial-Limb Development
Complete loss of Cwc27 in knockout mice (tm1b, tm1Lex) causes near-complete embryonic lethality, growth retardation, neural tube closure failure, absent limb buds and delayed digit separation. These are much more severe than the human syndrome but point to a developmental requirement for CWC27 that the hypomorphic retinal mouse does not show. Whether mis-splicing in neural crest, limb or brain precursors is the operative step has not been shown, so this node is linked to the variant node without a mis-splicing intermediate, and the neurodevelopmental features are attached to it without a known mechanism.
Animal models
Cwc27 tm1b knockout mouse Mouse partially recapitulates Shows a developmental requirement for Cwc27 in growth and in craniofacial and limb development.
Downstream
Brachydactyly
Short stature
Frontal bossing
Micrognathia
Downslanted palpebral fissures
Low-set ears
Intellectual disability
Delayed speech and language development
Delayed ability to walk
Show evidence (2 references)
PMID:28285769 SUPPORT Model organism
"Specifically, at E12.5, we observed marked growth retardation, neural tube closure failure, and absence of limb buds in Cwc27tm1b/tm1b embryos with the most severe defects (Figure 3I)."
Developmental defects in knockout embryos.
PMID:28285769 SUPPORT Model organism
"These phenotypes, though much more severe than the human clinical manifestations, demonstrate the delayed growth as well as compromised craniofacial and limb development in the Cwc27 mutants."
Authors relate the knockout defects to the human syndrome.
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Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for CWC27-Related Retinitis Pigmentosa With or Without Skeletal Anomalies 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

25
Cardiovascular 1
Attenuation of retinal blood vessels HP:0007843 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thinning of the retinal vessels, annotated with Attenuation of retinal blood vessels (HP:0007843). HP:0007843 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"For individual 5:II-1, funduscopy and fundus autofluorescence imaging show thinning of the retinal vessels and a reduced autofluorescence from the RPE layer consistent with outer retinal degeneration."
Vessel attenuation on fundus imaging.
Digestive 1
Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding delay, annotated with Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
Feeding delay among the neurological features.
Ear 1
Low-set ears HP:0000369 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Large and low-set ears, annotated with Low-set ears (HP:0000369). HP:0000369 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
Listed among the craniofacial anomalies.
Endocrine 1
Hypergonadotropic hypogonadism HP:0000815 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypergonadotropic hypogonadism (HP:0000815). HP:0000815 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31481716 SUPPORT Human clinical
"in addition to hypergonadotropic hypogonadism, hypoplastic/agenesic teeth, and cataracts, not previously associated with such phenotypic spectrum"
Hypergonadotropic hypogonadism in a single woman.
Eye 6
Rod-cone dystrophy VERY_FREQUENT HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinitis pigmentosa, annotated with Rod-cone dystrophy (HP:0000510). HP:0000510 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28285769 SUPPORT Human clinical
"We observed a common phenotype in the majority of these affected individuals, consisting of retinal degeneration (9/10), brachydactyly (9/10), craniofacial defects (8/10), short stature (8/10), and neurological defects (8/10)."
Retinal degeneration in 9 of 10 patients.
PMID:28285769 SUPPORT Human clinical
"In our cohort, retinal defects include RP in most affected individuals"
The retinal degeneration is retinitis pigmentosa in most patients.
Nyctalopia HP:0000662 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Night blindness, annotated with Nyctalopia (HP:0000662). HP:0000662 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28285769 SUPPORT Human clinical
"with night blindness occurring at around 10 years of age, followed by restriction of visual fields"
Night blindness from about age ten.
PMID:38956876 SUPPORT Human clinical
"The patient had poor vision, nyctalopia and nystagmus from childhood."
Childhood nyctalopia in a further patient.
Constriction of peripheral visual field HP:0001133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Restriction of visual fields, annotated with Constriction of peripheral visual field (HP:0001133). HP:0001133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"with night blindness occurring at around 10 years of age, followed by restriction of visual fields"
Field constriction follows night blindness.
Nystagmus HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38956876 SUPPORT Human clinical
"The patient had poor vision, nyctalopia and nystagmus from childhood."
Nystagmus from childhood in a patient with early-onset disease.
Chorioretinal atrophy HP:0000533 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chorioretinal atrophy (HP:0000533). HP:0000533 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38956876 SUPPORT Human clinical
"Fundoscopy revealed extensive chorioretinal atrophy with numerous scattered greyish pigmentation."
Extensive chorioretinal atrophy in one patient.
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31481716 SUPPORT Human clinical
"in addition to hypergonadotropic hypogonadism, hypoplastic/agenesic teeth, and cataracts, not previously associated with such phenotypic spectrum"
Cataracts in a single reported patient.
Head and Neck 7
Frontal bossing HP:0002007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Frontal bossing (HP:0002007). HP:0002007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
Listed among the craniofacial anomalies.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
Listed among the craniofacial anomalies.
Downslanted palpebral fissures HP:0000494 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Downslanted palpebral fissures (HP:0000494). HP:0000494 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
Listed among the craniofacial anomalies.
Sparse scalp hair HP:0002209 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse scalp hair (HP:0002209). HP:0002209 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36718996 SUPPORT Human clinical
"we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
Sparse scalp hair proposed as a core ectodermal feature.
PMID:28285769 SUPPORT Human clinical
"Note the high frontal hairline, sparse hair, eyebrows, and eyelashes, low-set ears, and thick lips."
Sparse hair in the two affected siblings of family 4.
Sparse eyebrow HP:0045075 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse eyebrows, annotated with Sparse eyebrow (HP:0045075). HP:0045075 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36718996 SUPPORT Human clinical
"we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
Sparse eyebrows as part of the ectodermal phenotype.
PMID:38956876 SUPPORT Human clinical
"scant hair, absent eyebrows and thin eyelashes were documented"
Absent eyebrows in a further patient, the severe end of the same feature.
Sparse eyelashes HP:0000653 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sparse eyelashes (HP:0000653). HP:0000653 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36718996 SUPPORT Human clinical
"we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
Sparse eyelashes as part of the ectodermal phenotype.
Hypodontia HP:0000668 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplastic or agenesic teeth, annotated with Hypodontia (HP:0000668). HP:0000668 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31481716 SUPPORT Human clinical
"in addition to hypergonadotropic hypogonadism, hypoplastic/agenesic teeth, and cataracts, not previously associated with such phenotypic spectrum"
Missing teeth in a single patient; dental anomalies are reported in other patients without further detail.
Integument 3
Nail dysplasia HP:0002164 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nail dysplasia (HP:0002164). HP:0002164 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36718996 SUPPORT Human clinical
"we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
Nail dysplasia as part of the ectodermal phenotype.
Ichthyosis HP:0008064 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ichthyosis (HP:0008064). HP:0008064 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Individuals 4:II-3 and 4:II-4 present extensive hair and skin problems including alopecia, absent eyebrows and eyelashes, ichthyosis, eczema, and keratosis."
Ichthyosis in one family, reported as a family-specific feature.
Cafe-au-lait spot HP:0000957 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cafe-au-lait spots, annotated with Cafe-au-lait spot (HP:0000957). HP:0000957 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38956876 SUPPORT Human clinical
"In addition, craniofacial abnormalities, short statue, brachydactyly, dental anomalies, cafe-au-lait spots, scant hair, absent eyebrows and thin eyelashes were documented."
Cafe-au-lait spots in a single patient.
Limbs 1
Brachydactyly VERY_FREQUENT HP:0001156 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Brachydactyly (HP:0001156). HP:0001156 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28285769 SUPPORT Human clinical
"We observed a common phenotype in the majority of these affected individuals, consisting of retinal degeneration (9/10), brachydactyly (9/10), craniofacial defects (8/10), short stature (8/10), and neurological defects (8/10)."
Brachydactyly in 9 of 10 patients.
CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z SUPPORT Other
"brachydactyly (affects primarily the distal phalanges)"
ClinGen summary of the digital involvement.
Nervous System 3
Intellectual disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
Intellectual disability among the neurological features, which were present in 8 of 10 patients.
Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Speech delay, annotated with Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
Speech delay among the neurological features.
Delayed ability to walk HP:0031936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed walking, annotated with Delayed ability to walk (HP:0031936). HP:0031936 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
Delayed walking among the neurological features.
Growth 1
Short stature VERY_FREQUENT HP:0004322 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short stature (HP:0004322). HP:0004322 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28285769 SUPPORT Human clinical
"We observed a common phenotype in the majority of these affected individuals, consisting of retinal degeneration (9/10), brachydactyly (9/10), craniofacial defects (8/10), short stature (8/10), and neurological defects (8/10)."
Short stature in 8 of 10 patients.
🧬

Genetic Associations

1
CWC27 (Causative biallelic nonsense, frameshift and splice-site variants acting by loss of function.)
Gene: CWC27 hgnc:10664 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CWC27 (hgnc:10664). hgnc:10664 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z SUPPORT Other
"The mechanism of pathogenicity is reported to be loss-of-function."
ClinGen states the disease mechanism.
PMID:38134094 SUPPORT Human clinical
"After testing the whole exome gene sequencing, the gene detection showed that the CWC27 gene was homozygous mutation, c.617(exon7)C>A (p.Ser206Ter)"
A further homozygous truncating variant in a child with growth failure.
💊

Medical Actions

1
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for an autosomal recessive disorder with 25 percent recurrence risk for carrier parents.
🐁

Animal Models

2
Cwc27 K338fs hypomorphic mouse
Carries a C-terminal frameshift close to the recurrent human p.Val335Serfs*13 allele. It is viable and develops late-onset retinal degeneration without extraocular disease, matching the retina-restricted human form.
Species
Mouse
Genotype
Cwc27(K338fs/K338fs), CRISPR-Cas9 frameshift in exon 11
Publication
PMID:28285769
Pathograph links
Photoreceptor Degeneration recapitulates fidelity: moderate observes: tissue Reproduces retinal dysfunction and outer retinal thinning, and its degeneration is reduced by AAV8 Cwc27 augmentation.
Limitations: The allele is hypomorphic and does not model the syndromic disease; mouse retina has no macula, and the mice were followed only to about six months.
Divergences from the human mechanism
species mismatch qualifying
The mouse retina is rod-dominated and lacks a macula, so cone-rich central retinal involvement seen in patients cannot be assessed.
Readouts
Scotopic ERG a-wave and b-wave amplitude
Direction: DECREASED
Interpretation: Reduced photoreceptor and bipolar responses reflect the retinal dysfunction.
Show evidence (1 reference)
PMID:28285769 SUPPORT Model organism
"ERG showed that the Cwc27K338fs/K338fs mice have about 50% reduction of a-wave and b-wave amplitudes compared with Cwc27K338fs/+ littermates, indicating a compromised retinal function (Figure 4B)."
The measured ERG reduction.
Outer retina thickness
Direction: DECREASED
Interpretation: Outer retinal thinning is the histological correlate of photoreceptor loss.
Show evidence (1 reference)
PMID:28285769 SUPPORT Model organism
"(C) H&E staining shows thinning of outer retina in Cwc27K338fs/K338fs mice at the age of 6 months, suggesting photoreceptor degeneration."
Histology at six months.
Show evidence (1 reference)
PMID:28285769 SUPPORT Model organism
"In mice, disruption of exon 1 (tm1Lex) or exon 3 (tm1b) resulted in a wide range of developmental abnormalities with nearly complete embryonic lethality, while the mice with a homozygous frameshift mutation in exon 11 display a late-onset retinal degeneration phenotype."
The exon 11 frameshift mouse models the retinal disease.
Retinal Mis-Splicing With Intron Retention measures fidelity: unknown observes: cellular Retinal bulk and single-cell RNA sequencing reports splicing changes in this model.
Limitations: The splicing changes have not been compared with patient retina, and which changes cause photoreceptor death is not shown.
Readouts
Retinal alternative splice-site usage and intron retention
Direction: ALTERED
Interpretation: Splicing pattern changes in mutant retina.
Show evidence (1 reference)
PMID:34726245 SUPPORT Model organism
"Bulk RNA and single cell RNA-sequencing of the mouse retina showed that there were gene expression and splicing pattern changes, including alternative splice site usage and intron retention."
The measured splicing changes.
Cwc27 tm1b knockout mouse
A null allele with near-complete pre-weaning lethality. Surviving and embryonic homozygotes show growth retardation, dystrophic photoreceptors, neural tube closure failure, limb bud and digit defects.
Species
Mouse
Genotype
Cwc27(tm1b/tm1b), exon 3 deletion (KOMP)
Publication
PMID:28285769
Pathograph links
Impaired Embryonic Growth and Craniofacial-Limb Development partially recapitulates fidelity: low observes: organism Shows a developmental requirement for Cwc27 in growth and in craniofacial and limb development.
Limitations: The null phenotype is far more severe than the human syndrome, whose truncating alleles escape complete nonsense-mediated decay and may retain residual function; neural tube defects and exencephaly are not human features.
Show evidence (1 reference)
PMID:28285769 SUPPORT Model organism
"These phenotypes, though much more severe than the human clinical manifestations, demonstrate the delayed growth as well as compromised craniofacial and limb development in the Cwc27 mutants."
The authors' own statement of fidelity and its limit.
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Source YAML

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name: CWC27-Related Retinitis Pigmentosa With or Without Skeletal Anomalies
creation_date: "2026-10-28T05:22:39Z"
category: Mendelian
description: >-
  CWC27-related retinitis pigmentosa with or without skeletal anomalies (RPSKA)
  is an autosomal recessive spliceosomopathy caused by biallelic
  protein-truncating or splice-disrupting variants in CWC27, a
  spliceosome-associated cyclophilin-like protein that joins the activated (Bact)
  spliceosome together with its partner CWC22. Its N-terminal cyclophilin
  domain has lost the catalytic residue and is thought to bind proline rather
  than isomerize it. The disease spans isolated retinal degeneration
  (retinitis pigmentosa, or Leber congenital amaurosis in one child) to a
  syndrome adding brachydactyly, craniofacial anomalies, short stature,
  developmental delay with intellectual disability, and ectodermal features
  such as sparse hair, eyebrows and eyelashes and dental anomalies. Night
  blindness typically begins near age ten and is followed by constriction of
  the visual fields. Severity tracks allele position: C-terminal truncations
  give the retina-restricted form, earlier truncations the syndrome, and the
  same split is reproduced by a hypomorphic C-terminal frameshift mouse
  (late-onset retinal degeneration) versus Cwc27 knockout mice (embryonic
  lethality with growth, craniofacial and limb defects). CWC27 is unusual among
  spliceosome genes in causing both the retinal and the craniofacial-skeletal
  spliceosomopathy phenotypes.
disease_term:
  preferred_term: metaphyseal chondrodysplasia-retinitis pigmentosa syndrome
  term:
    id: MONDO:0009598
    label: metaphyseal chondrodysplasia-retinitis pigmentosa syndrome
synonyms:
- Retinitis pigmentosa with or without skeletal anomalies
- RPSKA
- CWC27-related retinopathy with or without syndromic features
- CWC27-related spliceosomopathy
parents:
- Ophthalmological Disease
- Retinal Dystrophy
- Inherited retinal dystrophy
- Skeletal Dysplasia
- Spliceosomopathy
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous or compound heterozygous truncating and splice-site variants;
    heterozygous parents and heterozygous mice are unaffected.
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By whole-exome sequencing, recessive protein-truncating mutations in CWC27 were found in seven unrelated families that show a range of clinical phenotypes"
    explanation: Recessive truncating variants in seven families.
  - reference: CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z
    reference_title: "CWC27 / metaphyseal chondrodysplasia-retinitis pigmentosa syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The variants segregated fully with disease, and were not found in the heterozygous state."
    explanation: ClinGen summary of segregation across the curated probands.
pathophysiology:
- name: Biallelic CWC27 Loss-of-Function Variants
  conforms_to: "spliceosome_component_dysfunction#Germline Spliceosome Component Variant"
  description: >-
    Biallelic nonsense, frameshift and canonical splice-site variants truncate
    CWC27. Patient blood RNA and mouse retina show that the mutant transcripts
    escape complete nonsense-mediated decay, so truncated protein may persist.
    CWC27 binds CWC22 directly through its C-terminal region, forming a
    heterodimer that sits in the Bact spliceosome and stabilizes eIF4A3
    binding; the protein binding term records that shown interaction. No
    peptidyl-prolyl isomerase activity term is bound, because the human
    cyclophilin domain lacks a conserved active-site residue and is described
    as catalytically inactive. Allele position predicts severity: C-terminal
    truncations such as p.Val335Serfs*13 cause retina-restricted disease, while
    earlier truncations cause the syndromic form.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CWC27
    term:
      id: hgnc:10664
      label: CWC27
  molecular_functions:
  - preferred_term: CWC22 binding
    term:
      id: GO:0005515
      label: protein binding
  cellular_components:
  - preferred_term: spliceosomal complex
    term:
      id: GO:0005681
      label: spliceosomal complex
  evidence:
  - reference: CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z
    reference_title: "CWC27 / metaphyseal chondrodysplasia-retinitis pigmentosa syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "This curation includes ten variants (five nonsense, three frameshift, and two disrupting splicing) that have collectively been reported in ten probands in four publications"
    explanation: The variant spectrum across reported probands.
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, the affected individuals in families 3 and 7 with a frameshift mutation (p.Val335Serfs∗13) in the C-terminal part of the protein have a milder phenotype, whereas affected individuals with earlier CWC27 protein truncations have craniofacial defects, brachydactyly, short stature, and neurological defects as common features."
    explanation: Genotype-phenotype correlation by truncation position.
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, qRT-PCR on the RNA of the two affected individuals from family 4 showed that the CWC27 mRNA quantity was reduced by only 33%–43% compared with a control subject"
    explanation: In patient fibroblasts, mutant CWC27 transcripts are only partly degraded.
  - reference: PMID:32329775
    reference_title: "Structural and functional insights into CWC27/CWC22 heterodimer linking the exon junction complex to spliceosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "By biochemical and structural approaches, we showed that the interaction between the two proteins is direct and mediated by the C-terminus of CWC27 and the MIF4G domain of CWC22."
    explanation: Direct CWC27-CWC22 binding, the basis of the protein binding term.
  - reference: PMID:32329775
    reference_title: "Structural and functional insights into CWC27/CWC22 heterodimer linking the exon junction complex to spliceosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CWC27 and CWC22 are bound together outside of the spliceosome before being integrated together in the Bact spliceosome in which the heterodimer forms a stable landing platform for eIF4A3."
    explanation: Places the heterodimer in the Bact spliceosome.
  - reference: PMID:25478830
    reference_title: "Structure and evolution of the spliceosomal peptidyl-prolyl cis-trans isomerase Cwc27."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "This analysis revealed the specific loss of a crucial active-site residue in higher eukaryotic Cwc27 proteins, suggesting that the protein evolved from a prolyl isomerase to a pure proline binder."
    explanation: Why no isomerase activity term is bound on this node.
  downstream:
  - target: Retinal Mis-Splicing With Intron Retention
    causal_link_type: DIRECT
  - target: Impaired Embryonic Growth and Craniofacial-Limb Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Retinal Mis-Splicing With Intron Retention
  conforms_to: "spliceosome_component_dysfunction#Mis-Splicing of a Sensitive Transcript Subset"
  description: >-
    Evidence comes from the Cwc27 K338fs/K338fs mouse retina, where bulk and
    single-cell RNA sequencing found altered splice-site usage and intron
    retention alongside gene expression changes, the first in vivo evidence that
    CWC27 acts as a splicing factor. In a human RPE cell line (hTERT RPE-1),
    CWC27 knock-down changed expression of many of the same genes as CWC22
    knock-down. Which mis-spliced transcripts explain photoreceptor loss is not
    established.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34726245
    reference_title: "Cwc27, associated with retinal degeneration, functions as a splicing factor in vivo."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Bulk RNA and single cell RNA-sequencing of the mouse retina showed that there were gene expression and splicing pattern changes, including alternative splice site usage and intron retention."
    explanation: Mis-splicing in the hypomorphic mouse retina.
  - reference: PMID:32329775
    reference_title: "Structural and functional insights into CWC27/CWC22 heterodimer linking the exon junction complex to spliceosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Knock-down of either CWC27 or CWC22 in immortalized retinal pigment epithelial cells affects numerous common genes, indicating that these proteins cooperate, targeting the same pathways."
    explanation: Gene expression changes after CWC27 depletion in human RPE cells.
  downstream:
  - target: Retinal Endoplasmic Reticulum Stress
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Photoreceptor Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Retinal Endoplasmic Reticulum Stress
  description: >-
    CHOP staining in the Cwc27 K338fs/K338fs mouse retina suggests ER stress
    follows the splicing changes. The authors propose it as a likely
    contributor; it has not been tested by blocking ER stress.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: response to endoplasmic reticulum stress
    term:
      id: GO:0034976
      label: response to endoplasmic reticulum stress
    modifier: INCREASED
  evidence:
  - reference: PMID:34726245
    reference_title: "Cwc27, associated with retinal degeneration, functions as a splicing factor in vivo."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Positive staining for CHOP suggests that ER stress may be activated in response to the splicing pattern changes and is a likely contributor to the disease mechanism."
    explanation: Proposed ER stress downstream of mis-splicing in mouse retina.
  downstream:
  - target: Photoreceptor Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Photoreceptor Degeneration
  conforms_to: "spliceosome_component_dysfunction#Failure of Splicing-Sensitive Cell Populations"
  description: >-
    Photoreceptors degenerate, with loss of the outer nuclear layer and outer
    segments in patients. In mice the evidence comes from the hypomorphic
    K338fs model, whose degeneration is driven mainly by photoreceptor death,
    includes cones, and is reduced by AAV8 delivery of Cwc27 to
    photoreceptors. Whether the retinal pigment epithelium fails independently
    has not been studied.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: rod photoreceptor
    term:
      id: CL:0000604
      label: retinal rod cell
  - preferred_term: cone photoreceptor
    term:
      id: CL:0000573
      label: retinal cone cell
  biological_processes:
  - preferred_term: photoreceptor cell maintenance
    term:
      id: GO:0045494
      label: photoreceptor cell maintenance
    modifier: DECREASED
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "OCT through the retinal fovea shows a loss of volume of the outer nuclear layer (photoreceptor nuclei) and complete absence of the photoreceptor outer segments throughout the field of view."
    explanation: Photoreceptor loss on OCT in a patient.
  - reference: PMID:37479075
    reference_title: "Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By 6 months of age, Cwc27 mutant mice show a retinal degenerative phenotype, including morphological and functional abnormalities, primarily driven by the death of photoreceptors."
    explanation: Photoreceptor death drives the mouse retinal phenotype.
  - reference: PMID:37479075
    reference_title: "Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Immunostaining analyses revealed a notable decrease in photoreceptor degeneration, including cone cell degeneration, in the AAV-injected eyes compared to the PBS-injected eyes."
    explanation: Restoring Cwc27 in photoreceptors reduces rod and cone degeneration.
  downstream:
  - target: Rod-cone dystrophy
  - target: Nyctalopia
  - target: Constriction of peripheral visual field
  - target: Attenuation of retinal blood vessels
  - target: Chorioretinal atrophy
- name: Impaired Embryonic Growth and Craniofacial-Limb Development
  description: >-
    Complete loss of Cwc27 in knockout mice (tm1b, tm1Lex) causes near-complete
    embryonic lethality, growth retardation, neural tube closure failure,
    absent limb buds and delayed digit separation. These are much more severe
    than the human syndrome but point to a developmental requirement for CWC27
    that the hypomorphic retinal mouse does not show. Whether mis-splicing in
    neural crest, limb or brain precursors is the operative step has not been
    shown, so this node is linked to the variant node without a mis-splicing
    intermediate, and the neurodevelopmental features are attached to it
    without a known mechanism.
  biological_scale: ORGANISM
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Specifically, at E12.5, we observed marked growth retardation, neural tube closure failure, and absence of limb buds in Cwc27tm1b/tm1b embryos with the most severe defects (Figure 3I)."
    explanation: Developmental defects in knockout embryos.
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These phenotypes, though much more severe than the human clinical manifestations, demonstrate the delayed growth as well as compromised craniofacial and limb development in the Cwc27 mutants."
    explanation: Authors relate the knockout defects to the human syndrome.
  downstream:
  - target: Brachydactyly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short stature
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Frontal bossing
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Micrognathia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Downslanted palpebral fissures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Low-set ears
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed ability to walk
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Rod-cone dystrophy
  category: Ophthalmological
  frequency: VERY_FREQUENT
  description: >-
    Retinitis pigmentosa in most patients; one child had Leber congenital
    amaurosis. Retinal degeneration was present in 9 of 10 patients in the
    founding series.
  phenotype_term:
    preferred_term: Retinitis pigmentosa
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a common phenotype in the majority of these affected individuals, consisting of retinal degeneration (9/10), brachydactyly (9/10), craniofacial defects (8/10), short stature (8/10), and neurological defects (8/10)."
    explanation: Retinal degeneration in 9 of 10 patients.
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our cohort, retinal defects include RP in most affected individuals"
    explanation: The retinal degeneration is retinitis pigmentosa in most patients.
- name: Nyctalopia
  category: Ophthalmological
  phenotype_term:
    preferred_term: Night blindness
    term:
      id: HP:0000662
      label: Nyctalopia
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with night blindness occurring at around 10 years of age, followed by restriction of visual fields"
    explanation: Night blindness from about age ten.
  - reference: PMID:38956876
    reference_title: "A novel small deletion in CWC27 gene associated with CWC27-related spliceosomeopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had poor vision, nyctalopia and nystagmus from childhood."
    explanation: Childhood nyctalopia in a further patient.
- name: Constriction of peripheral visual field
  category: Ophthalmological
  phenotype_term:
    preferred_term: Restriction of visual fields
    term:
      id: HP:0001133
      label: Constriction of peripheral visual field
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with night blindness occurring at around 10 years of age, followed by restriction of visual fields"
    explanation: Field constriction follows night blindness.
- name: Nystagmus
  category: Ophthalmological
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:38956876
    reference_title: "A novel small deletion in CWC27 gene associated with CWC27-related spliceosomeopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient had poor vision, nyctalopia and nystagmus from childhood."
    explanation: Nystagmus from childhood in a patient with early-onset disease.
- name: Attenuation of retinal blood vessels
  category: Ophthalmological
  phenotype_term:
    preferred_term: Thinning of the retinal vessels
    term:
      id: HP:0007843
      label: Attenuation of retinal blood vessels
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "For individual 5:II-1, funduscopy and fundus autofluorescence imaging show thinning of the retinal vessels and a reduced autofluorescence from the RPE layer consistent with outer retinal degeneration."
    explanation: Vessel attenuation on fundus imaging.
- name: Chorioretinal atrophy
  category: Ophthalmological
  phenotype_term:
    preferred_term: Chorioretinal atrophy
    term:
      id: HP:0000533
      label: Chorioretinal atrophy
  evidence:
  - reference: PMID:38956876
    reference_title: "A novel small deletion in CWC27 gene associated with CWC27-related spliceosomeopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fundoscopy revealed extensive chorioretinal atrophy with numerous scattered greyish pigmentation."
    explanation: Extensive chorioretinal atrophy in one patient.
- name: Cataract
  category: Ophthalmological
  phenotype_term:
    preferred_term: Cataract
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:31481716
    reference_title: "Expanding the clinical and molecular spectrum of the CWC27-related spliceosomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to hypergonadotropic hypogonadism, hypoplastic/agenesic teeth, and cataracts, not previously associated with such phenotypic spectrum"
    explanation: Cataracts in a single reported patient.
- name: Brachydactyly
  category: Skeletal
  frequency: VERY_FREQUENT
  description: Affects mainly the distal phalanges; present in 9 of 10 patients in the founding series.
  phenotype_term:
    preferred_term: Brachydactyly
    term:
      id: HP:0001156
      label: Brachydactyly
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a common phenotype in the majority of these affected individuals, consisting of retinal degeneration (9/10), brachydactyly (9/10), craniofacial defects (8/10), short stature (8/10), and neurological defects (8/10)."
    explanation: Brachydactyly in 9 of 10 patients.
  - reference: CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z
    reference_title: "CWC27 / metaphyseal chondrodysplasia-retinitis pigmentosa syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "brachydactyly (affects primarily the distal phalanges)"
    explanation: ClinGen summary of the digital involvement.
- name: Short stature
  category: Growth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Short stature
    term:
      id: HP:0004322
      label: Short stature
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We observed a common phenotype in the majority of these affected individuals, consisting of retinal degeneration (9/10), brachydactyly (9/10), craniofacial defects (8/10), short stature (8/10), and neurological defects (8/10)."
    explanation: Short stature in 8 of 10 patients.
- name: Frontal bossing
  category: Craniofacial
  phenotype_term:
    preferred_term: Frontal bossing
    term:
      id: HP:0002007
      label: Frontal bossing
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
    explanation: Listed among the craniofacial anomalies.
- name: Micrognathia
  category: Craniofacial
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
    explanation: Listed among the craniofacial anomalies.
- name: Downslanted palpebral fissures
  category: Craniofacial
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
    explanation: Listed among the craniofacial anomalies.
- name: Low-set ears
  category: Craniofacial
  phenotype_term:
    preferred_term: Large and low-set ears
    term:
      id: HP:0000369
      label: Low-set ears
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Craniofacial anomalies include frontal bossing, large columella, micrognathia, down-slanting palpebral fissures, large and low-set ears, and hypoplasia of nares."
    explanation: Listed among the craniofacial anomalies.
- name: Intellectual disability
  category: Neurological
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
    explanation: Intellectual disability among the neurological features, which were present in 8 of 10 patients.
- name: Delayed speech and language development
  category: Neurological
  phenotype_term:
    preferred_term: Speech delay
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
    explanation: Speech delay among the neurological features.
- name: Delayed ability to walk
  category: Neurological
  phenotype_term:
    preferred_term: Delayed walking
    term:
      id: HP:0031936
      label: Delayed ability to walk
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
    explanation: Delayed walking among the neurological features.
- name: Feeding difficulties
  category: Neurological
  phenotype_term:
    preferred_term: Feeding delay
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological features include delays in speech, feeding, and walking as well as intellectual disability."
    explanation: Feeding delay among the neurological features.
- name: Sparse scalp hair
  category: Dermatological
  phenotype_term:
    preferred_term: Sparse scalp hair
    term:
      id: HP:0002209
      label: Sparse scalp hair
  evidence:
  - reference: PMID:36718996
    reference_title: "Further delineation of the CWC27-associated spliceosomeopathy: Case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
    explanation: Sparse scalp hair proposed as a core ectodermal feature.
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Note the high frontal hairline, sparse hair, eyebrows, and eyelashes, low-set ears, and thick lips."
    explanation: Sparse hair in the two affected siblings of family 4.
- name: Sparse eyebrow
  category: Dermatological
  phenotype_term:
    preferred_term: Sparse eyebrows
    term:
      id: HP:0045075
      label: Sparse eyebrow
  evidence:
  - reference: PMID:36718996
    reference_title: "Further delineation of the CWC27-associated spliceosomeopathy: Case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
    explanation: Sparse eyebrows as part of the ectodermal phenotype.
  - reference: PMID:38956876
    reference_title: "A novel small deletion in CWC27 gene associated with CWC27-related spliceosomeopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "scant hair, absent eyebrows and thin eyelashes were documented"
    explanation: Absent eyebrows in a further patient, the severe end of the same feature.
- name: Sparse eyelashes
  category: Dermatological
  phenotype_term:
    preferred_term: Sparse eyelashes
    term:
      id: HP:0000653
      label: Sparse eyelashes
  evidence:
  - reference: PMID:36718996
    reference_title: "Further delineation of the CWC27-associated spliceosomeopathy: Case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
    explanation: Sparse eyelashes as part of the ectodermal phenotype.
- name: Nail dysplasia
  category: Dermatological
  phenotype_term:
    preferred_term: Nail dysplasia
    term:
      id: HP:0002164
      label: Nail dysplasia
  evidence:
  - reference: PMID:36718996
    reference_title: "Further delineation of the CWC27-associated spliceosomeopathy: Case report and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we highlight ectodermal involvement including sparse scalp hair, eyebrows and lashes, pigmentary differences, nail dysplasia, and dental anomalies as a core phenotype associated with the CWC27 spliceosomopathy"
    explanation: Nail dysplasia as part of the ectodermal phenotype.
- name: Ichthyosis
  category: Dermatological
  phenotype_term:
    preferred_term: Ichthyosis
    term:
      id: HP:0008064
      label: Ichthyosis
  evidence:
  - reference: PMID:28285769
    reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals 4:II-3 and 4:II-4 present extensive hair and skin problems including alopecia, absent eyebrows and eyelashes, ichthyosis, eczema, and keratosis."
    explanation: Ichthyosis in one family, reported as a family-specific feature.
- name: Cafe-au-lait spot
  category: Dermatological
  phenotype_term:
    preferred_term: Cafe-au-lait spots
    term:
      id: HP:0000957
      label: Cafe-au-lait spot
  evidence:
  - reference: PMID:38956876
    reference_title: "A novel small deletion in CWC27 gene associated with CWC27-related spliceosomeopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, craniofacial abnormalities, short statue, brachydactyly, dental anomalies, cafe-au-lait spots, scant hair, absent eyebrows and thin eyelashes were documented."
    explanation: Cafe-au-lait spots in a single patient.
- name: Hypodontia
  category: Dental
  phenotype_term:
    preferred_term: Hypoplastic or agenesic teeth
    term:
      id: HP:0000668
      label: Hypodontia
  evidence:
  - reference: PMID:31481716
    reference_title: "Expanding the clinical and molecular spectrum of the CWC27-related spliceosomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to hypergonadotropic hypogonadism, hypoplastic/agenesic teeth, and cataracts, not previously associated with such phenotypic spectrum"
    explanation: Missing teeth in a single patient; dental anomalies are reported in other patients without further detail.
- name: Hypergonadotropic hypogonadism
  category: Endocrine
  phenotype_term:
    preferred_term: Hypergonadotropic hypogonadism
    term:
      id: HP:0000815
      label: Hypergonadotropic hypogonadism
  evidence:
  - reference: PMID:31481716
    reference_title: "Expanding the clinical and molecular spectrum of the CWC27-related spliceosomopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "in addition to hypergonadotropic hypogonadism, hypoplastic/agenesic teeth, and cataracts, not previously associated with such phenotypic spectrum"
    explanation: Hypergonadotropic hypogonadism in a single woman.
genetic:
- name: CWC27
  gene_term:
    preferred_term: CWC27
    term:
      id: hgnc:10664
      label: CWC27
  association: >-
    Causative biallelic nonsense, frameshift and splice-site variants acting by
    loss of function.
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z
    evidence:
    - reference: CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z
      reference_title: "CWC27 / metaphyseal chondrodysplasia-retinitis pigmentosa syndrome (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CWC27 | HGNC:10664 | metaphyseal chondrodysplasia-retinitis pigmentosa syndrome | MONDO:0009598 | AR | Definitive"
      explanation: ClinGen gene-disease validity record classifying this pair as Definitive.
  evidence:
  - reference: CGGV:assertion_95089ec9-1b91-4ee0-a743-a780d123aad0-2025-07-03T160000.000Z
    reference_title: "CWC27 / metaphyseal chondrodysplasia-retinitis pigmentosa syndrome (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The mechanism of pathogenicity is reported to be loss-of-function."
    explanation: ClinGen states the disease mechanism.
  - reference: PMID:38134094
    reference_title: "Retinitis pigmentosa with or without skeletal abnormalities due to homozygous mutations in the CWC27 gene: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After testing the whole exome gene sequencing, the gene detection showed that the CWC27 gene was homozygous mutation, c.617(exon7)C>A (p.Ser206Ter)"
    explanation: A further homozygous truncating variant in a child with growth failure.
animal_models:
- name: Cwc27 K338fs hypomorphic mouse
  species: Mouse
  genotype: Cwc27(K338fs/K338fs), CRISPR-Cas9 frameshift in exon 11
  publication: PMID:28285769
  description: >-
    Carries a C-terminal frameshift close to the recurrent human
    p.Val335Serfs*13 allele. It is viable and develops late-onset retinal
    degeneration without extraocular disease, matching the retina-restricted
    human form.
  modeled_mechanisms:
  - target: Photoreceptor Degeneration
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Reproduces retinal dysfunction and outer retinal thinning, and its
      degeneration is reduced by AAV8 Cwc27 augmentation.
    limitations: >-
      The allele is hypomorphic and does not model the syndromic disease; mouse
      retina has no macula, and the mice were followed only to about six months.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The mouse retina is rod-dominated and lacks a macula, so cone-rich
        central retinal involvement seen in patients cannot be assessed.
    readouts:
    - name: Scotopic ERG a-wave and b-wave amplitude
      target: Photoreceptor Degeneration
      direction: DECREASED
      interpretation: Reduced photoreceptor and bipolar responses reflect the retinal dysfunction.
      evidence:
      - reference: PMID:28285769
        reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "ERG showed that the Cwc27K338fs/K338fs mice have about 50% reduction of a-wave and b-wave amplitudes compared with Cwc27K338fs/+ littermates, indicating a compromised retinal function (Figure 4B)."
        explanation: The measured ERG reduction.
    - name: Outer retina thickness
      target: Photoreceptor Degeneration
      direction: DECREASED
      interpretation: Outer retinal thinning is the histological correlate of photoreceptor loss.
      evidence:
      - reference: PMID:28285769
        reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "(C) H&E staining shows thinning of outer retina in Cwc27K338fs/K338fs mice at the age of 6 months, suggesting photoreceptor degeneration."
        explanation: Histology at six months.
    evidence:
    - reference: PMID:28285769
      reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In mice, disruption of exon 1 (tm1Lex) or exon 3 (tm1b) resulted in a wide range of developmental abnormalities with nearly complete embryonic lethality, while the mice with a homozygous frameshift mutation in exon 11 display a late-onset retinal degeneration phenotype."
      explanation: The exon 11 frameshift mouse models the retinal disease.
  - target: Retinal Mis-Splicing With Intron Retention
    relationship: MEASURES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: >-
      Retinal bulk and single-cell RNA sequencing reports splicing changes in
      this model.
    limitations: >-
      The splicing changes have not been compared with patient retina, and
      which changes cause photoreceptor death is not shown.
    readouts:
    - name: Retinal alternative splice-site usage and intron retention
      target: Retinal Mis-Splicing With Intron Retention
      direction: ALTERED
      interpretation: Splicing pattern changes in mutant retina.
      evidence:
      - reference: PMID:34726245
        reference_title: "Cwc27, associated with retinal degeneration, functions as a splicing factor in vivo."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Bulk RNA and single cell RNA-sequencing of the mouse retina showed that there were gene expression and splicing pattern changes, including alternative splice site usage and intron retention."
        explanation: The measured splicing changes.
- name: Cwc27 tm1b knockout mouse
  species: Mouse
  genotype: Cwc27(tm1b/tm1b), exon 3 deletion (KOMP)
  publication: PMID:28285769
  description: >-
    A null allele with near-complete pre-weaning lethality. Surviving and
    embryonic homozygotes show growth retardation, dystrophic photoreceptors,
    neural tube closure failure, limb bud and digit defects.
  modeled_mechanisms:
  - target: Impaired Embryonic Growth and Craniofacial-Limb Development
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: >-
      Shows a developmental requirement for Cwc27 in growth and in
      craniofacial and limb development.
    limitations: >-
      The null phenotype is far more severe than the human syndrome, whose
      truncating alleles escape complete nonsense-mediated decay and may retain
      residual function; neural tube defects and exencephaly are not human
      features.
    evidence:
    - reference: PMID:28285769
      reference_title: "Mutations in the Spliceosome Component CWC27 Cause Retinal Degeneration with or without Additional Developmental Anomalies."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These phenotypes, though much more severe than the human clinical manifestations, demonstrate the delayed growth as well as compromised craniofacial and limb development in the Cwc27 mutants."
      explanation: The authors' own statement of fidelity and its limit.
treatments:
- name: Genetic Counseling
  description: >-
    Counseling for an autosomal recessive disorder with 25 percent recurrence
    risk for carrier parents.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
discussions:
- discussion_id: cwc27_gene_augmentation_human_translation
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Photoreceptor Degeneration
  prompt: >-
    Would AAV gene augmentation of CWC27 in photoreceptors, which reduces
    degeneration in the hypomorphic K338fs mouse, help patients with the
    retina-restricted or syndromic disease?
  rationale: >-
    The rescue was shown only in a hypomorphic mouse allele with late-onset
    degeneration, while most patients carry earlier truncations and many have
    systemic disease. Whether human photoreceptors are still present at the
    age of diagnosis, and whether the truncated proteins interfere with the
    transgene, are untested.
  evidence:
  - reference: PMID:37479075
    reference_title: "Gene augmentation therapy to rescue degenerative photoreceptors in a Cwc27 mutant mouse model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In this study, we demonstrated that subretinal injection of AAV8-GRK-Cwc27-FLAG in mutant mice can improve the functionality and morphology of the retina."
    explanation: The mouse rescue result whose human relevance is open.
notes: >-
  MONDO names this disease metaphyseal chondrodysplasia-retinitis pigmentosa
  syndrome after the historical OMIM title; ClinGen lumps isolated and
  syndromic CWC27 cases under one disease because the mechanism and
  inheritance do not differ, and this entry does the same. Metaphyseal
  chondrodysplasia itself is not described in the CWC27 reports used here, so
  it is not curated as a phenotype.