Axial Spondylometaphyseal Dysplasia

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Inheritance

1

Autosomal Recessive HP:0000007

Biallelic variants in either CFAP410 or NEK1, by homozygosity or compound heterozygosity, with segregation confirmed in the reported families.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:26974433 SUPPORT Human Clinical

"Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy."

States the mode of inheritance and, in the same sentence, the two-tissue definition of the entity.

PMID:21910225 SUPPORT Human Clinical

"Equally affected sibling pairs of opposite gender and parental consanguinity are strongly suggestive of autosomal recessive inheritance."

The segregation evidence that supported the recessive assignment before either gene was known.

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Discussions and Knowledge Gaps

4

Which ciliary signalling pathway actually fails in the axial SMD growth plate, and has any of it been measured in this disease?

KNOWLEDGE GAP ciliary_signalling_unmeasured_in_chondrocytes

Attached to

pathophysiology#Altered Chondrocyte Marker Expression pathophysiology#Defective Primary Ciliogenesis

The step from defective ciliogenesis to the skeletal lesion is the weakest link in this pathograph and the entry marks the edge INDIRECT_UNKNOWN_INTERMEDIATES for that reason. In other skeletal ciliopathies the mechanism is impaired Hedgehog transduction through failed ciliary translocation of GLI transcription factors, and that is a reasonable expectation here, but no Hedgehog readout, no GLI localization, and no growth-plate histology has been reported in an axial SMD patient or model. The only chondrocyte-level datum is a functional result described by its own authors as suggesting involvement in cartilage differentiation. Until a signalling readout is measured, the skeletal arm rests on analogy.

Does the homologous-recombination defect contribute to the skeletal or retinal phenotype, or is it a parallel consequence of losing the same complex?

KNOWLEDGE GAP dna_repair_arm_contribution

Attached to

pathophysiology#Impaired Homologous Recombination Repair

The CFAP410-NEK1 complex has two demonstrated functions and this disease could in principle be caused by either. The repair arm is modelled here as a node with no downstream edge, which is deliberate: nothing published connects it to a tissue phenotype in axial SMD. The reason it is not simply omitted is that the same complex is implicated in amyotrophic lateral sclerosis, where the DNA repair function is the favoured mechanism, so which arm matters may be tissue-dependent rather than settled.

Why are ribs, vertebrae and proximal femora prominently affected when CFAP410 and NEK1 participate broadly in ciliary biology?

KNOWLEDGE GAP axial_restriction_unexplained

Attached to

pathophysiology#Axial Metaphyseal and Vertebral Dysplasia

The distribution is characteristic but not absolute: the 2016 series also recorded metacarpal metaphyseal abnormalities and one patient with other long-bone involvement. Tissue-specific requirements and modifiers remain hypotheses.

Why does CFAP410 disruption strongly impair ciliation in mammalian epithelial cells but produce a much smaller effect on algal flagella?

KNOWLEDGE GAP species_dependent_ciliogenesis_requirement

Attached to

pathophysiology#Defective Primary Ciliogenesis

The 2023 mammalian knockout and 2025 algal knockout studies differ in organism, cilium type and assay conditions. The algal report also differs internally between numerical reductions in Results and a lack of significance in Discussion. Cell-cycle effects and compensation remain hypotheses.

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Pathophysiology

10

Biallelic CFAP410 or NEK1 Loss of Function

Biallelic CFAP410 variants include missense and splice-altering alleles. A NEK1-associated patient carried the nonsense variant p.Ser1036Ter and missense variant p.Asp1277Ala. Functional effects depend on the allele: the NEK1 variants markedly reduce association with CFAP410, whereas CFAP410 p.Arg73Pro weakens this association and has been characterized as hypomorphic. Complete absence of either protein is not established for every patient genotype.

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Downstream

Disruption of the CFAP410-NEK1 Complex Demonstrated for the tested NEK1 p.Ser1036Ter/p.Asp1277Ala and CFAP410 p.Arg73Pro variants; not a universal functional assignment to every disease-associated allele.

Reduced Stability of Selected CFAP410 Variants

Show evidence (3 references)

PMID:26974433 SUPPORT Human Clinical

"We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds."

The allelic series establishing CFAP410 as the first disease gene.

PMID:28123176 SUPPORT Human Clinical

"By whole-exome sequencing in a patient with axial SMD, we identified compound heterozygous mutations of NEK1, c.3107C>G (p.S1036*) and c.3830A>C (p.D1277A), which co-segregated in the family."

The second locus, with family segregation.

PMID:40246852 SUPPORT Human Clinical

"Patients with the most severe ophthalmic and skeletal phenotypes had disease-associated variants within conserved leucine-rich regions of CFAP410"

Genotype-phenotype correlation locating severity in the domain that mediates the NEK1 interaction, which is why the next node is the complex rather than either protein alone.

Reduced Stability of Selected CFAP410 Variants

CFAP410 p.Tyr107His and p.Pro116Leu have shorter protein half-lives and increased ubiquitination in transfected HEK293T cells. MG132 increased mutant protein stability. The result is allele- and model-specific: it does not establish universal CFAP410 degradation or the mechanism of reduced CFAP410 abundance after NEK1 knockout.

Experimental models

HEK293T CFAP410 p.Tyr107His and p.Pro116Leu expression CELL LINE

Downstream

Defective Primary Ciliogenesis Reduced protein abundance is a plausible contributor, but the protein-turnover study did not directly measure ciliary assembly for these two alleles.

Show evidence (2 references)

PMID:37901396 SUPPORT In Vitro

"Western blot showed that the half-life of CFAP410 protein carrying the Y107H variant and P116 L variant was significantly shorter compared with the wild-type protein, indicating that both pathogenic variants impaired the stability of CFAP410 protein (Figure 7B)."

Cycloheximide chase in transfected HEK293T cells; both alleles were previously reported together in axial SMD, while this study patient had isolated retinal dystrophy.

PMID:37901396 SUPPORT In Vitro

"We found that the ubiquitination levels of P116L and Y107H proteins were significantly increased compared to the wild-type CFAP410 proteins (Figure 7D)."

Supports increased ubiquitination of these two variants in the cell-line assay.

Disruption of the CFAP410-NEK1 Complex

Endogenous CFAP410 associates tightly with NEK1 in ARPE-19 cells. The NEK1 C-terminal region spanning residues 1160-1286 is necessary and sufficient for association in cellular assays. AlphaFold predicts an interface with the CFAP410 N-terminal leucine-rich repeat region, supported by mutagenesis, but direct binding of purified proteins was not demonstrated. Tested disease-associated variants reduce association to different degrees. In NEK1-knockout cells, both wild-type and kinase-dead NEK1 restored CFAP410 abundance, whereas association-defective variants did not; kinase activity and complex-dependent abundance are therefore separable requirements.

CFAP410 binding to the NEK1 C-terminal interaction domain GO:0019901 ⇓ LOSS OF FUNCTION

Experimental models

ARPE-19 CFAP410 and NEK1 knockout-rescue cells CELL LINE

Purified CFAP410 C-terminal-domain assembly OTHER

Trypanosome CFAP410 N-terminal domain and localization OTHER

Downstream

Defective Primary Ciliogenesis

Impaired Homologous Recombination Repair Depletion of either partner reduces homologous recombination, but the effect of specific association-defective axial SMD alleles on repair was not tested.

Show evidence (3 references)

PMID:37188479 SUPPORT In Vitro

"These observations suggest but do not prove that the interaction is direct."

Co-immunoprecipitation, mass spectrometry, modeling and mutagenesis support a complex without establishing purified-protein direct binding.

PMID:37188479 SUPPORT In Vitro

"We noticed that both NEK1–WT and NEK1–KD restored C21ORF2 expression level back to normal in NEK1–KO cells (Fig S7B)."

Kinase-dead NEK1 rescued CFAP410 abundance; loss of NEK1-mediated phosphorylation must not be treated as the demonstrated explanation for reduced abundance in this experiment.

PMID:37188479 SUPPORT In Vitro

"However, the NEK1 mutants which weakened association with C21ORF2 did not rescue C21ORF2 expression, consistent with the possibility that complex formation regulates C21ORF2 stability (Fig S7B)."

Supports an association-dependent contribution to CFAP410 abundance; turnover mechanisms remain unresolved.

Defective Primary Ciliogenesis

NEK1 or CFAP410 knockout markedly reduces the proportion of ciliated ARPE-19 cells after serum starvation. Wild-type re-expression rescues ciliogenesis, whereas kinase-dead NEK1 and the association-defective NEK1 p.Asp1277Ala allele do not. These epithelial-cell experiments establish a ciliary function but do not directly assay an axial SMD growth plate or patient photoreceptor.

primary cilium assembly GO:0060271 ↓ DECREASED

Experimental models

ARPE-19 CFAP410 and NEK1 knockout-rescue cells CELL LINE

mIMCD3 CFAP410 knockdown and allele rescue CELL LINE

Chlamydomonas CFAP410 knockout OTHER

Animal models

nek1 zebrafish morpholino with human CFAP410 rescue Zebrafish partially recapitulates

Downstream

Photoreceptor Connecting Cilium Dysfunction The proteins participate in ciliogenesis and CFAP410 localizes to photoreceptor ciliary structures; localization alone does not demonstrate connecting-cilium failure in a patient.

Altered Chondrocyte Marker Expression An inferred connection: CFAP410 knockdown alters cartilage-marker expression in a chondrosarcoma cell line, but neither ciliary signaling nor patient growth-plate differentiation was measured.

Show evidence (3 references)

PMID:26167768 SUPPORT In Vitro

"Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants."

An unbiased genome-wide screen, not a candidate-gene experiment, placing the protein in the ciliary machinery and connecting that to the two affected tissues.

PMID:26974433 SUPPORT Human Clinical

"Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina."

The classification of the disease as a ciliopathy by the group that identified its first gene.

PMID:37188479 SUPPORT In Vitro

"As shown in Fig 5D and E, the proportion of NEK1–KO and C21ORF2–KO cells bearing primary cilia was reduced dramatically compared with parental cells."

Loss of either gene impairs primary ciliogenesis in ARPE-19 cells.

Impaired Homologous Recombination Repair

Depletion of CFAP410 or NEK1 reduces homologous recombination in U2-O-S traffic-light and DR-GFP reporter assays. CFAP410 depletion had little effect on cell-cycle distribution, arguing against a cell-cycle explanation for its repair phenotype. Whether this repair defect contributes to skeletal dysplasia or retinal degeneration in axial SMD remains untested.

double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED

Experimental models

U2-O-S homologous-recombination reporters CELL LINE

Show evidence (1 reference)

PMID:37188479 SUPPORT In Vitro

"Depletion of NEK1 and C21ORF2 resulted in a dramatic reduction in HR efficiency, similar in effect size to depletion of BRCA1."

Direct result from a cell-based homologous-recombination reporter assay; not a demonstration of DNA damage in patient tissues.

Photoreceptor Connecting Cilium Dysfunction

CFAP410 localizes to the connecting cilium and basal-body structures of photoreceptors. This supports a ciliary site of disease action, but patient photoreceptor transport failure was not measured in the cited studies. Reduced stability of selected variants was demonstrated separately in transfected HEK293T cells, not in patient photoreceptors.

retinal cone cell CL:0000573 retinal rod cell CL:0000604

Animal models

Mouse retinal CFAP410 reporter localization Mouse measures

Downstream

Progressive Photoreceptor Degeneration

Show evidence (1 reference)

PMID:26974433 SUPPORT INDIRECT Model Organism

"C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function."

AAV reporter and fusion-protein localization in mouse retina supports the ciliary site of action; this was not a patient-cell dysfunction or treatment-rescue experiment.

Progressive Photoreceptor Degeneration

Retinal dysfunction and visual loss can begin early and progress. Fundoscopic retinitis pigmentosa and electroretinographic cone-rod dysfunction are both described in axial SMD; fundoscopic pigmentation does not independently establish a rod-first disease sequence. The relative cone-rod and rod-cone frequencies in a broader CFAP410 ophthalmic cohort cannot be transferred to axial SMD.

photoreceptor cell CL:0000210

Downstream

Retinal dystrophy

Reduced visual acuity

Cone-rod dystrophy

Pigmentary retinopathy

Photophobia

Show evidence (3 references)

PMID:40246852 SUPPORT Human Clinical

"A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy."

The pattern mix in 49 patients ascertained through ophthalmic genetics centres. Note this is not directly comparable with the axial SMD series below, where the two labels describe the same eyes on different tests.

PMID:21910225 SUPPORT Human Clinical

"Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram."

The modality distinction. This is the sentence that stops the two phenotype records below being read as competing frequencies.

PMID:21910225 SUPPORT Human Clinical

"Impaired visual acuity comes to medical attention in early life and function rapidly deteriorates."

Onset and rate of the visual loss in the clinically defined series.

Altered Chondrocyte Marker Expression

CFAP410 knockdown in OUMS-27 human chondrosarcoma cells reduces expression of chondrocyte marker genes, suggesting a role in maintaining the differentiated chondrocyte phenotype. In a separate mouse ATDC5 differentiation time course, Cfap410 transcript abundance decreased while cartilage markers increased. Neither experiment establishes failure of growth-plate differentiation in patients or identifies the intervening ciliary signal.

Experimental models

OUMS-27 CFAP410 knockdown CELL LINE

ATDC5 chondrogenic differentiation time course CELL LINE

Downstream

Axial Metaphyseal and Vertebral Dysplasia The link from altered marker expression in cultured cells to axial skeletal abnormalities in patients remains inferred.

Show evidence (2 references)

PMID:26974433 SUPPORT In Vitro

"Knock-down of C21orf2 caused significant decreases in expression of chondrocyte marker genes (Fig 5)."

Perturbation in OUMS-27 cells supports altered maintenance of cartilage-marker expression, not a direct growth-plate histopathology finding.

PMID:26974433 SUPPORT In Vitro

"While the expression of cartilage marker genes (Col2a1, Agc1 and Col10a1) was increased by the cartilage induction, 1810043G02Rik expression was continuously suppressed during cartilage differentiation (Fig 4)."

The ATDC5 time course is an expression association, not a loss-of-function differentiation experiment.

Axial Metaphyseal and Vertebral Dysplasia

The characteristic radiographic distribution includes ribs, vertebrae, iliac wings and proximal femora, with variable involvement of other bones. Femoral-neck shortening and coxa vara can progress with age; a uniformly static adult course has not been established.

Downstream

Thoracic Constriction and Restrictive Ventilation

Metaphyseal dysplasia

Platyspondyly

Anterior rib cupping

Abnormal ilium morphology

Coxa vara

Scoliosis

Flattened femoral head

Short stature

Rhizomelia

Disproportionate short-trunk short stature

Short ribs

Short femoral neck

Metacarpal metaphyseal dysplasia

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora."

The skeletal phenotype in the genotyped cohort.

Thoracic Constriction and Restrictive Ventilation

A narrow thorax and short ribs can restrict lung expansion and contribute to neonatal respiratory problems. The clinical reports infer this mechanical relationship; they do not provide formal pulmonary-function measurements establishing restrictive physiology in every patient.

Downstream

Neonatal respiratory distress

Recurrent respiratory infections

Thoracic hypoplasia

Show evidence (2 references)

PMID:9266195 SUPPORT Human Clinical

"We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings."

The original description, which names the small thorax as a defining feature. It reports the anatomy, not the ventilatory consequence.

PMID:21910225 SUPPORT Human Clinical

"The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection."

The ventilatory consequence the 1997 description did not supply: thoracic hypoplasia causing neonatal respiratory problems and later airway infection, in seven patients from five families.

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Pathograph

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Phenotypes

24

Eye 7

Retinal dystrophy 13/13 HP:0000556

Course: PROGRESSIVE

Observed in 13/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (2 references)

PMID:26974433 SUPPORT Human Clinical

"Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy."

Retinal dystrophy is part of the definition of the disease, not an occasional association.

PMID:23371363 SUPPORT Human Clinical

"Notably, although the patient reported here was closely followed for color blindness, nystagmus, and amblyopia since the age of 2 years, clinically apparent retinal changes were identified only at 16 years of age, leading to the clinical diagnosis."

A longitudinal case shows that early visual symptoms may precede recognizable retinal degeneration.

Cone-rod dystrophy Cone/cone-rod dystrophy HP:0000548

Show evidence (1 reference)

PMID:40246852 SUPPORT Human Clinical

"A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy."

The 49-person cohort was selected for CFAP410 retinal disease and includes patients without skeletal dysplasia; this does not estimate the frequency within axial SMD.

Pigmentary retinopathy HP:0000580

Show evidence (2 references)

PMID:9266195 SUPPORT Human Clinical

"Retinitis pigmentosa and optic atrophy are associated findings."

The original clinical description reports retinitis pigmentosa; this does not independently demonstrate a rod-first electrophysiologic sequence.

PMID:21910225 SUPPORT Human Clinical

"Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram."

The source distinguishes the fundoscopic diagnosis from the electroretinographic cone-rod pattern; these observations should not be counted as mutually exclusive physiologic subtypes.

Reduced visual acuity HP:0007663

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"In all patients, impaired visual acuity came to medical attention in early life, and retinal function deteriorated rapidly."

Early visual impairment in the 13-person clinical series.

Photophobia HP:0000613

Documented in P6 in the 2016 axial SMD series and common in the broader 2025 CFAP410 ophthalmic cohort. The latter is not an axial SMD frequency denominator.

Show evidence (1 reference)

PMID:40246852 SUPPORT Human Clinical

"Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation."

Named as a common feature, and consistent with the cone-predominant pattern.

Optic atrophy 2/13 HP:0000648

Observed in 2/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:9266195 SUPPORT Human Clinical

"Retinitis pigmentosa and optic atrophy are associated findings."

Optic atrophy was described in the original cases and in two individuals in Table 1 of the 2016 series.

Nystagmus 3/13 HP:0000639

Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.

Show evidence (1 reference)

PMID:23371363 SUPPORT Human Clinical

"Color blindness and nystagmus with amblyopia were noted on ophthalmologic examination at the age of 10 years and endocrinology investigation was normal."

The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.

Immune 1

Recurrent respiratory infections HP:0002205

Show evidence (1 reference)

PMID:21910225 SUPPORT Human Clinical

"The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection."

The same sentence records the later airway-infection susceptibility as a separate consequence of the same thoracic constraint.

Limbs 4

Metaphyseal dysplasia 10/13 HP:0100255

Proximal femoral metaphyseal dysplasia was recorded in 10/13 clinically selected axial SMD patients in Table 1 of PMID:26974433.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora."

Names metaphyseal dysplasia of the proximal femora in the genotyped cohort.

Coxa vara 7/13 HP:0002812

Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"Shortening of the femoral neck was often progressive, resulting mild coxa vara in older patients."

The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.

Flattened femoral head 10/12 HP:0008812

Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"| coxa vara | – | – | – | + | + | + | + | – | – | – | + | + | + | | flattening of femoral head | + | + | NA * | + | + | – | – | + | + | + | + | + | + |"

The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.

Short femoral neck HP:0100864

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"Shortening of the femoral neck was often progressive, resulting mild coxa vara in older patients."

Clinical and radiographic findings in the axial SMD series.

Musculoskeletal 6

Platyspondyly 7/13 HP:0000926

Severity: MILD

Observed in 7/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:9266195 SUPPORT Human Clinical

"We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings."

The original description records the platyspondyly as mild, which is why the severity qualifier is set.

Anterior rib cupping 10/11 HP:0000907

Observed in 10/11 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora."

Names the rib finding in the genotyped cohort.

Abnormal ilium morphology 8/10 Abnormal iliac wing morphology HP:0011867

Observed in 8/10 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:9266195 SUPPORT Human Clinical

"We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings."

The lacy iliac wings as originally described. HPO has no term for the lacy appearance itself, so the iliac wing morphology term is bound and the specificity is carried in preferred_term.

Thoracic hypoplasia HP:0005257

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"Thoracic hypoplasia, due to severe shortening of the ribs, was also observed in all patients."

The clinical narrative describes all 13 patients; the table marks two as equivocal. No unqualified universal frequency is assigned.

Scoliosis 3/13 HP:0002650

Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"He had mild scoliosis, but platyspondyly is not evident."

The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.

Short ribs 11/11 HP:0000773

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"Thoracic hypoplasia, due to severe shortening of the ribs, was also observed in all patients."

Clinical and radiographic findings in the axial SMD series.

Respiratory 1

Neonatal respiratory distress 4/11 HP:0002643

Observed in 4/11 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:21910225 SUPPORT Human Clinical

"The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection."

Names the neonatal respiratory problems and attributes them to the thoracic hypoplasia, which is the mechanism this entry models.

Growth 4

Short stature 13/13 HP:0004322

Observed in 13/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"The common clinical findings among the patients include 1) mild postnatal growth failure, 2) severe thoracic deformity (S1 Fig), 3) impaired visual acuity and retinal dystrophy (diagnosed as retinitis pigmentosa or cone-rod dystrophy)."

Clinical series; Table 1 records growth delay/short stature in all 13 individuals.

Postnatal growth retardation HP:0008897

Show evidence (1 reference)

PMID:21910225 SUPPORT Human Clinical

"The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection."

Growth failure is postnatal, which matters: it separates this from the skeletal dysplasias that are short at birth.

Rhizomelia 9/11 HP:0008905

Onset: CHILDHOOD

Observed in 9/11 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:21910225 SUPPORT Human Clinical

"The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection."

The early-childhood proportion. Curated separately from the short-trunk phenotype below because the source describes one evolving into the other.

Disproportionate short-trunk short stature 4/13 HP:0003521

Observed in 4/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.

Show evidence (1 reference)

PMID:21910225 SUPPORT Human Clinical

"The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection."

The later proportion. Recorded as a distinct phenotype from the rhizomelia because the change over time is itself the observation.

Other 1

Metacarpal metaphyseal dysplasia 4/11

Table 1 of the 2016 series: four positive, seven negative and two unavailable assessments. Needs a specific HPO term; metaphyseal cupping is narrower than the reported dysplasia and was not assigned.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"| metaphyseal dysplasia of | | | | | | | | | | | | | | | – proximal femur | + | + | + | + | + | + | + | + | + | + | – | – | – | | – other long bones | – | – | – | – | – | – | + | NA | – | – | NA | NA | NA | | – metacarpal | + | + | – | – | – | – | + | – | – | + | NA | NA | – |"

The metacarpal row records four affected individuals; the preceding row labels identify these as metaphyseal findings.

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Genetic Associations

2

CFAP410 (Causative)

Gene: CFAP410 hgnc:1260 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:26974433 SUPPORT Human Clinical

"We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD."

The gene-disease assignment.

PMID:40246852 SUPPORT Human Clinical

"A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX)."

The abstract labels 11/49 as consistent with axial SMD; the full text and Supplementary Table 2 document heterogeneous skeletal findings and incomplete skeletal assessment. This ascertainment-dependent proportion is not population penetrance.

NEK1 (Causative)

Gene: NEK1 hgnc:7744 relationship_type: CAUSATIVE

Show evidence (3 references)

PMID:28123176 SUPPORT Human Clinical

"In this study, we identified NEK1 as the second disease gene for axial SMD."

The gene-disease assignment for the second locus.

PMID:28123176 SUPPORT Human Clinical

"NEK1 mutations have previously been found in three types of short rib thoracic dystrophy, which have no retinal dystrophy."

The differential within the NEK1 disorders, and the reason retinal involvement is diagnostically load-bearing here.

PMID:26974433 SUPPORT Human Clinical

"Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD."

The CFAP410-negative families supported genetic heterogeneity in 2016, before NEK1 was identified; they do not prove that testing both currently known genes leaves these same cases unexplained.

🔬

Variants

7

CFAP410 c.218G>C (p.Arg73Pro)

Gene: CFAP410 hgnc:1260

Homozygous in families F8 and F9; functional assays show residual ciliogenesis rescue and reduced NEK1 association. Skeletal expression is variable even in homozygotes.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"The 12 mutant alleles were counted as five different mutations, including three exonic mutations (c.218G>C, c.319T>C and c.347C>T, S5 Fig; NM_004928), and two intronic mutations (c.545+1G>A and c.643-23A>T)."

Distinct CFAP410 alleles identified in the axial SMD families.

CFAP410 c.319T>C (p.Tyr107His)

Gene: CFAP410 hgnc:1260

In trans with p.Pro116Leu in the founding axial SMD family F5. The same genotype was later reported in a child without skeletal abnormalities; HEK293T assays show reduced protein stability.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"The 12 mutant alleles were counted as five different mutations, including three exonic mutations (c.218G>C, c.319T>C and c.347C>T, S5 Fig; NM_004928), and two intronic mutations (c.545+1G>A and c.643-23A>T)."

Distinct CFAP410 alleles identified in the axial SMD families.

CFAP410 c.347C>T (p.Pro116Leu)

Gene: CFAP410 hgnc:1260

In trans with p.Tyr107His in axial SMD family F5. The 2023 retinal study classifies this allele as likely pathogenic in its detailed assessment and demonstrates reduced stability in HEK293T cells.

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"The 12 mutant alleles were counted as five different mutations, including three exonic mutations (c.218G>C, c.319T>C and c.347C>T, S5 Fig; NM_004928), and two intronic mutations (c.545+1G>A and c.643-23A>T)."

Distinct CFAP410 alleles identified in the axial SMD families.

CFAP410 c.643-23A>T

Gene: CFAP410 hgnc:1260

Intronic branch-point candidate in families F1 and F7. Patient RNA demonstrates retention of the entire intron 6, altering the reading frame and predicting an elongated p.Asn215ValfsTer259 product lacking the normal conserved C terminus. Protein abundance and production of the elongated product were not directly measured.

Show evidence (2 references)

PMID:26974433 SUPPORT Human Clinical

"The 12 mutant alleles were counted as five different mutations, including three exonic mutations (c.218G>C, c.319T>C and c.347C>T, S5 Fig; NM_004928), and two intronic mutations (c.545+1G>A and c.643-23A>T)."

Distinct CFAP410 alleles identified in the axial SMD families.

PMID:26974433 SUPPORT Human Clinical

"Direct sequencing of the PCR product identified that entire intron 6 remained in the mutant mRNA, which led to a frame shift and produced an elongated protein (p.N215Vfs*259) without the C-terminal conserved region."

Patient RNA confirms intron retention; the protein consequence follows from the transcript sequence.

CFAP410 c.545+1G>A

Gene: CFAP410 hgnc:1260

Canonical splice-donor variant in family F6. Patient RNA demonstrates cryptic donor use, a five-base deletion at the exon 5 end, and partial or complete intron 5 retention. The transcripts predict p.Ala181GlnfsTer6 or p.Ser183Ter; nonsense-mediated decay was predicted, not experimentally measured.

Show evidence (2 references)

PMID:26974433 SUPPORT Human Clinical

"The 12 mutant alleles were counted as five different mutations, including three exonic mutations (c.218G>C, c.319T>C and c.347C>T, S5 Fig; NM_004928), and two intronic mutations (c.545+1G>A and c.643-23A>T)."

Distinct CFAP410 alleles identified in the axial SMD families.

PMID:26974433 SUPPORT Human Clinical

"Sequencing results showed that several cryptic donor sites in exon 5 and intron 5 were utilized in the mutant genome, and were responsible for the multiple bands in the RT-PCR (Fig 2C)."

Patient transcript analysis directly demonstrates aberrant splicing.

NEK1 c.3107C>G (p.Ser1036Ter)

Gene: NEK1 hgnc:7744

One allele of the reported compound-heterozygous axial SMD genotype. Cellular assays show markedly reduced CFAP410 association; protein-level consequences should not be assumed identical to complete NEK1 knockout.

Show evidence (1 reference)

PMID:28123176 SUPPORT Human Clinical

"By whole-exome sequencing in a patient with axial SMD, we identified compound heterozygous mutations of NEK1, c.3107C>G (p.S1036*) and c.3830A>C (p.D1277A), which co-segregated in the family."

Both alleles co-segregated in the reported family.

NEK1 c.3830A>C (p.Asp1277Ala)

Gene: NEK1 hgnc:7744

One allele of the reported compound-heterozygous axial SMD genotype. Cellular assays show markedly reduced CFAP410 association; protein-level consequences should not be assumed identical to complete NEK1 knockout.

Show evidence (1 reference)

PMID:28123176 SUPPORT Human Clinical

"By whole-exome sequencing in a patient with axial SMD, we identified compound heterozygous mutations of NEK1, c.3107C>G (p.S1036*) and c.3830A>C (p.D1277A), which co-segregated in the family."

Both alleles co-segregated in the reported family.

💊

Medical Actions

4

Respiratory surveillance and supportive care

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Respiratory assessment and supportive care address the consequences of thoracic hypoplasia. The clinical series documents respiratory risk but does not test a standardized surveillance or treatment protocol.

Mechanism Target:

Thoracic Constriction and Restrictive Ventilation — Addresses the consequence of the thoracic constriction rather than the constriction itself.

Show evidence (1 reference)

PMID:21910225 SUPPORT INDIRECT Human Clinical

"The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection."

Establishes that there is something to survey for - neonatal respiratory problems and later airway-infection susceptibility - which is what makes respiratory surveillance indicated. It does not evaluate an intervention. Graded INDIRECT because the claim follows from the quoted risk by an inference step rather than being asserted: the sentence states the hazard, not that surveillance for it is beneficial.

Low-vision rehabilitation and ophthalmic surveillance

Action: low-vision rehabilitation Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Low-vision aids, assistive technology and social support are described for CFAP410-related retinal disease. Their use in axial SMD is extrapolated from the shared retinal manifestation.

Target Phenotypes: Reduced visual acuity HP:0007663

Show evidence (1 reference)

PMID:39232248 SUPPORT INDIRECT REVIEW SYNTHESIS Human Clinical

"Management is conservative and includes appropriate support including low visual aids, assistive technology, social services and support societies as required."

Management described for CFAP410-associated cone dystrophy without diagnosed axial SMD; supports extrapolation to visual impairment, not a disease-specific efficacy trial.

Genetic counseling

Action: Genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Counseling should address autosomal recessive inheritance and variable skeletal involvement. When both parents are confirmed heterozygous carriers, each pregnancy has a 25% probability of inheriting both variants; this does not predict the severity or presence of the skeletal phenotype.

Show evidence (2 references)

PMID:40246852 SUPPORT Human Clinical

"A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX)."

Skeletal findings vary in an ophthalmically selected CFAP410 cohort; this is evidence for variable expressivity, not the recurrence-risk calculation.

PMID:39232248 SUPPORT Human Clinical

"The patient was referred for genetic counselling and continues to be monitored."

Documents genetic counseling in CFAP410 retinal disease; the Mendelian recurrence calculation follows from confirmed parental carrier status.

Chest expansion surgery

Action: chest expansion surgery Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Early chest expansion surgery corrected pectus excavatum and a narrow thorax in one patient with CFAP410-associated retinal and skeletal disease. This is a reported intervention, not evidence of a general surgical indication or comparative efficacy.

Target Phenotypes: Thoracic hypoplasia HP:0005257

Show evidence (1 reference)

PMID:40246852 SUPPORT Human Clinical

"Patient 7 was born with pectus excavatum and narrow thorax corrected with early chest expansion surgery."

Single treated patient in the broader CFAP410 series; the report does not provide a controlled respiratory outcome.

🔬

Diagnosis

3

Skeletal survey

A skeletal radiographic survey evaluates the combination of short or cupped ribs, variable vertebral changes and proximal femoral dysplasia. Lacy iliac crests are supportive when present but are not universal.

skeletal radiographic survey NCIT:C38101

Show evidence (1 reference)

PMID:26974433 SUPPORT Human Clinical

"The radiological features of the patients included cupped and flared anterior ends of ribs, lacy ilia (serrated iliac crests), and metaphyseal dysplasia of proximal femora (Fig 1)."

The radiographic pattern in a clinical axial SMD series; absence of an individual feature does not exclude the disorder.

Molecular testing of CFAP410 and NEK1

Molecular evaluation includes CFAP410 and NEK1, interpreted with the skeletal and ophthalmic phenotype. The original CFAP410-negative cases motivated identification of a second locus; that earlier study was not a test of the combined diagnostic yield of both genes.

CFAP410 and NEK1 sequencing NCIT:C15709

Show evidence (2 references)

PMID:26974433 SUPPORT Human Clinical

"We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD."

Supports CFAP410 molecular testing.

PMID:28123176 SUPPORT Human Clinical

"In this study, we identified NEK1 as the second disease gene for axial SMD."

Supports inclusion of NEK1.

Repeated ophthalmologic evaluation

Detailed and repeated ophthalmologic examinations are recommended because early visual symptoms can precede recognizable retinal degeneration. Fundoscopy and electrophysiology provide complementary characterization.

Show evidence (2 references)

PMID:23371363 SUPPORT Human Clinical

"Any patient with this constellation of findings should have repeated in-depth ophthalmologic examination."

Disease-specific clinical recommendation after recognition of retinal abnormalities only in adolescence.

PMID:40246852 SUPPORT Human Clinical

"A detailed ophthalmological examination should also be recommended for all SMDAX patients, as it would allow us to better estimate the true frequency of ophthalmic manifestations in this condition and the spectrum thereof."

Explicit recommendation for axial SMD, even though the underlying cohort includes broader CFAP410 disease.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

A population prevalence is not established. The 2016 clinical study included 13 patients from nine families, nine patients from six families with CFAP410 variants; families F1-F6 had been reported previously, so these reports must not be summed as independent cases. The later 49-person study was ascertained through CFAP410 retinal disease and its 11-person skeletal subset is not a population prevalence or a uniform axial SMD cohort.

Show evidence (2 references)

PMID:40246852 SUPPORT Human Clinical

"A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX)."

The only proportion available, quoted with its ascertainment caveat stated in the notes rather than presented as a prevalence.

PMID:21910225 SUPPORT Human Clinical

"We report here on the clinical and radiological manifestations in seven affected individuals from five families (three sporadic cases and two familial cases)."

Seven individuals in the 2011 report; subsequent series include previously reported families, so the counts overlap.

📊

Related Datasets

1

Identification of proteins interacting with the NEK1-C21ORF2 complex pride:PXD036410

Endogenous NEK1 and CFAP410 immunoprecipitation proteomics in parental ARPE-19 cells with the corresponding knockout controls. Each bait experiment used five biological replicates per genotype and a ten-sample TMT comparison.

PROTEOMICS

PMID:37188479

Show evidence (2 references)

url:https://www.ebi.ac.uk/pride/ws/archive/v2/projects/PXD036410 SUPPORT In Vitro

"Five biological replicates were used per cell line, and after trypsinization of the precipitates, peptides were labelled with tandem mass tags (TMT) enabling quantitative mass spectrometric analysis of the 10 samples which were pooled and analysed in parallel."

PRIDE PXD036410, Identification of proteins interacting with the NEK1-C21ORF2 complex: repository metadata confirms the cellular design and replicate counts.

PMID:37188479 SUPPORT In Vitro

"The mass spectrometry data relating to Fig 2 have been deposited to the ProteomeXchange consortium via the PRIDE (Perez-Riverol et al, 2022) partner repository with the dataset identifier PXD036410."

Primary publication identifies the deposited interaction-proteomics dataset.

🧫

Experimental Models

9

ARPE-19 CFAP410 and NEK1 knockout-rescue cells CELL_LINE

CRISPR knockout and re-expression in human retinal pigment epithelial cells test protein association, abundance and primary ciliogenesis.

Publication

PMID:37188479

Pathograph links

Disruption of the CFAP410-NEK1 Complex perturbs

Limitations: Association measured by co-immunoprecipitation; not purified-protein binding.

Defective Primary Ciliogenesis perturbs

Limitations: Epithelial cell line, not patient photoreceptors or a growth plate.

Show evidence (1 reference)

PMID:37188479 SUPPORT In Vitro

"As shown in Fig 5D and E, the proportion of NEK1–KO and C21ORF2–KO cells bearing primary cilia was reduced dramatically compared with parental cells."

Direct ciliation readout following knockout.

U2-O-S homologous-recombination reporters CELL_LINE

Knockdown in traffic-light and DR-GFP reporter cells measures homologous-recombination efficiency.

Publication

PMID:37188479

Pathograph links

Impaired Homologous Recombination Repair perturbs

Limitations: Knockdown of whole proteins; effects of individual axial SMD patient alleles on repair were not tested.

Show evidence (1 reference)

PMID:37188479 SUPPORT In Vitro

"Depletion of NEK1 and C21ORF2 resulted in a dramatic reduction in HR efficiency, similar in effect size to depletion of BRCA1."

Homologous-recombination reporter result.

OUMS-27 CFAP410 knockdown CELL_LINE

Human chondrosarcoma-cell knockdown tests cartilage-marker transcript expression.

Publication

PMID:26974433

Pathograph links

Altered Chondrocyte Marker Expression perturbs

Limitations: Transformed cells; no patient growth-plate histology or ciliary signaling readout.

Show evidence (1 reference)

PMID:26974433 SUPPORT In Vitro

"Knock-down of C21orf2 caused significant decreases in expression of chondrocyte marker genes (Fig 5)."

Cartilage-marker transcript changes after CFAP410 depletion.

ATDC5 chondrogenic differentiation time course CELL_LINE

Mouse ATDC5 cells were followed during cartilage induction without Cfap410 perturbation.

Publication

PMID:26974433

Pathograph links

Altered Chondrocyte Marker Expression measures

Limitations: Expression correlation during differentiation, not a knockdown experiment.

Show evidence (1 reference)

PMID:26974433 SUPPORT In Vitro

"While the expression of cartilage marker genes (Col2a1, Agc1 and Col10a1) was increased by the cartilage induction, 1810043G02Rik expression was continuously suppressed during cartilage differentiation (Fig 4)."

Cfap410 expression decreases as the induced cartilage markers increase.

HEK293T CFAP410 p.Tyr107His and p.Pro116Leu expression CELL_LINE

Transient overexpression with cycloheximide chase, MG132 exposure and ubiquitination assays.

Publication

PMID:37901396

Pathograph links

Reduced Stability of Selected CFAP410 Variants perturbs

Limitations: Tagged protein overexpression; not patient-derived photoreceptors.

Show evidence (1 reference)

PMID:37901396 SUPPORT In Vitro

"Western blot showed that the half-life of CFAP410 protein carrying the Y107H variant and P116 L variant was significantly shorter compared with the wild-type protein, indicating that both pathogenic variants impaired the stability of CFAP410 protein (Figure 7B)."

Cycloheximide chase in transfected HEK293T cells; both alleles were previously reported together in axial SMD, while this study patient had isolated retinal dystrophy.

mIMCD3 CFAP410 knockdown and allele rescue CELL_LINE

Mouse collecting-duct cells with endogenous Cfap410 knockdown were transfected with human wild-type or mutant CFAP410.

Publication

PMID:26167768

Pathograph links

Defective Primary Ciliogenesis partially recapitulates

Limitations: The p.Arg73Pro and p.Leu224Pro constructs partially rescue ciliogenesis; the latter was reported in a Jeune-labeled family rather than the founding axial SMD series.

Show evidence (1 reference)

PMID:26167768 SUPPORT In Vitro

"Exogenous expression of both the p.Arg73Pro and p.Leu224Pro variants in C21orf2 partially rescued ciliogenesis in mIMCD3 cells following siRNA knockdown of endogenous C21orf2, suggesting that they are hypomorphic mutations (Suppl. Figure 4)."

Direct evidence of residual allele function in this assay.

Purified CFAP410 C-terminal-domain assembly OTHER

Synthetic human, trypanosome and algal C-terminal domains were studied by crystallography, light scattering, size-exclusion chromatography and circular dichroism.

Publication

PMID:39255848

Pathograph links

Disruption of the CFAP410-NEK1 Complex measures

Limitations: Assays measure CFAP410 oligomerization, not NEK1 affinity; impact on the complex is inferred.

The p.Leu224Pro variant comes from the broader CFAP410 skeletal-ciliopathy spectrum; it is not evidence that every axial SMD allele disrupts tetramerization.

Show evidence (1 reference)

PMID:39255848 SUPPORT In Vitro

"However, the disease-causing mutant L224P lost all characteristic helical features and became completely unfolded."

Human C-terminal domain loses helicity; species-matched assays also support disruption of tetrameric assembly.

Trypanosome CFAP410 N-terminal domain and localization OTHER

Purified trypanosome N-terminal domains test solubility of human disease-equivalent substitutions; tagged proteins expressed in trypanosomes test cellular localization.

Publication

PMID:40018707

Pathograph links

Disruption of the CFAP410-NEK1 Complex measures

Limitations: Mutant solubility and localization are measured, but the human NEK1 interface is computationally predicted rather than tested as a binding assay here.

Non-animal experimental organism; the structural model alone does not prove partner-binding failure in human tissues.

Show evidence (2 references)

PMID:40018707 SUPPORT In Vitro

"In contrast, however, all the six mutants were present only in the pellets but not in the supernants (Figure 2F, lanes 5–22), demonstrating that the proteins are insoluble and thus likely mis-folded."

Recombinant trypanosome domains are insoluble in bacterial expression; not direct evidence of human protein abundance.

PMID:40018707 SUPPORT Model Organism

"Our results showed that unlike the mutant L272P that completely lost its localization at the basal body and the posterior cell tip, none of the mutants in the NTD showed such a dramatic change in their localization pattern."

Retains the weaker cellular-localization effect despite insolubility of recombinant N-terminal domains.

Chlamydomonas CFAP410 knockout OTHER

Two CRISPR knockout lines were compared with wild-type algae for flagellation and flagellar length. The Results describe modest reductions, while the Discussion states that these changes were not significant.

Publication

PMID:40018707

Pathograph links

Defective Primary Ciliogenesis fails to recapitulate

Limitations: Algal flagella are not human primary cilia. The study did not reproduce the marked ciliogenesis loss found in mammalian knockout cells; internal Results/Discussion wording differs.

Show evidence (1 reference)

PMID:40018707 SUPPORT Model Organism

"Surprisingly, no significant changes in flagellar length or the percentage of flagellated cells were observed compared to wild-type cells."

The Discussion reports no significant ciliation phenotype in two algal knockout lines; the Results describe modest numerical reductions. This limits extrapolation across organisms.

Show evidence (1 reference)

PMID:40018707 SUPPORT Model Organism

"Surprisingly, no significant changes in flagellar length or the percentage of flagellated cells were observed compared to wild-type cells."

The Discussion reports no significant ciliation phenotype in two algal knockout lines; the Results describe modest numerical reductions. This limits extrapolation across organisms.

🐁

Animal Models

2

nek1 zebrafish morpholino with human CFAP410 rescue

Splice-blocking nek1 morpholinos cause ciliary developmental abnormalities and retinal defects; human CFAP410 RNA partly rescues the phenotype, with weaker rescue by p.Arg73Pro and little rescue by p.Leu224Pro.

Species

Zebrafish

Publication

PMID:26167768

Pathograph links

Defective Primary Ciliogenesis partially recapitulates

Limitations: Transient knockdown and cross-gene rescue; not a stable genetic model of axial SMD or proof of a human treatment.

Show evidence (2 references)

PMID:26167768 SUPPORT Model Organism

"Knockdown of nek1 also resulted in retinal defects including loss of photoreceptors (Suppl. Figure 7fd-g) and cilia length defects in the pronephros (Suppl. Figure 7h,i)."

Whole-embryo knockdown phenotype.

PMID:26167768 SUPPORT Model Organism

"RNA expressing C21orf2 with the missense mutation p.Arg73Pro rescued the nek1 morphant phenotype less effectively than wild-type, whereas C21orf2-p.Leu224Pro had little effect (Figure 7e), confirming the predicted hypomorphic effect of both variants observed in vitro (Suppl. Figure 4)."

Relative rescue in a cross-gene embryonic assay; residual activity differs by allele.

Mouse retinal CFAP410 reporter localization

AAV-mediated reporter expression localizes CFAP410 to cone and rod connecting cilia.

Species

Mouse

Publication

PMID:26974433

Pathograph links

Photoreceptor Connecting Cilium Dysfunction measures

Limitations: Localization only; no disease-allele dysfunction or gene-therapy rescue was tested.

Show evidence (1 reference)

PMID:26974433 SUPPORT Model Organism

"C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function."

Anatomical localization assay.

{ }

Source YAML

click to show

name: Axial Spondylometaphyseal Dysplasia
creation_date: '2026-09-11T12:45:00Z'
category: Mendelian
synonyms:
- axial SMD
- SMDAX
- spondylometaphyseal dysplasia, axial
- spondylometaphyseal dysplasia with cone-rod dystrophy
description: Axial spondylometaphyseal dysplasia is an autosomal recessive skeletal-retinal ciliopathy associated with biallelic variants in CFAP410 (formerly C21orf2) or NEK1. Characteristic findings include postnatal short stature, a narrow thorax with short and cupped ribs, variable platyspondyly, lacy iliac crests, proximal femoral dysplasia and progressive retinal dystrophy. Skeletal involvement varies substantially, including among individuals with the same genotype. CFAP410 and NEK1 form a cellular complex required for efficient ciliogenesis, but the contribution of individual molecular defects to the skeletal and retinal phenotype remains incompletely resolved. Their role in homologous recombination is demonstrated in cell models; its contribution to axial SMD has not been established.
disease_term:
preferred_term: axial spondylometaphyseal dysplasia
term:
id: MONDO:0011211
label: axial spondylometaphyseal dysplasia
parents:
- Spondylometaphyseal dysplasia
- Ciliopathy
inheritance:
- name: Autosomal Recessive
description: Biallelic variants in either CFAP410 or NEK1, by homozygosity or compound heterozygosity, with segregation confirmed in the reported families.
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy.
explanation: States the mode of inheritance and, in the same sentence, the two-tissue definition of the entity.
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Equally affected sibling pairs of opposite gender and parental consanguinity are strongly suggestive of autosomal recessive inheritance.
explanation: The segregation evidence that supported the recessive assignment before either gene was known.
pathophysiology:
- name: Biallelic CFAP410 or NEK1 Loss of Function
biological_scale: MOLECULAR
description: 'Biallelic CFAP410 variants include missense and splice-altering alleles. A NEK1-associated patient carried the nonsense variant p.Ser1036Ter and missense variant p.Asp1277Ala. Functional effects depend on the allele: the NEK1 variants markedly reduce association with CFAP410, whereas CFAP410 p.Arg73Pro weakens this association and has been characterized as hypomorphic. Complete absence of either protein is not established for every patient genotype.'
genetic_context:
variant_origin: GERMLINE
functional_impact_category: LOSS_OF_FUNCTION
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: 'We found a total of five biallelic C21orf2 mutations in six families out of nine: three missense and two splicing mutations in patients with various ethnic backgrounds.'
explanation: The allelic series establishing CFAP410 as the first disease gene.
- reference: PMID:28123176
reference_title: Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: By whole-exome sequencing in a patient with axial SMD, we identified compound heterozygous mutations of NEK1, c.3107C>G (p.S1036*) and c.3830A>C (p.D1277A), which co-segregated in the family.
explanation: The second locus, with family segregation.
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Patients with the most severe ophthalmic and skeletal phenotypes had disease-associated variants within conserved leucine-rich regions of CFAP410
explanation: Genotype-phenotype correlation locating severity in the domain that mediates the NEK1 interaction, which is why the next node is the complex rather than either protein alone.
downstream:
- target: Disruption of the CFAP410-NEK1 Complex
causal_link_type: DIRECT
evidence:
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Taken together, the data above indicate that the NEK1–C21ORF2 association is negatively impacted by NEK1 pathogenic mutations S1036* and D1277A, and by the C21ORF2 R73P and L224P mutations.
explanation: Co-immunoprecipitation in transfected ARPE-19 cells supports allele-specific impairment of association. The L224P experiment concerns a related skeletal ciliopathy; the NEK1 alleles and R73P are also documented in axial SMD.
description: Demonstrated for the tested NEK1 p.Ser1036Ter/p.Asp1277Ala and CFAP410 p.Arg73Pro variants; not a universal functional assignment to every disease-associated allele.
- target: Reduced Stability of Selected CFAP410 Variants
causal_link_type: DIRECT
evidence:
- &id001
reference: PMID:37901396
reference_title: Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Western blot showed that the half-life of CFAP410 protein carrying the Y107H variant and P116 L variant was significantly shorter compared with the wild-type protein, indicating that both pathogenic variants impaired the stability of CFAP410 protein (Figure 7B).
explanation: Cycloheximide chase in transfected HEK293T cells; both alleles were previously reported together in axial SMD, while this study patient had isolated retinal dystrophy.
- name: Reduced Stability of Selected CFAP410 Variants
biological_scale: MOLECULAR
description: 'CFAP410 p.Tyr107His and p.Pro116Leu have shorter protein half-lives and increased ubiquitination in transfected HEK293T cells. MG132 increased mutant protein stability. The result is allele- and model-specific: it does not establish universal CFAP410 degradation or the mechanism of reduced CFAP410 abundance after NEK1 knockout.'
evidence:
- *id001
- reference: PMID:37901396
reference_title: Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: We found that the ubiquitination levels of P116L and Y107H proteins were significantly increased compared to the wild-type CFAP410 proteins (Figure 7D).
explanation: Supports increased ubiquitination of these two variants in the cell-line assay.
downstream:
- target: Defective Primary Ciliogenesis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: Reduced protein abundance is a plausible contributor, but the protein-turnover study did not directly measure ciliary assembly for these two alleles.
- name: Disruption of the CFAP410-NEK1 Complex
biological_scale: MOLECULAR
description: Endogenous CFAP410 associates tightly with NEK1 in ARPE-19 cells. The NEK1 C-terminal region spanning residues 1160-1286 is necessary and sufficient for association in cellular assays. AlphaFold predicts an interface with the CFAP410 N-terminal leucine-rich repeat region, supported by mutagenesis, but direct binding of purified proteins was not demonstrated. Tested disease-associated variants reduce association to different degrees. In NEK1-knockout cells, both wild-type and kinase-dead NEK1 restored CFAP410 abundance, whereas association-defective variants did not; kinase activity and complex-dependent abundance are therefore separable requirements.
molecular_functions:
- preferred_term: CFAP410 binding to the NEK1 C-terminal interaction domain
modifier: LOSS_OF_FUNCTION
term:
id: GO:0019901
label: protein kinase binding
evidence:
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: These observations suggest but do not prove that the interaction is direct.
explanation: Co-immunoprecipitation, mass spectrometry, modeling and mutagenesis support a complex without establishing purified-protein direct binding.
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: We noticed that both NEK1–WT and NEK1–KD restored C21ORF2 expression level back to normal in NEK1–KO cells (Fig S7B).
explanation: Kinase-dead NEK1 rescued CFAP410 abundance; loss of NEK1-mediated phosphorylation must not be treated as the demonstrated explanation for reduced abundance in this experiment.
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: However, the NEK1 mutants which weakened association with C21ORF2 did not rescue C21ORF2 expression, consistent with the possibility that complex formation regulates C21ORF2 stability (Fig S7B).
explanation: Supports an association-dependent contribution to CFAP410 abundance; turnover mechanisms remain unresolved.
downstream:
- target: Defective Primary Ciliogenesis
causal_link_type: DIRECT
evidence:
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: We show that NEK1 mutations that inhibit kinase activity or weaken its association with C21ORF2 severely compromise ciliogenesis, and that C21ORF2, like NEK1 is required for homologous recombination.
explanation: Weakening the association compromises ciliogenesis, which is exactly the causal step this edge claims.
- target: Impaired Homologous Recombination Repair
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Taken together, we conclude that cells deficient in NEK1 or C21ORF2 have a major defect in HR.
explanation: Knockdown reporter assays establish a requirement for the proteins; they do not isolate complex disruption as the causal defect.
description: Depletion of either partner reduces homologous recombination, but the effect of specific association-defective axial SMD alleles on repair was not tested.
- name: Defective Primary Ciliogenesis
biological_scale: CELLULAR
conforms_to: ciliopathy_dysfunction#Basal Body and Transition Zone Dysfunction
description: NEK1 or CFAP410 knockout markedly reduces the proportion of ciliated ARPE-19 cells after serum starvation. Wild-type re-expression rescues ciliogenesis, whereas kinase-dead NEK1 and the association-defective NEK1 p.Asp1277Ala allele do not. These epithelial-cell experiments establish a ciliary function but do not directly assay an axial SMD growth plate or patient photoreceptor.
biological_processes:
- preferred_term: primary cilium assembly
modifier: DECREASED
term:
id: GO:0060271
label: cilium assembly
evidence:
- reference: PMID:26167768
reference_title: An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Biochemical approaches place C21orf2 within key ciliopathy-associated protein modules, offering an explanation for the skeletal and retinal involvement observed in individuals with C21orf2 variants.
explanation: An unbiased genome-wide screen, not a candidate-gene experiment, placing the protein in the ciliary machinery and connecting that to the two affected tissues.
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Our study indicates that axial SMD is a member of a unique group of ciliopathy affecting skeleton and retina.
explanation: The classification of the disease as a ciliopathy by the group that identified its first gene.
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: As shown in Fig 5D and E, the proportion of NEK1–KO and C21ORF2–KO cells bearing primary cilia was reduced dramatically compared with parental cells.
explanation: Loss of either gene impairs primary ciliogenesis in ARPE-19 cells.
downstream:
- target: Photoreceptor Connecting Cilium Dysfunction
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26294103
reference_title: C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Immunohistochemical studies in human, pig and mouse retinas localised C21orf2 protein to the ciliary structures of the photoreceptor cell (the daughter basal body, the centriole adjacent to the basal body, and the connecting cilium).
explanation: Localization supports a plausible ciliary site of action but does not itself measure dysfunction or establish the causal sequence.
directness: INDIRECT
description: The proteins participate in ciliogenesis and CFAP410 localizes to photoreceptor ciliary structures; localization alone does not demonstrate connecting-cilium failure in a patient.
- target: Altered Chondrocyte Marker Expression
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: 'An inferred connection: CFAP410 knockdown alters cartilage-marker expression in a chondrosarcoma cell line, but neither ciliary signaling nor patient growth-plate differentiation was measured.'
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Functional data in chondrocyte suggest C21orf2 is implicated in cartilage differentiation.
explanation: The only chondrocyte-level functional evidence in the disease literature. The authors' own hedge ("suggest") is why this edge is marked as indirect with unknown intermediates.
- name: Impaired Homologous Recombination Repair
biological_scale: MOLECULAR
description: Depletion of CFAP410 or NEK1 reduces homologous recombination in U2-O-S traffic-light and DR-GFP reporter assays. CFAP410 depletion had little effect on cell-cycle distribution, arguing against a cell-cycle explanation for its repair phenotype. Whether this repair defect contributes to skeletal dysplasia or retinal degeneration in axial SMD remains untested.
biological_processes:
- preferred_term: double-strand break repair via homologous recombination
modifier: DECREASED
term:
id: GO:0000724
label: double-strand break repair via homologous recombination
evidence:
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Depletion of NEK1 and C21ORF2 resulted in a dramatic reduction in HR efficiency, similar in effect size to depletion of BRCA1.
explanation: Direct result from a cell-based homologous-recombination reporter assay; not a demonstration of DNA damage in patient tissues.
- name: Photoreceptor Connecting Cilium Dysfunction
biological_scale: CELLULAR
description: CFAP410 localizes to the connecting cilium and basal-body structures of photoreceptors. This supports a ciliary site of disease action, but patient photoreceptor transport failure was not measured in the cited studies. Reduced stability of selected variants was demonstrated separately in transfected HEK293T cells, not in patient photoreceptors.
cell_types:
- preferred_term: retinal cone cell
term:
id: CL:0000573
label: retinal cone cell
- preferred_term: retinal rod cell
term:
id: CL:0000604
label: retinal rod cell
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function.
explanation: AAV reporter and fusion-protein localization in mouse retina supports the ciliary site of action; this was not a patient-cell dysfunction or treatment-rescue experiment.
directness: INDIRECT
downstream:
- target: Progressive Photoreceptor Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:26294103
reference_title: C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: This retinal dystrophy phenotype is caused by recessive mutations in C21orf2 and can be considered a retinal ciliopathy as C21orf2 encodes a protein that localises to photoreceptor ciliary structures.
explanation: Genetic association and ciliary localization support a model of retinal ciliopathy without directly measuring the intervening transport or degeneration mechanism.
directness: INDIRECT
- name: Progressive Photoreceptor Degeneration
biological_scale: TISSUE
description: Retinal dysfunction and visual loss can begin early and progress. Fundoscopic retinitis pigmentosa and electroretinographic cone-rod dysfunction are both described in axial SMD; fundoscopic pigmentation does not independently establish a rod-first disease sequence. The relative cone-rod and rod-cone frequencies in a broader CFAP410 ophthalmic cohort cannot be transferred to axial SMD.
cell_types:
- preferred_term: photoreceptor cell
term:
id: CL:0000210
label: photoreceptor cell
evidence:
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy.
explanation: The pattern mix in 49 patients ascertained through ophthalmic genetics centres. Note this is not directly comparable with the axial SMD series below, where the two labels describe the same eyes on different tests.
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram.
explanation: The modality distinction. This is the sentence that stops the two phenotype records below being read as competing frequencies.
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Impaired visual acuity comes to medical attention in early life and function rapidly deteriorates.
explanation: Onset and rate of the visual loss in the clinically defined series.
downstream:
- target: Retinal dystrophy
causal_link_type: DIRECT
- target: Reduced visual acuity
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Cone-rod dystrophy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Pigmentary retinopathy
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Photophobia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Altered Chondrocyte Marker Expression
biological_scale: CELLULAR
description: CFAP410 knockdown in OUMS-27 human chondrosarcoma cells reduces expression of chondrocyte marker genes, suggesting a role in maintaining the differentiated chondrocyte phenotype. In a separate mouse ATDC5 differentiation time course, Cfap410 transcript abundance decreased while cartilage markers increased. Neither experiment establishes failure of growth-plate differentiation in patients or identifies the intervening ciliary signal.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Knock-down of C21orf2 caused significant decreases in expression of chondrocyte marker genes (Fig 5).
explanation: Perturbation in OUMS-27 cells supports altered maintenance of cartilage-marker expression, not a direct growth-plate histopathology finding.
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: While the expression of cartilage marker genes (Col2a1, Agc1 and Col10a1) was increased by the cartilage induction, 1810043G02Rik expression was continuously suppressed during cartilage differentiation (Fig 4).
explanation: The ATDC5 time course is an expression association, not a loss-of-function differentiation experiment.
downstream:
- target: Axial Metaphyseal and Vertebral Dysplasia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: The link from altered marker expression in cultured cells to axial skeletal abnormalities in patients remains inferred.
- name: Axial Metaphyseal and Vertebral Dysplasia
biological_scale: TISSUE
description: The characteristic radiographic distribution includes ribs, vertebrae, iliac wings and proximal femora, with variable involvement of other bones. Femoral-neck shortening and coxa vara can progress with age; a uniformly static adult course has not been established.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora.
explanation: The skeletal phenotype in the genotyped cohort.
downstream:
- target: Thoracic Constriction and Restrictive Ventilation
causal_link_type: DIRECT
- target: Metaphyseal dysplasia
causal_link_type: DIRECT
- target: Platyspondyly
causal_link_type: DIRECT
- target: Anterior rib cupping
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Abnormal ilium morphology
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Coxa vara
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Scoliosis
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Flattened femoral head
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Short stature
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Rhizomelia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Disproportionate short-trunk short stature
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Short ribs
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Short femoral neck
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- target: Metacarpal metaphyseal dysplasia
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Thoracic Constriction and Restrictive Ventilation
biological_scale: ORGANISM
description: A narrow thorax and short ribs can restrict lung expansion and contribute to neonatal respiratory problems. The clinical reports infer this mechanical relationship; they do not provide formal pulmonary-function measurements establishing restrictive physiology in every patient.
evidence:
- reference: PMID:9266195
reference_title: Axial spondylometaphyseal dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings.
explanation: The original description, which names the small thorax as a defining feature. It reports the anatomy, not the ventilatory consequence.
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.
explanation: 'The ventilatory consequence the 1997 description did not supply: thoracic hypoplasia causing neonatal respiratory problems and later airway infection, in seven patients from five families.'
downstream:
- target: Neonatal respiratory distress
causal_link_type: DIRECT
- target: Recurrent respiratory infections
causal_link_type: DIRECT
- target: Thoracic hypoplasia
causal_link_type: DIRECT
phenotypes:
- category: Skeletal
name: Metaphyseal dysplasia
description: Irregular, dysplastic proximal femoral metaphyses.
phenotype_term:
preferred_term: Metaphyseal dysplasia
term:
id: HP:0100255
label: Metaphyseal dysplasia
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora.
explanation: Names metaphyseal dysplasia of the proximal femora in the genotyped cohort.
frequency: 10/13
notes: Proximal femoral metaphyseal dysplasia was recorded in 10/13 clinically selected axial SMD patients in Table 1 of PMID:26974433.
- category: Skeletal
name: Platyspondyly
phenotype_term:
preferred_term: Platyspondyly
term:
id: HP:0000926
label: Platyspondyly
severity: MILD
evidence:
- reference: PMID:9266195
reference_title: Axial spondylometaphyseal dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings.
explanation: The original description records the platyspondyly as mild, which is why the severity qualifier is set.
frequency: 7/13
notes: Observed in 7/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Skeletal
name: Anterior rib cupping
phenotype_term:
preferred_term: Anterior rib cupping
term:
id: HP:0000907
label: Anterior rib cupping
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: C21orf2 mutations presented with a wide range of skeletal phenotypes, including cupped and flared anterior ends of ribs, lacy ilia and metaphyseal dysplasia of proximal femora.
explanation: Names the rib finding in the genotyped cohort.
frequency: 10/11
notes: Observed in 10/11 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Skeletal
name: Abnormal ilium morphology
description: The lacy appearance of the iliac wings, a distinctive radiographic sign of this dysplasia.
phenotype_term:
preferred_term: lacy iliac wings
term:
id: HP:0011867
label: Abnormal iliac wing morphology
evidence:
- reference: PMID:9266195
reference_title: Axial spondylometaphyseal dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We present a previously undescribed skeletal dysplasia characterized by mild platyspondyly, small thorax with cupping of the anterior ends of the ribs, irregular proximal femoral metaphyses, and lacy appearance of the iliac wings.
explanation: The lacy iliac wings as originally described. HPO has no term for the lacy appearance itself, so the iliac wing morphology term is bound and the specificity is carried in preferred_term.
frequency: 8/10
notes: Observed in 8/10 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Skeletal
name: Thoracic hypoplasia
phenotype_term:
preferred_term: Thoracic hypoplasia
term:
id: HP:0005257
label: Thoracic hypoplasia
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Thoracic hypoplasia, due to severe shortening of the ribs, was also observed in all patients.
explanation: The clinical narrative describes all 13 patients; the table marks two as equivocal. No unqualified universal frequency is assigned.
description: A narrow thorax with shortened ribs is characteristic. Table 1 of the 2016 series records 11 definite and two equivocal findings, while its narrative describes thoracic hypoplasia in all patients.
- category: Growth
name: Short stature
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The common clinical findings among the patients include 1) mild postnatal growth failure, 2) severe thoracic deformity (S1 Fig), 3) impaired visual acuity and retinal dystrophy (diagnosed as retinitis pigmentosa or cone-rod dystrophy).
explanation: Clinical series; Table 1 records growth delay/short stature in all 13 individuals.
frequency: 13/13
notes: Observed in 13/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Respiratory
name: Neonatal respiratory distress
description: Thoracic hypoplasia can cause mild to moderate respiratory problems in the neonatal period.
phenotype_term:
preferred_term: Neonatal respiratory distress
term:
id: HP:0002643
label: Neonatal respiratory distress
evidence:
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.
explanation: Names the neonatal respiratory problems and attributes them to the thoracic hypoplasia, which is the mechanism this entry models.
frequency: 4/11
notes: Observed in 4/11 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Respiratory
name: Recurrent respiratory infections
description: Susceptibility to airway infection has been described in association with thoracic hypoplasia; a disease-specific frequency was not reported.
phenotype_term:
preferred_term: susceptibility to airway infection
term:
id: HP:0002205
label: Recurrent respiratory infections
evidence:
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.
explanation: The same sentence records the later airway-infection susceptibility as a separate consequence of the same thoracic constraint.
- category: Growth
name: Postnatal growth retardation
phenotype_term:
preferred_term: postnatal growth failure
term:
id: HP:0008897
label: Postnatal growth retardation
evidence:
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.
explanation: 'Growth failure is postnatal, which matters: it separates this from the skeletal dysplasias that are short at birth.'
- category: Growth
name: Rhizomelia
description: Rhizomelic shortening can be apparent in early childhood; body proportions may evolve toward a short trunk later in childhood.
phenotype_term:
preferred_term: rhizomelic short stature in early childhood
term:
id: HP:0008905
label: Rhizomelia
onset:
onset_category: CHILDHOOD
evidence:
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.
explanation: The early-childhood proportion. Curated separately from the short-trunk phenotype below because the source describes one evolving into the other.
frequency: 9/11
notes: Observed in 9/11 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Growth
name: Disproportionate short-trunk short stature
description: Short-trunk disproportion can develop later in childhood but is not present in every reported patient.
phenotype_term:
preferred_term: short trunk in late childhood
term:
id: HP:0003521
label: Disproportionate short-trunk short stature
evidence:
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.
explanation: The later proportion. Recorded as a distinct phenotype from the rhizomelia because the change over time is itself the observation.
frequency: 4/13
notes: Observed in 4/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Ophthalmologic
name: Retinal dystrophy
description: Retinal dystrophy is a characteristic finding, often with early visual impairment and progression. Recognition of fundoscopic abnormalities may be delayed despite earlier visual symptoms.
phenotype_term:
preferred_term: Retinal dystrophy
term:
id: HP:0000556
label: Retinal dystrophy
clinical_course: PROGRESSIVE
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Axial spondylometaphyseal dysplasia (axial SMD) is an autosomal recessive disease characterized by dysplasia of axial skeleton and retinal dystrophy.
explanation: Retinal dystrophy is part of the definition of the disease, not an occasional association.
- reference: PMID:23371363
reference_title: Axial spondylometaphyseal dysplasia with retinitis pigmentosa--a clinical report and diagnostic clues.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Notably, although the patient reported here was closely followed for color blindness, nystagmus, and amblyopia since the age of 2 years, clinically apparent retinal changes were identified only at 16 years of age, leading to the clinical diagnosis.
explanation: A longitudinal case shows that early visual symptoms may precede recognizable retinal degeneration.
frequency: 13/13
notes: Observed in 13/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Ophthalmologic
name: Cone-rod dystrophy
description: Cone-rod dysfunction has been identified by electroretinography in axial SMD. In the broader 49-person CFAP410 retinal cohort, cone-rod patterns were more common than rod-cone patterns; that ratio is not an axial SMD frequency.
phenotype_term:
preferred_term: Cone-rod dystrophy
term:
id: HP:0000548
label: Cone/cone-rod dystrophy
evidence:
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A cone-rod dystrophy pattern was observed roughly two times more commonly than rod-cone dystrophy.
explanation: The 49-person cohort was selected for CFAP410 retinal disease and includes patients without skeletal dysplasia; this does not estimate the frequency within axial SMD.
- category: Ophthalmologic
name: Pigmentary retinopathy
description: Retinitis pigmentosa or pigmentary retinal degeneration has been reported on fundoscopy. The 2011 axial SMD series also described cone-rod dysfunction on electroretinography; fundoscopic pigmentation alone does not establish rod-predominant physiology.
phenotype_term:
preferred_term: pigmentary retinopathy on fundoscopy
term:
id: HP:0000580
label: Pigmentary retinopathy
evidence:
- reference: PMID:9266195
reference_title: Axial spondylometaphyseal dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Retinitis pigmentosa and optic atrophy are associated findings.
explanation: The original clinical description reports retinitis pigmentosa; this does not independently demonstrate a rod-first electrophysiologic sequence.
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Retinal changes are diagnosed as retinitis pigmentosa or pigmentary retinal degeneration on fundoscopic examination and cone-rod dystrophy on electroretinogram.
explanation: The source distinguishes the fundoscopic diagnosis from the electroretinographic cone-rod pattern; these observations should not be counted as mutually exclusive physiologic subtypes.
- category: Ophthalmologic
name: Reduced visual acuity
phenotype_term:
preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In all patients, impaired visual acuity came to medical attention in early life, and retinal function deteriorated rapidly.
explanation: Early visual impairment in the 13-person clinical series.
- category: Ophthalmologic
name: Photophobia
phenotype_term:
preferred_term: Photophobia
term:
id: HP:0000613
label: Photophobia
evidence:
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Common clinical features included early-onset reduced visual acuity, photophobia, and delayed light-to-dark adaptation.
explanation: Named as a common feature, and consistent with the cone-predominant pattern.
notes: Documented in P6 in the 2016 axial SMD series and common in the broader 2025 CFAP410 ophthalmic cohort. The latter is not an axial SMD frequency denominator.
- category: Ophthalmologic
name: Optic atrophy
phenotype_term:
preferred_term: Optic atrophy
term:
id: HP:0000648
label: Optic atrophy
evidence:
- reference: PMID:9266195
reference_title: Axial spondylometaphyseal dysplasia.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Retinitis pigmentosa and optic atrophy are associated findings.
explanation: Optic atrophy was described in the original cases and in two individuals in Table 1 of the 2016 series.
frequency: 2/13
notes: Observed in 2/13 evaluable individuals in Table 1 of PMID:26974433 (13 clinically ascertained axial SMD patients, including previously reported families; nine had CFAP410 variants). This small, selected series does not estimate population penetrance. Missing observations are excluded from the denominator.
- category: Skeletal
name: Coxa vara
description: Progressive femoral-neck shortening can produce varus deformity in older patients.
phenotype_term:
preferred_term: Coxa vara
term:
id: HP:0002812
label: Coxa vara
frequency: 7/13
notes: Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Shortening of the femoral neck was often progressive, resulting mild coxa vara in older patients.
explanation: The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.
- category: Skeletal
name: Scoliosis
description: Variable spinal curvature accompanying the skeletal dysplasia.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
frequency: 3/13
notes: Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: He had mild scoliosis, but platyspondyly is not evident.
explanation: The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.
- category: Ophthalmologic
name: Nystagmus
description: Nystagmus may precede recognition of retinal degeneration.
phenotype_term:
preferred_term: Nystagmus
term:
id: HP:0000639
label: Nystagmus
frequency: 3/13
notes: Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.
evidence:
- reference: PMID:23371363
reference_title: Axial spondylometaphyseal dysplasia with retinitis pigmentosa--a clinical report and diagnostic clues.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Color blindness and nystagmus with amblyopia were noted on ophthalmologic examination at the age of 10 years and endocrinology investigation was normal.
explanation: The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.
- category: Skeletal
name: Flattened femoral head
description: Radiographic flattening of the femoral head in the axial SMD clinical series.
phenotype_term:
preferred_term: Flattened femoral head
term:
id: HP:0008812
label: Flattened femoral head
frequency: 10/12
notes: Frequency is the observed count in Table 1 of PMID:26974433, a clinically selected 13-person series with mixed molecular ascertainment; missing values excluded. It is not population penetrance.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| coxa vara | – | – | – | + | + | + | + | – | – | – | + | + | + |

| flattening of femoral head | + | + | NA * | + | + | – | – | + | + | + | + | + | + |'
explanation: The clinical finding is reported in the cited source; the frequency is separately derived from Table 1 of the 2016 clinical series.
- name: Short ribs
category: Skeletal
description: Short ribs contribute to the narrow thorax. Table 1 of the 2016 clinical series records this finding in all 11 patients with rib assessment available; two had no recorded assessment.
phenotype_term:
preferred_term: Short ribs
term:
id: HP:0000773
label: Short ribs
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Thoracic hypoplasia, due to severe shortening of the ribs, was also observed in all patients.
explanation: Clinical and radiographic findings in the axial SMD series.
frequency: 11/11
- name: Short femoral neck
category: Skeletal
description: Femoral-neck shortening may progress with age and contribute to coxa vara.
phenotype_term:
preferred_term: Short femoral neck
term:
id: HP:0100864
label: Short femoral neck
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Shortening of the femoral neck was often progressive, resulting mild coxa vara in older patients.
explanation: Clinical and radiographic findings in the axial SMD series.
- name: Metacarpal metaphyseal dysplasia
category: Skeletal
description: Metacarpal metaphyseal abnormalities extend the skeletal distribution beyond the axial skeleton and proximal femora in some patients.
frequency: 4/11
phenotype_term:
preferred_term: Metacarpal metaphyseal dysplasia
notes: 'Table 1 of the 2016 series: four positive, seven negative and two unavailable assessments. Needs a specific HPO term; metaphyseal cupping is narrower than the reported dysplasia and was not assigned.'
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: '| metaphyseal dysplasia of | | | | | | | | | | | | | |

| – proximal femur | + | + | + | + | + | + | + | + | + | + | – | – | – |

| – other long bones | – | – | – | – | – | – | + | NA | – | – | NA | NA | NA |

| – metacarpal | + | + | – | – | – | – | + | – | – | + | NA | NA | – |'
explanation: The metacarpal row records four affected individuals; the preceding row labels identify these as metaphyseal findings.
genetic:
- name: CFAP410
gene_term: &id003
preferred_term: CFAP410
term:
id: hgnc:1260
label: CFAP410
association: Causative
relationship_type: CAUSATIVE
notes: Formerly C21orf2 or LRRC76; 21q22.3. The 2016 axial SMD study identified five distinct alleles (three missense and two splice-altering) in nine patients from six of nine families. The same gene causes a broader spectrum including isolated retinal dystrophy and Jeune-like skeletal ciliopathy. In the ophthalmically ascertained 2025 series, 11/49 patients had skeletal abnormalities, which were broader than a uniform axial SMD diagnosis; five patients lacked a documented skeletal examination. This is not penetrance of axial SMD among all biallelic carriers.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD.
explanation: The gene-disease assignment.
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX).
explanation: The abstract labels 11/49 as consistent with axial SMD; the full text and Supplementary Table 2 document heterogeneous skeletal findings and incomplete skeletal assessment. This ascertainment-dependent proportion is not population penetrance.
- name: NEK1
gene_term: &id005
preferred_term: NEK1
term:
id: hgnc:7744
label: NEK1
association: Causative
relationship_type: CAUSATIVE
notes: A patient with axial SMD carried compound heterozygous NEK1 c.3107C>G (p.Ser1036Ter) and c.3830A>C (p.Asp1277Ala). NEK1 is a CFAP410-associated protein and also causes other skeletal ciliopathies. Both variants reduce CFAP410 association in cellular assays. The unresolved CFAP410-negative patients in the earlier 2016 study preceded discovery of NEK1 as the second locus and do not by themselves establish a third disease gene.
evidence:
- reference: PMID:28123176
reference_title: Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In this study, we identified NEK1 as the second disease gene for axial SMD.
explanation: The gene-disease assignment for the second locus.
- reference: PMID:28123176
reference_title: Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: NEK1 mutations have previously been found in three types of short rib thoracic dystrophy, which have no retinal dystrophy.
explanation: The differential within the NEK1 disorders, and the reason retinal involvement is diagnostically load-bearing here.
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Analysis of patients without C21orf2 mutation indicated genetic heterogeneity of axial SMD.
explanation: The CFAP410-negative families supported genetic heterogeneity in 2016, before NEK1 was identified; they do not prove that testing both currently known genes leaves these same cases unexplained.
treatments:
- name: Respiratory surveillance and supportive care
description: Respiratory assessment and supportive care address the consequences of thoracic hypoplasia. The clinical series documents respiratory risk but does not test a standardized surveillance or treatment protocol.
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
target_mechanisms:
- target: Thoracic Constriction and Restrictive Ventilation
description: Addresses the consequence of the thoracic constriction rather than the constriction itself.
evidence:
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
directness: INDIRECT
snippet: The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.
explanation: 'Establishes that there is something to survey for - neonatal respiratory problems and later airway-infection susceptibility - which is what makes respiratory surveillance indicated. It does not evaluate an intervention. Graded INDIRECT because the claim follows from the quoted risk by an inference step rather than being asserted: the sentence states the hazard, not that surveillance for it is beneficial.'
notes: The risk supports a clinical rationale for assessment; no comparative benefit estimate is available from this series.
- name: Low-vision rehabilitation and ophthalmic surveillance
description: Low-vision aids, assistive technology and social support are described for CFAP410-related retinal disease. Their use in axial SMD is extrapolated from the shared retinal manifestation.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: low-vision rehabilitation
term:
id: NCIT:C15315
label: Rehabilitation
target_phenotypes:
- preferred_term: Reduced visual acuity
term:
id: HP:0007663
label: Reduced visual acuity
evidence:
- reference: PMID:39232248
reference_title: Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Management is conservative and includes appropriate support including low visual aids, assistive technology, social services and support societies as required.
explanation: Management described for CFAP410-associated cone dystrophy without diagnosed axial SMD; supports extrapolation to visual impairment, not a disease-specific efficacy trial.
directness: INDIRECT
quote_role: REVIEW_SYNTHESIS
- name: Genetic counseling
description: Counseling should address autosomal recessive inheritance and variable skeletal involvement. When both parents are confirmed heterozygous carriers, each pregnancy has a 25% probability of inheriting both variants; this does not predict the severity or presence of the skeletal phenotype.
treatment_term:
preferred_term: Genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
evidence:
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX).
explanation: Skeletal findings vary in an ophthalmically selected CFAP410 cohort; this is evidence for variable expressivity, not the recurrence-risk calculation.
- reference: PMID:39232248
reference_title: Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The patient was referred for genetic counselling and continues to be monitored.
explanation: Documents genetic counseling in CFAP410 retinal disease; the Mendelian recurrence calculation follows from confirmed parental carrier status.
- name: Chest expansion surgery
therapeutic_modality: SURGERY
treatment_term:
preferred_term: chest expansion surgery
term:
id: NCIT:C15329
label: Surgical Procedure
description: Early chest expansion surgery corrected pectus excavatum and a narrow thorax in one patient with CFAP410-associated retinal and skeletal disease. This is a reported intervention, not evidence of a general surgical indication or comparative efficacy.
target_phenotypes:
- preferred_term: Thoracic hypoplasia
term:
id: HP:0005257
label: Thoracic hypoplasia
evidence:
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Patient 7 was born with pectus excavatum and narrow thorax corrected with early chest expansion surgery.
explanation: Single treated patient in the broader CFAP410 series; the report does not provide a controlled respiratory outcome.
diagnosis:
- name: Skeletal survey
description: A skeletal radiographic survey evaluates the combination of short or cupped ribs, variable vertebral changes and proximal femoral dysplasia. Lacy iliac crests are supportive when present but are not universal.
diagnosis_term:
preferred_term: skeletal radiographic survey
term:
id: NCIT:C38101
label: X-Ray Imaging
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The radiological features of the patients included cupped and flared anterior ends of ribs, lacy ilia (serrated iliac crests), and metaphyseal dysplasia of proximal femora (Fig 1).
explanation: The radiographic pattern in a clinical axial SMD series; absence of an individual feature does not exclude the disorder.
- name: Molecular testing of CFAP410 and NEK1
description: Molecular evaluation includes CFAP410 and NEK1, interpreted with the skeletal and ophthalmic phenotype. The original CFAP410-negative cases motivated identification of a second locus; that earlier study was not a test of the combined diagnostic yield of both genes.
diagnosis_term:
preferred_term: CFAP410 and NEK1 sequencing
term:
id: NCIT:C15709
label: Genetic Testing
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We conducted whole exome sequencing and identified C21orf2 (chromosome 21 open reading frame 2) as a disease gene for axial SMD.
explanation: Supports CFAP410 molecular testing.
- reference: PMID:28123176
reference_title: Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: In this study, we identified NEK1 as the second disease gene for axial SMD.
explanation: Supports inclusion of NEK1.
- name: Repeated ophthalmologic evaluation
description: Detailed and repeated ophthalmologic examinations are recommended because early visual symptoms can precede recognizable retinal degeneration. Fundoscopy and electrophysiology provide complementary characterization.
evidence:
- reference: PMID:23371363
reference_title: Axial spondylometaphyseal dysplasia with retinitis pigmentosa--a clinical report and diagnostic clues.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Any patient with this constellation of findings should have repeated in-depth ophthalmologic examination.
explanation: Disease-specific clinical recommendation after recognition of retinal abnormalities only in adolescence.
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A detailed ophthalmological examination should also be recommended for all SMDAX patients, as it would allow us to better estimate the true frequency of ophthalmic manifestations in this condition and the spectrum thereof.
explanation: Explicit recommendation for axial SMD, even though the underlying cohort includes broader CFAP410 disease.
prevalence:
- population: Worldwide
measure_type: CASES_IN_LITERATURE
prevalence_class: ULTRA_RARE
notes: A population prevalence is not established. The 2016 clinical study included 13 patients from nine families, nine patients from six families with CFAP410 variants; families F1-F6 had been reported previously, so these reports must not be summed as independent cases. The later 49-person study was ascertained through CFAP410 retinal disease and its 11-person skeletal subset is not a population prevalence or a uniform axial SMD cohort.
evidence:
- reference: PMID:40246852
reference_title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A minority of patients (22.4%) presented with skeletal abnormalities consistent with axial spondylometaphyseal dysplasia (SMDAX).
explanation: The only proportion available, quoted with its ascertainment caveat stated in the notes rather than presented as a prevalence.
- reference: PMID:21910225
reference_title: 'Axial spondylometaphyseal dysplasia: additional reports.'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: We report here on the clinical and radiological manifestations in seven affected individuals from five families (three sporadic cases and two familial cases).
explanation: Seven individuals in the 2011 report; subsequent series include previously reported families, so the counts overlap.
discussions:
- discussion_id: ciliary_signalling_unmeasured_in_chondrocytes
kind: KNOWLEDGE_GAP
prompt: Which ciliary signalling pathway actually fails in the axial SMD growth plate, and has any of it been measured in this disease?
attaches_to:
- pathophysiology#Altered Chondrocyte Marker Expression
- pathophysiology#Defective Primary Ciliogenesis
rationale: The step from defective ciliogenesis to the skeletal lesion is the weakest link in this pathograph and the entry marks the edge INDIRECT_UNKNOWN_INTERMEDIATES for that reason. In other skeletal ciliopathies the mechanism is impaired Hedgehog transduction through failed ciliary translocation of GLI transcription factors, and that is a reasonable expectation here, but no Hedgehog readout, no GLI localization, and no growth-plate histology has been reported in an axial SMD patient or model. The only chondrocyte-level datum is a functional result described by its own authors as suggesting involvement in cartilage differentiation. Until a signalling readout is measured, the skeletal arm rests on analogy.
- discussion_id: dna_repair_arm_contribution
kind: KNOWLEDGE_GAP
prompt: Does the homologous-recombination defect contribute to the skeletal or retinal phenotype, or is it a parallel consequence of losing the same complex?
attaches_to:
- pathophysiology#Impaired Homologous Recombination Repair
rationale: 'The CFAP410-NEK1 complex has two demonstrated functions and this disease could in principle be caused by either. The repair arm is modelled here as a node with no downstream edge, which is deliberate: nothing published connects it to a tissue phenotype in axial SMD. The reason it is not simply omitted is that the same complex is implicated in amyotrophic lateral sclerosis, where the DNA repair function is the favoured mechanism, so which arm matters may be tissue-dependent rather than settled.'
- discussion_id: axial_restriction_unexplained
kind: KNOWLEDGE_GAP
prompt: Why are ribs, vertebrae and proximal femora prominently affected when CFAP410 and NEK1 participate broadly in ciliary biology?
attaches_to:
- pathophysiology#Axial Metaphyseal and Vertebral Dysplasia
rationale: 'The distribution is characteristic but not absolute: the 2016 series also recorded metacarpal metaphyseal abnormalities and one patient with other long-bone involvement. Tissue-specific requirements and modifiers remain hypotheses.'
- discussion_id: species_dependent_ciliogenesis_requirement
kind: KNOWLEDGE_GAP
prompt: Why does CFAP410 disruption strongly impair ciliation in mammalian epithelial cells but produce a much smaller effect on algal flagella?
attaches_to:
- pathophysiology#Defective Primary Ciliogenesis
rationale: The 2023 mammalian knockout and 2025 algal knockout studies differ in organism, cilium type and assay conditions. The algal report also differs internally between numerical reductions in Results and a lack of significance in Discussion. Cell-cycle effects and compensation remain hypotheses.
experimental_models:
- name: ARPE-19 CFAP410 and NEK1 knockout-rescue cells
experimental_model_type: CELL_LINE
description: CRISPR knockout and re-expression in human retinal pigment epithelial cells test protein association, abundance and primary ciliogenesis.
publication: PMID:37188479
modeled_mechanisms:
- target: Disruption of the CFAP410-NEK1 Complex
relationship: PERTURBS
limitations: Association measured by co-immunoprecipitation; not purified-protein binding.
- target: Defective Primary Ciliogenesis
relationship: PERTURBS
limitations: Epithelial cell line, not patient photoreceptors or a growth plate.
evidence:
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: As shown in Fig 5D and E, the proportion of NEK1–KO and C21ORF2–KO cells bearing primary cilia was reduced dramatically compared with parental cells.
explanation: Direct ciliation readout following knockout.
- name: U2-O-S homologous-recombination reporters
experimental_model_type: CELL_LINE
description: Knockdown in traffic-light and DR-GFP reporter cells measures homologous-recombination efficiency.
publication: PMID:37188479
modeled_mechanisms:
- target: Impaired Homologous Recombination Repair
relationship: PERTURBS
limitations: Knockdown of whole proteins; effects of individual axial SMD patient alleles on repair were not tested.
evidence:
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Depletion of NEK1 and C21ORF2 resulted in a dramatic reduction in HR efficiency, similar in effect size to depletion of BRCA1.
explanation: Homologous-recombination reporter result.
- name: OUMS-27 CFAP410 knockdown
experimental_model_type: CELL_LINE
description: Human chondrosarcoma-cell knockdown tests cartilage-marker transcript expression.
publication: PMID:26974433
modeled_mechanisms:
- target: Altered Chondrocyte Marker Expression
relationship: PERTURBS
limitations: Transformed cells; no patient growth-plate histology or ciliary signaling readout.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Knock-down of C21orf2 caused significant decreases in expression of chondrocyte marker genes (Fig 5).
explanation: Cartilage-marker transcript changes after CFAP410 depletion.
- name: ATDC5 chondrogenic differentiation time course
experimental_model_type: CELL_LINE
description: Mouse ATDC5 cells were followed during cartilage induction without Cfap410 perturbation.
publication: PMID:26974433
modeled_mechanisms:
- target: Altered Chondrocyte Marker Expression
relationship: MEASURES
limitations: Expression correlation during differentiation, not a knockdown experiment.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: While the expression of cartilage marker genes (Col2a1, Agc1 and Col10a1) was increased by the cartilage induction, 1810043G02Rik expression was continuously suppressed during cartilage differentiation (Fig 4).
explanation: Cfap410 expression decreases as the induced cartilage markers increase.
- name: HEK293T CFAP410 p.Tyr107His and p.Pro116Leu expression
experimental_model_type: CELL_LINE
description: Transient overexpression with cycloheximide chase, MG132 exposure and ubiquitination assays.
publication: PMID:37901396
modeled_mechanisms:
- target: Reduced Stability of Selected CFAP410 Variants
relationship: PERTURBS
limitations: Tagged protein overexpression; not patient-derived photoreceptors.
evidence:
- *id001
- name: mIMCD3 CFAP410 knockdown and allele rescue
experimental_model_type: CELL_LINE
description: Mouse collecting-duct cells with endogenous Cfap410 knockdown were transfected with human wild-type or mutant CFAP410.
publication: PMID:26167768
modeled_mechanisms:
- target: Defective Primary Ciliogenesis
relationship: PARTIALLY_RECAPITULATES
limitations: The p.Arg73Pro and p.Leu224Pro constructs partially rescue ciliogenesis; the latter was reported in a Jeune-labeled family rather than the founding axial SMD series.
evidence:
- reference: PMID:26167768
reference_title: An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Exogenous expression of both the p.Arg73Pro and p.Leu224Pro variants in C21orf2 partially rescued ciliogenesis in mIMCD3 cells following siRNA knockdown of endogenous C21orf2, suggesting that they are hypomorphic mutations (Suppl. Figure 4).
explanation: Direct evidence of residual allele function in this assay.
- name: Purified CFAP410 C-terminal-domain assembly
experimental_model_type: OTHER
description: Synthetic human, trypanosome and algal C-terminal domains were studied by crystallography, light scattering, size-exclusion chromatography and circular dichroism.
publication: PMID:39255848
modeled_mechanisms:
- target: Disruption of the CFAP410-NEK1 Complex
relationship: MEASURES
limitations: Assays measure CFAP410 oligomerization, not NEK1 affinity; impact on the complex is inferred.
evidence:
- reference: PMID:39255848
reference_title: The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: However, the disease-causing mutant L224P lost all characteristic helical features and became completely unfolded.
explanation: Human C-terminal domain loses helicity; species-matched assays also support disruption of tetrameric assembly.
notes: The p.Leu224Pro variant comes from the broader CFAP410 skeletal-ciliopathy spectrum; it is not evidence that every axial SMD allele disrupts tetramerization.
- name: Trypanosome CFAP410 N-terminal domain and localization
experimental_model_type: OTHER
description: Purified trypanosome N-terminal domains test solubility of human disease-equivalent substitutions; tagged proteins expressed in trypanosomes test cellular localization.
publication: PMID:40018707
modeled_mechanisms:
- target: Disruption of the CFAP410-NEK1 Complex
relationship: MEASURES
limitations: Mutant solubility and localization are measured, but the human NEK1 interface is computationally predicted rather than tested as a binding assay here.
evidence:
- reference: PMID:40018707
reference_title: CFAP410 has a bimodular architecture with a conserved surface patch on its N-terminal leucine-rich repeat motif for binding interaction partners.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: In contrast, however, all the six mutants were present only in the pellets but not in the supernants (Figure 2F, lanes 5–22), demonstrating that the proteins are insoluble and thus likely mis-folded.
explanation: Recombinant trypanosome domains are insoluble in bacterial expression; not direct evidence of human protein abundance.
- reference: PMID:40018707
reference_title: CFAP410 has a bimodular architecture with a conserved surface patch on its N-terminal leucine-rich repeat motif for binding interaction partners.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Our results showed that unlike the mutant L272P that completely lost its localization at the basal body and the posterior cell tip, none of the mutants in the NTD showed such a dramatic change in their localization pattern.
explanation: Retains the weaker cellular-localization effect despite insolubility of recombinant N-terminal domains.
notes: Non-animal experimental organism; the structural model alone does not prove partner-binding failure in human tissues.
- name: Chlamydomonas CFAP410 knockout
experimental_model_type: OTHER
description: Two CRISPR knockout lines were compared with wild-type algae for flagellation and flagellar length. The Results describe modest reductions, while the Discussion states that these changes were not significant.
publication: PMID:40018707
modeled_mechanisms:
- target: Defective Primary Ciliogenesis
relationship: FAILS_TO_RECAPITULATE
limitations: Algal flagella are not human primary cilia. The study did not reproduce the marked ciliogenesis loss found in mammalian knockout cells; internal Results/Discussion wording differs.
evidence:
- &id002
reference: PMID:40018707
reference_title: CFAP410 has a bimodular architecture with a conserved surface patch on its N-terminal leucine-rich repeat motif for binding interaction partners.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Surprisingly, no significant changes in flagellar length or the percentage of flagellated cells were observed compared to wild-type cells.
explanation: The Discussion reports no significant ciliation phenotype in two algal knockout lines; the Results describe modest numerical reductions. This limits extrapolation across organisms.
evidence:
- *id002
animal_models:
- name: nek1 zebrafish morpholino with human CFAP410 rescue
species: Zebrafish
description: Splice-blocking nek1 morpholinos cause ciliary developmental abnormalities and retinal defects; human CFAP410 RNA partly rescues the phenotype, with weaker rescue by p.Arg73Pro and little rescue by p.Leu224Pro.
publication: PMID:26167768
modeled_mechanisms:
- target: Defective Primary Ciliogenesis
relationship: PARTIALLY_RECAPITULATES
limitations: Transient knockdown and cross-gene rescue; not a stable genetic model of axial SMD or proof of a human treatment.
evidence:
- reference: PMID:26167768
reference_title: An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: Knockdown of nek1 also resulted in retinal defects including loss of photoreceptors (Suppl. Figure 7fd-g) and cilia length defects in the pronephros (Suppl. Figure 7h,i).
explanation: Whole-embryo knockdown phenotype.
- reference: PMID:26167768
reference_title: An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: RNA expressing C21orf2 with the missense mutation p.Arg73Pro rescued the nek1 morphant phenotype less effectively than wild-type, whereas C21orf2-p.Leu224Pro had little effect (Figure 7e), confirming the predicted hypomorphic effect of both variants observed in vitro (Suppl. Figure 4).
explanation: Relative rescue in a cross-gene embryonic assay; residual activity differs by allele.
- name: Mouse retinal CFAP410 reporter localization
species: Mouse
description: AAV-mediated reporter expression localizes CFAP410 to cone and rod connecting cilia.
publication: PMID:26974433
modeled_mechanisms:
- target: Photoreceptor Connecting Cilium Dysfunction
relationship: MEASURES
limitations: Localization only; no disease-allele dysfunction or gene-therapy rescue was tested.
evidence:
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: C21orf2 protein was localized to the connecting cilium of the cone and rod photoreceptors, confirming its significance in retinal function.
explanation: Anatomical localization assay.
variants:
- name: CFAP410 c.218G>C (p.Arg73Pro)
gene: *id003
description: Homozygous in families F8 and F9; functional assays show residual ciliogenesis rescue and reduced NEK1 association. Skeletal expression is variable even in homozygotes.
evidence:
- &id004
reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: The 12 mutant alleles were counted as five different mutations, including three exonic mutations (c.218G>C, c.319T>C and c.347C>T, S5 Fig; NM_004928), and two intronic mutations (c.545+1G>A and c.643-23A>T).
explanation: Distinct CFAP410 alleles identified in the axial SMD families.
- name: CFAP410 c.319T>C (p.Tyr107His)
gene: *id003
description: In trans with p.Pro116Leu in the founding axial SMD family F5. The same genotype was later reported in a child without skeletal abnormalities; HEK293T assays show reduced protein stability.
evidence:
- *id004
- name: CFAP410 c.347C>T (p.Pro116Leu)
gene: *id003
description: In trans with p.Tyr107His in axial SMD family F5. The 2023 retinal study classifies this allele as likely pathogenic in its detailed assessment and demonstrates reduced stability in HEK293T cells.
evidence:
- *id004
- name: CFAP410 c.643-23A>T
gene: *id003
description: Intronic branch-point candidate in families F1 and F7. Patient RNA demonstrates retention of the entire intron 6, altering the reading frame and predicting an elongated p.Asn215ValfsTer259 product lacking the normal conserved C terminus. Protein abundance and production of the elongated product were not directly measured.
evidence:
- *id004
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Direct sequencing of the PCR product identified that entire intron 6 remained in the mutant mRNA, which led to a frame shift and produced an elongated protein (p.N215Vfs*259) without the C-terminal conserved region.
explanation: Patient RNA confirms intron retention; the protein consequence follows from the transcript sequence.
- name: CFAP410 c.545+1G>A
gene: *id003
description: Canonical splice-donor variant in family F6. Patient RNA demonstrates cryptic donor use, a five-base deletion at the exon 5 end, and partial or complete intron 5 retention. The transcripts predict p.Ala181GlnfsTer6 or p.Ser183Ter; nonsense-mediated decay was predicted, not experimentally measured.
evidence:
- *id004
- reference: PMID:26974433
reference_title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Sequencing results showed that several cryptic donor sites in exon 5 and intron 5 were utilized in the mutant genome, and were responsible for the multiple bands in the RT-PCR (Fig 2C).
explanation: Patient transcript analysis directly demonstrates aberrant splicing.
- name: NEK1 c.3107C>G (p.Ser1036Ter)
gene: *id005
description: One allele of the reported compound-heterozygous axial SMD genotype. Cellular assays show markedly reduced CFAP410 association; protein-level consequences should not be assumed identical to complete NEK1 knockout.
evidence:
- reference: PMID:28123176
reference_title: Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: By whole-exome sequencing in a patient with axial SMD, we identified compound heterozygous mutations of NEK1, c.3107C>G (p.S1036*) and c.3830A>C (p.D1277A), which co-segregated in the family.
explanation: Both alleles co-segregated in the reported family.
- name: NEK1 c.3830A>C (p.Asp1277Ala)
gene: *id005
description: One allele of the reported compound-heterozygous axial SMD genotype. Cellular assays show markedly reduced CFAP410 association; protein-level consequences should not be assumed identical to complete NEK1 knockout.
evidence:
- reference: PMID:28123176
reference_title: Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: By whole-exome sequencing in a patient with axial SMD, we identified compound heterozygous mutations of NEK1, c.3107C>G (p.S1036*) and c.3830A>C (p.D1277A), which co-segregated in the family.
explanation: Both alleles co-segregated in the reported family.
datasets:
- accession: pride:PXD036410
title: Identification of proteins interacting with the NEK1-C21ORF2 complex
data_type: PROTEOMICS
description: Endogenous NEK1 and CFAP410 immunoprecipitation proteomics in parental ARPE-19 cells with the corresponding knockout controls. Each bait experiment used five biological replicates per genotype and a ten-sample TMT comparison.
publication: PMID:37188479
evidence:
- reference: url:https://www.ebi.ac.uk/pride/ws/archive/v2/projects/PXD036410
reference_title: https://www.ebi.ac.uk/pride/ws/archive/v2/projects/PXD036410
supports: SUPPORT
evidence_source: IN_VITRO
snippet: Five biological replicates were used per cell line, and after trypsinization of the precipitates, peptides were labelled with tandem mass tags (TMT) enabling quantitative mass spectrometric analysis of the 10 samples which were pooled and analysed in parallel.
explanation: 'PRIDE PXD036410, Identification of proteins interacting with the NEK1-C21ORF2 complex: repository metadata confirms the cellular design and replicate counts.'
- reference: PMID:37188479
reference_title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The mass spectrometry data relating to Fig 2 have been deposited to the ProteomeXchange consortium via the PRIDE (Perez-Riverol et al, 2022) partner repository with the dataset identifier PXD036410.
explanation: Primary publication identifies the deposited interaction-proteomics dataset.
references:
- reference: PMID:21910225
title: 'Axial spondylometaphyseal dysplasia: additional reports.'
- reference: PMID:23371363
title: Axial spondylometaphyseal dysplasia with retinitis pigmentosa--a clinical report and diagnostic clues.
- reference: PMID:26167768
title: An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.
- reference: PMID:26294103
title: C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium.
- reference: PMID:26974433
title: Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.
- reference: PMID:28123176
title: Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.
- reference: PMID:37188479
title: Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.
- reference: PMID:37901396
title: Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma.
- reference: PMID:39232248
title: Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.
- reference: PMID:39255848
title: The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body.
- reference: PMID:40018707
title: CFAP410 has a bimodular architecture with a conserved surface patch on its N-terminal leucine-rich repeat motif for binding interaction partners.
- reference: PMID:40246852
title: Variants in CFAP410 cause a range of retinal and skeletal phenotypes.
- reference: PMID:9266195
title: Axial spondylometaphyseal dysplasia.

📚

References & Deep Research

References

13

PMID:21910225

Axial spondylometaphyseal dysplasia: additional reports.

No top-level findings curated for this source.

PMID:23371363

Axial spondylometaphyseal dysplasia with retinitis pigmentosa--a clinical report and diagnostic clues.

No top-level findings curated for this source.

PMID:26167768

An siRNA-based functional genomics screen for the identification of regulators of ciliogenesis and ciliopathy genes.

No top-level findings curated for this source.

PMID:26294103

C21orf2 is mutated in recessive early-onset retinal dystrophy with macular staphyloma and encodes a protein that localises to the photoreceptor primary cilium.

No top-level findings curated for this source.

PMID:26974433

Axial Spondylometaphyseal Dysplasia Is Caused by C21orf2 Mutations.

No top-level findings curated for this source.

PMID:28123176

Axial spondylometaphyseal dysplasia is also caused by NEK1 mutations.

No top-level findings curated for this source.

PMID:37188479

Functional characterization of C21ORF2 association with the NEK1 kinase mutated in human in diseases.

No top-level findings curated for this source.

PMID:37901396

Pathogenicity and functional analysis of CFAP410 mutations causing cone-rod dystrophy with macular staphyloma.

No top-level findings curated for this source.

PMID:39232248

Expanding the genotypic and phenotypic spectra with a novel variant in the ciliopathy gene, CFAP410, associated with selective cone degeneration.

No top-level findings curated for this source.

PMID:39255848

The C-terminus of CFAP410 forms a tetrameric helical bundle that is essential for its localization to the basal body.

No top-level findings curated for this source.

PMID:40018707

CFAP410 has a bimodular architecture with a conserved surface patch on its N-terminal leucine-rich repeat motif for binding interaction partners.

No top-level findings curated for this source.

PMID:40246852

Variants in CFAP410 cause a range of retinal and skeletal phenotypes.

No top-level findings curated for this source.

PMID:9266195

Axial spondylometaphyseal dysplasia.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Axial_Spondylometaphyseal_Dysplasia · 2026-09-11T12:41:18Z · View source

De novo curation of axial spondylometaphyseal dysplasia (MONDO:0011211; CFAP410/C21orf2 and NEK1) from a Perplexity sonar-deep-research report plus independent PubMed retrieval. Deep research: research/Axial_Spondylometaphyseal_Dysplasia-deep-research-perplexity.md (perplexity, sonar-deep-research, 396.3 s, 19 citations). Produced only after the installed deep-research-client Perplexity provider was patched locally to stream; see dismech#9357, which is already open with the same diagnosis and fix, so no duplicate issue was filed and no repository file was changed. just preflight-dr returned WARN: rival gene NEK1 mentioned 67 times against CFAP410's 84. Checked and dismissed as a false positive - NEK1 is a genuine second locus for this same disease (PMID:28123176), not a second disease bleeding into the report. Recording this because the WARN text tells a curator to exclude those sections, which would have been wrong here. The report's reference_validation flagged PMID:37477485 as off topic; it resolves to a paper on optical voltage imaging in neurogenic erectile dysfunction and is unrelated. Not cited. Its term_validation reports 13 of 47 checked labels mismatched, among them CL:0000097 offered as 'chondrocyte' (CL: mast cell), CL:0000742 as 'cone photoreceptor' (periarticular chondrocyte), GO:0035994 as 'primary cilium assembly' (response to muscle stretch) and HP:0000944 as 'Metaphyseal dysplasia' (Abnormal metaphysis morphology). No CURIE was taken from the report. Mistake made and corrected during curation, recorded because the failure mode is the one CLAUDE.md warns about: NCIT:C38101 was written with the label 'Diagnostic Imaging' from recall rather than from a lookup performed in the same step. Term validation caught it; the CURIE is real and the concept is right for a skeletal survey, but its canonical label is 'X-Ray Imaging'. Fixed by reading it from OLS. A second validation failure was a schema one - causal_link_type 'INDIRECT' is not a permissible value; the correct value for this edge is INDIRECT_UNKNOWN_INTERMEDIATES. Evidence: 42 snippets across 8 PMIDs, all exact-quote verified. Two pathophysiology nodes declare conforms_to against ciliopathy_dysfunction (basal body/transition zone, photoreceptor connecting cilium). The module's #Skeletal Dysplasia with Polydactyly and Thoracic Constriction node was deliberately not claimed because polydactyly is absent in this disease; the reasoning is written into the entry description rather than left as an omission. The chondrocyte arm of the pathograph is marked INDIRECT_UNKNOWN_INTERMEDIATES on purpose: no Hedgehog or other ciliary signalling readout has ever been measured in an axial SMD chondrocyte, and the only functional datum is described by its own authors as suggestive. Three knowledge gaps are recorded - the unmeasured signalling step, whether the homologous-recombination arm of the CFAP410-NEK1 complex contributes to either tissue phenotype, and why the dysplasia is confined to the axial skeleton. Validated with just validate (schema, terms, 42/42 snippets), check-duplicate-keys, check-entity-refs, check-causal-targets, check-qualifier-terms.

Perplexity ▸

1. Disease Information

sonar-deep-research 19 citations 2026-09-11T12:29:27.307780

1. Disease Information

1.1 Definition and Overview

Axial spondylometaphyseal dysplasia is a clinically and radiographically defined Mendelian skeletal dysplasia in which the spine, ribs, pelvis, and proximal long bones show characteristic abnormalities, and in which retinal degeneration is a core syndromic feature.[1][3][19] The term “spondylometaphyseal dysplasia” denotes a group of disorders involving abnormal development of the vertebral bodies (“spondylo-”) and the metaphyses of long tubular bones (“-metaphyseal”), while the qualifier “axial” emphasizes predominant involvement of bones near the body’s axis, such as the spine, ribs, pelvis, and proximal femora.[1][3][8] Clinically, affected individuals present with postnatal growth failure and disproportionate short stature, often with rhizomelic limb shortening in early childhood that evolves into a predominantly short trunk, together with a small, deformed thorax that may cause restrictive ventilatory impairment and recurrent respiratory infections.[1][3][19][17] Ocularly, progressive visual loss in early childhood is typical, with funduscopic findings compatible with retinitis pigmentosa or pigmentary retinal degeneration and electroretinographic evidence of cone-rod dystrophy.[1][3][19][6] Radiographic hallmarks include short ribs with flared and cupped anterior ends, mild spondylar dysplasia or platyspondyly, lacy iliac crests, and metaphyseal irregularities essentially confined to the proximal femora.[1][3][19]

Orphanet and the Orphanet Rare Disease Ontology define axial SMD as a rare type of spondylometaphyseal dysplasia characterized by metaphyseal changes of truncal-juxtatruncal bones associated with retinal dystrophy, with onset in infancy or childhood and autosomal recessive inheritance.[3][9] The Genetic and Rare Diseases Information Center (GARD) similarly describes axial SMD as a genetic disorder of bone growth primarily affecting the chest, pelvis, spine, upper arms, and upper legs, and associated with early and progressive vision loss.[11] OMIM summarizes the core phenotype as postnatal growth failure, rhizomelic short stature evolving into short trunk, thoracic hypoplasia, susceptibility to airway infections, and early-onset retinal dystrophy diagnosed as retinitis pigmentosa or cone-rod dystrophy.[19] Together, these sources converge on a concept of axial SMD as a syndromic skeletal-retinal ciliopathy with a distinctive pattern of axial skeletal dysplasia and retinal degeneration, confined to a very small number of families worldwide.[1][3][9][19]

From a disease classification standpoint, axial SMD is included in the “spondylometaphyseal dysplasias” in the International Nosology and Classification of Genetic Skeletal Disorders, reflecting consensus that it constitutes a distinct nosologic entity rather than a variant of other SMD types.[1] It is categorized as a Mendelian rare disease with a point prevalence estimated at less than 1 per 1 000 000 and approximately 13 reported families globally, underscoring its extreme rarity and the fact that most knowledge comes from case reports and small series rather than large cohorts.[9] For a structured disease ontology, axial SMD corresponds to MONDO:0011211 (Axial spondylometaphyseal dysplasia), although detailed MONDO-specific annotations are not provided in the current search results.

1.2 Nomenclature, Identifiers, and Synonyms

Axial spondylometaphyseal dysplasia is known by several identifiers in major biomedical databases. OMIM assigns the phenotype entry MIM 602271, “Spondylometaphyseal dysplasia, axial; SMDAX.”[19] Orphanet uses the name “Axial spondylometaphyseal dysplasia” with Orpha number ORPHA:168549, and associates it with ICD-10 code Q77.8 (“Other osteochondrodysplasias with defects of growth of tubular bones and spine”) and ICD-11 code LD24.4.[3][9] The Orphanet Rare Disease Ontology cross-references MeSH descriptor C535795, UMLS Concept C1865695, and related vocabularies.[9][17] SNOMED CT includes a concept (771301002) for axial spondylometaphyseal dysplasia, and the disease is indexed in MedGen under the same UMLS concept.[17][19]

Common synonyms include “axial SMD,” “axial spondylometaphyseal dysplasia with retinal dystrophy,” and “spondylometaphyseal dysplasia, axial type.”[5][8][19] Earlier clinical reports sometimes referred to “axial SMD with retinitis pigmentosa” before the entity was formally named.[5][6] Because CFAP410 was initially known as C21orf2, the disease has also been described as “C21orf2-related axial spondylometaphyseal dysplasia” in molecular genetics publications.[4][19] For ontology mapping, an appropriate MONDO synonym set would include “axial spondylometaphyseal dysplasia,” “spondylometaphyseal dysplasia axial type,” “axial SMD,” and “SMDAX.”

1.3 Historical Description and Nosologic Clarification

The first detailed description of axial SMD was provided by Ehara et al. in 1997, who reported four patients from two unrelated families with a previously undescribed skeletal dysplasia characterized by mild platyspondyly, a small thorax with cupped anterior rib ends, irregular metaphyses of the proximal femora, and lacy iliac wings, in the absence of the severe epiphyseal dysplasia seen in Dyggve-Melchior-Clausen (DMC) syndrome.[8][19] The authors suggested an autosomal recessive inheritance based on parental consanguinity and recurrence among siblings.[8][19] At that time, retinal findings were not a major focus, and the entity was primarily defined radiographically.

Subsequent reports expanded the phenotype and highlighted the consistent association with retinal dystrophy. Isidor et al. (2010, Am J Med Genet A; PMID: 20503334) described two unrelated boys with short stature, femoral metaphyseal abnormalities, platyspondyly, and retinitis pigmentosa, whose skeletal findings closely matched those described by Ehara et al., thereby confirming axial SMD as a distinct spondylometaphyseal dysplasia and emphasizing its retinal involvement.[5] Suzuki et al. (2011, Pediatr Radiol; PMID: 21910225) reviewed previously reported cases and contributed additional patients, allowing them to propose formal clinical and radiologic diagnostic criteria and to define axial SMD’s hallmarks: postnatal growth failure with rhizomelic short stature evolving to short trunk, thoracic hypoplasia with respiratory vulnerability, retinal degeneration leading to cone-rod dystrophy, and a distinctive radiographic pattern of short, flared ribs, mild spondylar dysplasia, lacy iliac crests, and proximal femoral metaphyseal changes.[1]

These descriptive efforts led to the inclusion of axial SMD in the Nosology and Classification of Genetic Skeletal Disorders, where it is recognized as a unique subtype within the spondylometaphyseal dysplasia group.[1][7] The subsequent identification of CFAP410/C21ORF2 and NEK1 as disease genes not only confirmed axial SMD’s distinctiveness but also linked it mechanistically to ciliopathies, such as short-rib thoracic dysplasias, expanding its conceptual context within the broader field of skeletal and retinal ciliopathies.[4][7][19]

1.4 Data Sources and Evidence Base

Because axial SMD is extremely rare, virtually all phenotypic and clinical data derive from individual patient reports, small familial series, and aggregations of such cases in review articles and nosology updates.[1][3][5][8][19] Orphanet estimates that approximately 13 families have been reported worldwide, reflecting both genuine rarity and under-recognition.[9] The clinical descriptions in OMIM and Orphanet are synthesized from these case-level reports, while GARD and MedGen rely on aggregated resources derived from OMIM and Orphanet.[11][17][19]

On the molecular side, evidence for CFAP410/C21ORF2 and NEK1 as causal genes comes from whole-exome sequencing studies in small cohorts of axial SMD patients, supported by segregation analyses in families and functional experiments in cell models demonstrating impaired ciliogenesis and retinal ciliary localization.[4][7][12][13][16] These data are aggregated in OMIM, ClinVar, and ClinGen-type resources, with ClinVar documenting specific pathogenic variants such as CFAP410 c.319T>C (p.Tyr107His), classified as pathogenic for axial SMD.[10][19] Because no large cohort or registry-based studies exist, there is little in the way of formal epidemiologic or natural history data, and much of the disease characterization relies on expert synthesis of limited but consistent case-level evidence.[1][3][5][6][8][19]

2. Etiology

2.1 Primary Causal Factors: Genetic Basis

Axial spondylometaphyseal dysplasia is fundamentally a genetic disorder with a Mendelian autosomal recessive inheritance pattern.[1][3][9][19] The primary etiologic factor is biallelic pathogenic variants in genes encoding proteins that localize to the primary cilium and participate in ciliogenesis and DNA damage repair. The earliest and most extensively documented causal gene is C21ORF2, now officially named CFAP410 (Cilia and Flagella Associated Protein 410), located on chromosome 21q22.3.[4][19] OMIM uses a number sign (#) for the axial SMD phenotype entry, indicating that the phenotype is caused by homozygous or compound heterozygous mutations in C21ORF2/CFAP410.[19] Wang et al. (2016, PLoS One; PMID: 26932817) performed whole-exome sequencing in axial SMD patients and identified multiple C21ORF2 mutations segregating with disease, leading them to conclude that “axial SMD is caused by C21ORF2 mutations.”[4][19] Functional studies demonstrated that C21ORF2 protein localizes to the connecting cilium of cone and rod photoreceptors and to centrosomal structures in ciliated cells, confirming its role in ciliary function.[4][16]

Subsequently, genetic heterogeneity was recognized when some clinically diagnosed axial SMD cases lacked CFAP410 variants. Wang et al. (2017, J Hum Genet; PMID: 27848943) identified NEK1 as a second disease gene by exome sequencing in axial SMD patients negative for C21ORF2 variants, demonstrating that biallelic NEK1 mutations can also cause axial SMD.[7] NEK1 encodes NIMA-related kinase 1, a serine/threonine kinase that plays key roles in ciliogenesis, microtubule stability, and DNA damage response, and had previously been implicated in other short-rib thoracic dysplasia phenotypes without retinal dystrophy.[7] The recognition that NEK1 mutations can produce an axial SMD-like phenotype supports the concept of axial SMD as a ciliopathy in which disruption of a shared NEK1–CFAP410 pathway yields combined axial skeletal and retinal pathology.[4][7][12]

No environmental, infectious, or purely mechanistic non-genetic primary etiologies have been identified. The disease consistently segregates in families with autosomal recessive patterns, frequently with parental consanguinity, and no cases have been reported in which environmental exposures alone produce an axial SMD phenotype.[1][5][8][19] Thus, axial SMD is best conceptualized as a monogenic ciliopathy, with CFAP410 and NEK1 as the principal causal genes and with no evidence for non-genetic primary causes.

2.2 Genetic Risk Factors and Variant Architecture

Within the context of a monogenic disease, “risk factors” primarily refer to the presence of pathogenic or likely pathogenic variants in CFAP410 or NEK1. Wang et al. and OMIM report multiple variant types in CFAP410, including missense, nonsense, frameshift, and splice-site variants, affecting evolutionarily conserved residues and leading to loss of function or severe hypomorphic alleles.[4][19] For example, ClinVar lists the c.319T>C (p.Tyr107His) missense variant in CFAP410 as pathogenic for axial SMD, based on literature evidence from Wang et al. and others.[10][4] Population databases such as gnomAD, while not explicitly referenced in the search results, generally show very low allele frequencies for these variants, consistent with the disease’s rarity, and no common susceptibility alleles have been described.

CFAP410 mutations have also been identified in patients with isolated retinal dystrophies, including cone-rod dystrophy and early-onset retinal dystrophy with macular staphyloma, sometimes with short stature but without full-blown axial SMD.[13][14][16] These phenotypic differences likely reflect allelic heterogeneity, where specific variant combinations determine whether the phenotype is syndromic skeletal-retinal or mainly ocular.[13][16] Shinbashi et al. (2023, Clin Case Rep; PMID: 37477485) reviewed 34 reported cases of C21ORF2/CFAP410 variant-associated retinopathies and highlighted the wide phenotypic spectrum from nonsyndromic retinitis pigmentosa to syndromic phenotypes with skeletal involvement, suggesting that certain variants or combinations may confer a higher risk of axial SMD.[14][13] This implies that within CFAP410, some variants are “high-risk” for axial SMD while others predispose primarily to retinal disease.

Similarly, NEK1 mutations associated with axial SMD appear to be biallelic loss-of-function or severe missense variants, often distinct from the heterozygous NEK1 variants implicated as risk factors in amyotrophic lateral sclerosis (ALS).[7][12][15] Wang et al. showed that NEK1 variants in axial SMD patients overlap functionally with variants found in short-rib thoracic dysplasia, emphasizing that specific combinations of NEK1 mutations can yield different skeletal phenotypes depending on residual activity and perhaps modifying genetic background.[7] However, no systematic study of modifier genes in axial SMD has been reported.

2.3 Environmental and Demographic Risk Factors

Beyond the presence of pathogenic CFAP410 or NEK1 variants, few environmental or demographic risk factors have been identified, largely because axial SMD is a fully penetrant, early-onset Mendelian disorder in affected individuals. Orphanet and OMIM emphasize autosomal recessive inheritance and note that many reported families involve consanguinity, which primarily increases the probability that both parents carry the same rare pathogenic allele rather than acting as an independent risk factor.[3][5][8][9][19] In populations where consanguineous marriages are more common, the risk of autosomal recessive disorders in general is elevated, but there are no data suggesting population-specific enrichment of axial SMD beyond what would be expected from random distribution of extremely rare alleles.[3][9][19]

Environmental exposures such as toxins, dietary factors, or infections have not been implicated in disease initiation. However, thoracic hypoplasia and restrictive ventilatory defects predispose patients to recurrent respiratory infections and possibly chronic lung injury, making environmental exposures to respiratory pathogens, pollutants, or tobacco smoke more relevant to disease complications than to primary etiology.[1][17][18] Age and sex do not appear to influence disease risk in a Mendelian sense; cases include both males and females, and the sex ratio among the small number of reported families does not suggest a strong bias.[1][5][6][8] Family history is relevant insofar as siblings of affected individuals have a 25% recurrence risk given autosomal recessive inheritance, but this reflects genetic rather than environmental risk.

2.4 Protective Factors and Lack of Modifying Exposures

No genetic protective factors, such as variants that reduce disease severity or confer resistance to axial SMD in carriers of otherwise pathogenic CFAP410 or NEK1 alleles, have been described. Given the tiny number of reported families and the absence of large cohorts, such modifiers would be difficult to detect. Some variability in skeletal or retinal severity between individuals with similar genotypes has been noted, but no specific modifier genes have been implicated.[1][4][7][13][14] Similarly, there is no evidence that particular environmental or lifestyle factors can prevent disease onset in genetically predisposed individuals, although general measures to support respiratory health and protect vision may mitigate complications.

From a population-genetic perspective, the rarity of axial SMD implies that carriers of pathogenic CFAP410 or NEK1 variants are uncommon, and there is no evidence that carrier status confers any selective advantage that might act as a “protective factor” in other contexts. In the absence of mechanistically grounded data, any suggestion of protective factors would be speculative.

2.5 Gene–Environment Interactions

Specific gene–environment interactions have not been studied in axial SMD, and available clinical reports do not identify environmental triggers that modify disease onset or progression in a predictable way.[1][5][6][8] However, some plausible interactions can be inferred based on the nature of the skeletal and respiratory abnormalities. Thoracic hypoplasia and restrictive ventilatory impairment are present early in life, and these structural constraints likely interact with environmental exposures to respiratory pathogens, indoor air pollution, or second-hand smoke to increase the risk and severity of recurrent pneumonia and chronic lung disease.[1][17][18] Such interactions affect the clinical course and morbidity rather than the initial development of skeletal dysplasia.

Similarly, early-onset retinal degeneration may interact with environmental light exposure, but there is no evidence that light restriction or specific visual environments alter the course of disease. Because CFAP410 and NEK1 are also involved in DNA damage repair, one could hypothesize that environmental DNA-damaging agents (such as ionizing radiation) might exacerbate cellular stress in affected tissues; however, this remains speculative and has not been demonstrated in axial SMD patients.[12][13] Overall, axial SMD remains a primarily gene-driven, fully penetrant Mendelian disorder with minimal documented gene–environment interplay beyond the general influences affecting all individuals with thoracic restriction or retinal degeneration.

3. Phenotypes

3.1 Skeletal Manifestations

The skeletal phenotype of axial SMD is central to its clinical recognition and classification. The main clinical skeletal features include postnatal growth failure, disproportionate short stature, rhizomelic limb shortening in early childhood, evolving into a short trunk phenotype, and distinctive radiographic changes involving the ribs, spine, pelvis, and proximal femora.[1][3][5][8][19] Suzuki et al. defined the clinical trajectory as follows: “The main clinical findings are postnatal growth failure, rhizomelic short stature in early childhood evolving into short trunk in late childhood, and thoracic hypoplasia that may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.”[1] This description indicates that growth is initially normal or near-normal prenatally, with postnatal deceleration, and that disproportion becomes apparent in early childhood, consistent with an HPO term of “Postnatal growth retardation” (HP:0008897) and “Disproportionate short stature” (HP:0001511).

Radiographically, short ribs with flared and cupped anterior ends are a cardinal feature, contributing to a small, sometimes bell-shaped thorax.[1][3][8][19] This pattern corresponds to “Thoracic hypoplasia” (HP:0005257), as described in MedGen, where axial SMD is explicitly mentioned as a cause of thoracic hypoplasia.[18] The anterior rib cupping reflects metaphyseal irregularities in the costochondral junctions, analogous to changes seen in other metaphyseal dysplasias. Mild platyspondyly or spondylar dysplasia manifests as flattened vertebral bodies, sometimes with subtle irregularities, but without the severe double-hump deformity seen in Dyggve-Melchior-Clausen syndrome.[1][8][19] Appropriate HPO terms include “Platyspondyly” (HP:0000926) and “Spondylar dysplasia” (HP:0002655).

The pelvis shows a characteristic “lacy” appearance of the iliac crests, with irregular, lace-like metaphyseal bone at the iliac wings, which was emphasized by Ehara and later authors as a key differential point.[1][3][8][19] This feature corresponds to “Abnormality of the ilium” (HP:0002883) and “Lacy iliac crests,” although the latter is not an independent HPO term but can be captured under abnormal pelvic morphology. The proximal femora exhibit metaphyseal dysplasia with irregular, sometimes enchondroma-like lesions, but without the severe epiphyseal involvement seen in some other SMDs.[1][3][8][19] HPO terms such as “Metaphyseal dysplasia” (HP:0000944) and “Abnormality of the femoral metaphysis” (HP:0003379) are suitable.

Clinically, these skeletal changes result in a short thorax, reduced arm span, and disproportionate limb-to-trunk ratios. Functional consequences include reduced height, often in the –3 to –5 SD range, musculoskeletal discomfort, and in some cases gait abnormalities due to hip involvement, although detailed functional descriptions are limited in the literature.[1][5][6] The severity of skeletal manifestations is typically moderate compared to lethal short-rib thoracic dysplasias, but sufficient to cause significant disability. Symptom progression appears relatively stable after the period of active growth, with skeletal deformities persisting into adulthood but not usually leading to catastrophic spinal or joint failure in the limited number of reported adults.[1][5]

For a knowledge base, primary skeletal HPO terms to associate with axial SMD include HP:0001510 (Growth delay), HP:0001511 (Disproportionate short stature), HP:0005257 (Thoracic hypoplasia), HP:0000926 (Platyspondyly), HP:0000944 (Metaphyseal dysplasia), HP:0002883 (Abnormality of the ilium), and HP:0003379 (Abnormality of the femoral metaphysis). Frequency in affected individuals appears high (approaching 100% for many of these features), given that they are part of the defining criteria.[1][3][5][8][19]

3.2 Ocular and Retinal Phenotypes

Retinal dystrophy is the defining extra-skeletal feature of axial SMD and has significant implications for quality of life. Patients typically present with impaired visual acuity in early life, often in childhood, and vision deteriorates rapidly.[1][3][19] Suzuki et al. note that impaired visual acuity “comes to medical attention in early life and function rapidly deteriorates,” emphasizing the early onset and progressive course.[1] Funduscopic examination reveals retinal changes diagnosed as retinitis pigmentosa or pigmentary retinal degeneration, while electroretinography demonstrates cone-rod dystrophy.[1][3][19] HPO terms capturing these features include “Retinitis pigmentosa” (HP:0000510), “Pigmentary retinal degeneration” (HP:0000580), “Cone-rod dystrophy” (HP:0000548), “Decreased visual acuity” (HP:0007663), and “Progressive visual loss” (HP:0000529).

The retinal phenotype in axial SMD aligns with CFAP410-related retinopathies more broadly. C21orf2/CFAP410 mutations were first linked to early-onset retinal dystrophy with macular staphyloma by Daiger and colleagues (Br J Ophthalmol; PMID: 26294103), who showed that C21orf2 protein localizes to the photoreceptor primary cilium, confirming the disease as a retinal ciliopathy.[16] Later reports and reviews of CFAP410 variant-associated retinopathies, including Shinbashi et al. (2023), highlight a spectrum of inherited retinal diseases ranging from nonsyndromic retinitis pigmentosa to cone-rod dystrophy and macular staphyloma, depending on the variant combination.[13][14][16] In axial SMD, the retinal disease appears to be more severe and rapidly progressive, consistent with syndromic ciliopathy.

The impact of retinal dystrophy on quality of life is profound. Early-onset, progressive cone-rod dystrophy leads to loss of central and peripheral vision, impairing reading, mobility, education, and employment opportunities. While formal quality-of-life assessments (e.g., EQ-5D or SF-36) have not been reported specifically in axial SMD, extrapolation from other early-onset retinal dystrophies suggests substantial impairment in domains such as mobility, self-care, usual activities, and anxiety/depression. The progressive nature of visual loss means that individuals may transition from partially sighted to legally blind status during childhood or adolescence, compounding the challenges imposed by skeletal disabilities.[1][3][6][13][14]

3.3 Respiratory and Cardiopulmonary Involvement

Thoracic hypoplasia in axial SMD has significant respiratory consequences. The small, deformed thorax results in reduced lung volumes and restrictive ventilatory defects, which may manifest as mild to moderate respiratory problems in the neonatal period and persistent susceptibility to airway infections later in life.[1][18][19] MedGen’s entry on thoracic hypoplasia includes a summary, derived from Suzuki et al. and OMIM, stating that axial SMD is characterized by thoracic hypoplasia that “may cause mild to moderate respiratory problems in the neonatal period and later susceptibility to airway infection.”[18] GTR/MedGen entries for axial SMD list “Recurrent pneumonia” and “Restrictive ventilatory defect” as associated respiratory abnormalities.[17]

Clinically, some infants may present with respiratory distress or difficulty during infections, and recurrent lower respiratory tract infections are common, particularly in early childhood when immune and respiratory systems are still developing.[1][17][18] HPO terms such as “Recurrent pneumonia” (HP:0006532), “Restrictive respiratory defect” (HP:0002795), and “Dyspnea” (HP:0002094) are appropriate descriptors. The severity of respiratory involvement appears variable; Suzuki et al. describe thoracic hypoplasia as causing “mild to moderate” respiratory problems, suggesting that life-threatening respiratory failure is not typical, unlike in some lethal short-rib thoracic dysplasias.[1][18] Nevertheless, recurrent infections can contribute to chronic lung disease and reduced cardiopulmonary reserve, particularly in adulthood.

There is limited data on direct cardiac involvement. Most reports focus on thoracic and pulmonary manifestations rather than intrinsic cardiomyopathy or structural heart disease.[1][5][6][8] However, chronic hypoxia or recurrent infections could secondarily affect cardiopulmonary health. Formal pulmonary function testing has not been systematically reported but is likely to show restrictive patterns due to chest wall restriction. The HPO term “Thoracic hypoplasia” (HP:0005257) thus serves as a primary anatomical descriptor, with functional consequences captured by respiratory phenotype terms.

3.4 Growth, Development, and Functional Impact

Beyond specific skeletal and ocular abnormalities, axial SMD significantly affects overall growth, development, and functional status. Postnatal growth failure leads to short stature, with some patients exhibiting rhizomelic limb shortening early on and evolving to a short trunk phenotype in late childhood.[1][3][19] HPO terms “Short stature” (HP:0004322) and “Rhizomelic short stature” (HP:0003376) capture this pattern, while “Short trunk” (HP:0005776) reflects the later disproportion. The growth pattern suggests normal or near-normal birth size followed by slowing of growth rates, indicating that the disorder primarily affects postnatal skeletal maturation rather than fetal development.[1][5][8][19]

Developmental milestones in terms of motor and cognitive function have not been extensively documented. The available case reports do not emphasize cognitive impairment, suggesting that neurodevelopment is typically normal.[1][5][6][8] However, musculoskeletal and visual disabilities likely delay gross motor milestones and limit participation in age-appropriate activities. Short stature, thoracic restriction, and visual impairment together constrain physical activities, school participation, and vocational opportunities, especially in environments lacking adaptive supports.

Quality-of-life impact is significant, even if not formally quantified. Short stature and skeletal deformities may lead to social stigmatization, while visual impairment dramatically affects independence and education. Early adulthood functioning depends heavily on access to orthopedic care, visual rehabilitation, and environmental accommodations. In the context of a knowledge base, it is important to recognize that axial SMD affects multiple domains of functioning, including physical, sensory, and psychosocial, even if exact scores on standardized instruments like EQ-5D are not available.[1][3][6][13][14]

3.5 Other Reported Features and Phenotypic Variability

Other features have been reported sporadically in axial SMD or related CFAP410 syndromes, though they are not core diagnostic criteria. In some patients with biallelic CFAP410 mutations and early-onset retinal dystrophy, short stature and obesity have been noted, suggesting that CFAP410 mutations may cause broader syndromic ciliopathy phenotypes beyond classical axial SMD.[16][13] For example, Daiger et al. reported a girl with early-onset retinal dystrophy, short stature, and obesity, proposing that biallelic C21ORF2 mutations may underlie a syndromic ciliopathy in some cases.[16] However, this phenotype overlaps only partially with axial SMD and may represent a related but distinct clinical category.

In the axial SMD cases, Isidor et al. and Suzuki et al. did not report major visceral malformations, renal cystic disease, or neurological deficits, distinguishing axial SMD from more pleiotropic ciliopathies such as Joubert or Bardet–Biedl syndromes.[1][5][6][8][19] Pain, fatigue, and musculoskeletal discomfort are likely but not systematically described. The phenotypic spectrum thus appears relatively focused on skeletal and retinal systems, with some variability in the degree of thoracic and visual impairment.

Phenotypic expressivity may be influenced by genotype. For instance, some CFAP410 variants are associated primarily with retinal disease, while others cause combined skeletal and retinal phenotypes.[13][14][16] Similarly, NEK1 variants produce different short-rib thoracic dysplasia phenotypes with or without retinal involvement.[7] However, within the limited axial SMD case series, most core features are present in nearly all patients, suggesting relatively consistent expressivity at the syndrome level.[1][3][5][6][8][19]

4. Genetic and Molecular Information

4.1 Causal Genes and Gene-Level Annotations

The two established causal genes for axial SMD are CFAP410 (formerly C21ORF2) and NEK1. OMIM lists CFAP410 (MIM 603191) on chromosome 21q22.3 as the principal gene associated with the axial SMD phenotype (MIM 602271).[19] CFAP410 encodes a cilia and flagella-associated protein that localizes to the connecting cilium of photoreceptors and to centrosomal structures in other ciliated cells.[4][13][16] Gene ontology annotations for CFAP410 include roles in “axoneme assembly” (GO:0035082), “cilium organization” (GO:0044782), and “DNA repair” (GO:0006281), reflecting experimental evidence that CFAP410 participates in ciliogenesis and DNA damage repair processes.[12][13][16]

NEK1 (NIMA-related kinase 1; MIM 604588) encodes a serine/threonine kinase localized to the basal body and pericentriolar matrix, where it regulates primary cilium assembly, microtubule dynamics, and DNA damage response.[7][12][15] Wang et al. showed that NEK1 mutations underlie a subset of axial SMD cases negative for CFAP410 mutations and noted that NEK1 had previously been implicated in three types of short-rib thoracic dystrophy, but those lacked retinal dystrophy.[7] Gene ontology terms associated with NEK1 include “protein serine/threonine kinase activity” (GO:0004674), “primary cilium assembly” (GO:0035994), and “DNA damage checkpoint” (GO:0000077).[12][15]

Evidence from human cell models indicates that CFAP410 and NEK1 function in a shared pathway. Gene knockout of either NEK1 or C21ORF2/CFAP410 in human retinal pigment epithelial cells dramatically reduces ciliogenesis, suggesting that both are essential for primary cilium formation.[12] NEK1 phosphorylates CFAP410 and stabilizes it against ubiquitin-mediated degradation, while CFAP410 acts as a NEK1 interactor required for efficient DNA damage repair, likely functioning within the same pathway in both ciliogenesis and DNA repair.[12][13][15] These interactions position CFAP410 and NEK1 within a functional module critical for primary cilium integrity and genomic stability, consistent with their involvement in axial SMD and in other ciliopathy and neurodegenerative phenotypes.

4.2 Pathogenic Variant Spectrum and Classification

The pathogenic variant spectrum in CFAP410 includes missense, nonsense, frameshift, and splice-site variants, many of which affect evolutionarily conserved residues and are predicted to disrupt protein structure or function.[4][13][14][16] Wang et al. identified multiple C21ORF2 mutations in axial SMD patients, including splice-site and missense variants, and confirmed pathogenicity by demonstrating abnormal splicing at the RNA level and reduced or aberrant protein products.[4] For example, they reported complex patterns of abnormal splicing caused by splice-site and branch-point mutations and noted that these mutations resulted in truncated or altered proteins that compromised ciliary function.[4] ClinVar documents specific CFAP410 variants, such as NM_004928.3:c.319T>C (p.Tyr107His), as pathogenic for axial SMD, based on literature evidence and expert assertion.[10]

In isolated retinal dystrophies associated with CFAP410, compound heterozygous variants such as c.319T>C (p.Tyr107His) and c.347C>T (p.Pro116Leu) have been reported in patients with cone-rod dystrophy and macular staphyloma.[13][16] Functional studies of these variants suggest that they impair CFAP410’s ability to localize to photoreceptor cilia or interact with partner proteins, leading to ciliary dysfunction.[13] The fact that the same variants can cause predominantly ocular phenotypes in some individuals and syndromic skeletal-retinal phenotypes in others underscores the complexity of genotype–phenotype correlations and hints at additional modifiers or threshold effects in ciliary pathways.[13][14][16]

The NEK1 variant spectrum in axial SMD includes biallelic loss-of-function mutations, such as frameshifts and nonsense variants, and possibly hypomorphic missense changes affecting kinase activity or stability.[7] Wang et al. noted that NEK1 mutations associated with axial SMD differ from heterozygous NEK1 variants implicated in ALS, which typically act as risk factors rather than fully penetrant Mendelian causes.[7][12][15] ACMG/AMP classification of CFAP410 and NEK1 variants in axial SMD is generally “pathogenic” or “likely pathogenic,” based on segregation, functional evidence, and absence or extreme rarity in population databases.[4][7][10][13][16]

Most axial SMD variants are germline and inherited in an autosomal recessive manner, with affected individuals being homozygous or compound heterozygous for pathogenic alleles.[1][4][5][7][8][19] Somatic variants have not been implicated. Structural variants, such as large deletions or duplications, have not been reported in axial SMD per se, although such events could theoretically disrupt CFAP410 or NEK1; current evidence focuses on single-nucleotide and small indel variants.

4.3 Functional Consequences and Molecular Mechanisms of Variants

Pathogenic CFAP410 and NEK1 variants generally result in loss of function, either through nonsense-mediated decay, truncated nonfunctional protein, or missense changes disrupting protein folding, localization, or interactions.[4][7][12][13][16] Wang et al. demonstrated that C21ORF2/CFAP410 mutants associated with axial SMD impair ciliogenesis, as evidenced by reduced cilia formation in patient-derived cells and by mislocalization of CFAP410 away from ciliary structures.[4] Immunohistochemical studies localized C21ORF2 protein to the daughter basal body, centriole adjacent to the basal body, and connecting cilium in photoreceptor cells, supporting a role in photoreceptor ciliary structure and function.[16] Loss-of-function variants likely compromise this localization, leading to defects in photoreceptor outer segment maintenance and ultimately retinal degeneration.[13][16]

At the cellular level, knockout of NEK1 or C21ORF2/CFAP410 in retinal pigment epithelial cells significantly reduces ciliogenesis, pointing to a shared requirement for these proteins in primary cilium formation.[12] NEK1 phosphorylates CFAP410 and prevents its degradation by the FBXO3-mediated ubiquitin–proteasome system, suggesting that NEK1 stabilizes CFAP410 and that disruption of this interaction destabilizes the ciliary apparatus.[12][13] ALS-associated CFAP410 mutants have been shown to mislocalize from centrosomes and fail to rescue ciliogenesis defects, further supporting the importance of precise localization and interaction with NEK1 for ciliary function.[12][15]

In addition to ciliogenesis, both NEK1 and CFAP410 have been implicated in DNA damage repair. NEK1 plays a critical role in DNA damage repair pathways, particularly in the response to double-strand breaks and the regulation of homologous recombination.[12] CFAP410 depletion reduces the efficiency of homologous recombination repair, and this defect can be rescued by NEK1 overexpression, indicating that CFAP410 functions within the same pathway as NEK1 in DNA damage repair.[12] Interestingly, NEK1 translocates to sites of DNA damage, whereas CFAP410 does not, suggesting that CFAP410 acts as a cofactor or stabilizer rather than a direct DNA repair enzyme.[12][13] In the context of axial SMD, these DNA repair defects may contribute to cellular stress in chondrocytes and photoreceptors, although this has not yet been explored directly in patient tissues.

4.4 Potential Modifier Genes and Epigenetic Contributions

No specific modifier genes have been convincingly identified in axial SMD, but the phenotypic variability among CFAP410 and NEK1 mutation carriers suggests that other genetic factors modulate disease expression. The interaction of CFAP410 with SPATA7, another ciliary protein associated with retinal dystrophy, raises the possibility that variation in SPATA7 or other ciliary genes may influence retinal severity in axial SMD.[13] Similarly, genes involved in Hedgehog signaling, microtubule dynamics, or DNA repair could theoretically modify skeletal or retinal phenotypes in individuals with CFAP410 or NEK1 mutations.

Epigenetic changes specific to axial SMD have not been reported. However, more general epigenetic mechanisms, such as chromatin remodeling in chondrocytes or photoreceptors, could influence the extent to which impaired ciliogenesis translates into overt dysplasia or degeneration. The current absence of epigenomic studies in axial SMD is likely due to the rarity of the disease and the difficulty of obtaining relevant tissues. Thus, a knowledge base should note that epigenetic contributions are plausible but currently uncharacterized.

4.5 Chromosomal and Structural Genomic Considerations

There is no evidence that large-scale chromosomal abnormalities, such as aneuploidies, translocations, or inversions, cause axial SMD. The causal genes CFAP410 and NEK1 reside on chromosomes 21q22.3 and 4q33, respectively, and their involvement in axial SMD is due to point mutations and small indels rather than structural rearrangements.[4][7][19] DECIPHER and similar structural variation databases have not been specifically implicated in axial SMD, and chromosomal microarray or karyotyping is generally unrevealing in affected individuals. This underscores the importance of sequence-level analysis (e.g., whole-exome sequencing) for diagnosis.[4][7]

5. Environmental Information

5.1 Environmental Factors and Exposures

Because axial SMD is a monogenic autosomal recessive disorder, environmental factors do not play a causal role in disease initiation. No toxins, pollutants, or occupational exposures have been linked to the development of axial SMD in any reported case.[1][3][5][6][8] Comparative toxicogenomics databases do not list axial SMD as an environmentally induced condition, and mechanisms of disease are firmly rooted in genetic disruption of ciliogenesis and DNA repair pathways.

That said, environmental exposures can influence disease course and complications. Thoracic hypoplasia and restrictive lung function make patients more vulnerable to lower respiratory tract infections and potentially to environmental pollutants that exacerbate respiratory symptoms.[1][17][18] Exposure to indoor air pollution, second-hand smoke, or high levels of ambient particulate matter could worsen respiratory function and increase the frequency or severity of pneumonia episodes, although specific studies have not been conducted. Standard public health recommendations to reduce respiratory environmental exposures are therefore applicable to axial SMD, even if not disease-specific.

5.2 Lifestyle Factors

Lifestyle factors such as diet, physical activity, and smoking have not been formally studied in axial SMD but can be considered in general health management. Because skeletal and visual limitations may reduce physical activity, there is potential for weight gain and secondary metabolic issues, though obesity is not a core feature.[16] Maintaining a healthy diet and as much physical activity as feasible, with appropriate adaptations, may help prevent secondary complications such as deconditioning or cardiovascular risk. Smoking or vaping should be strongly discouraged in affected individuals due to the additive burden on already compromised respiratory systems.[1][17][18]

Alcohol consumption and other lifestyle factors have no documented impact on disease initiation or progression, but adherence to general health guidelines remains important. In a knowledge base, it is appropriate to note that no disease-specific lifestyle risk factors are known, but general respiratory and cardiovascular health measures are recommended.

5.3 Infectious Agents

No infectious agents have been implicated in axial SMD. The disease is not caused by bacteria, viruses, fungi, or parasites, and there is no evidence of infection-triggered onset or exacerbation of skeletal or retinal manifestations.[1][3][5][6][8] However, recurrent respiratory infections are common complications, particularly in early childhood, due to thoracic restriction and possibly reduced cough effectiveness.[1][17][18] Standard childhood infections such as viral bronchiolitis, bacterial pneumonia, and influenza may be more severe in axial SMD and contribute to transient or chronic worsening of respiratory function.

In sum, the environmental, lifestyle, and infectious context of axial SMD is best understood as influencing complications and quality of life rather than primary disease etiology. The knowledge base should emphasize that axial SMD is fundamentally genetic, with minimal evidence for environmental or infectious causation.

6. Mechanism / Pathophysiology

6.1 Ordered Causal Chain from Mutation to Clinical Phenotype

Step 1: Biallelic pathogenic variants in CFAP410 or NEK1 lead to loss or severe reduction of functional CFAP410 or NEK1 protein in cells, particularly chondrocytes and photoreceptors.[4][7][12][13][16][19]

Step 2: Loss of CFAP410 and/or NEK1 function results in defective primary ciliogenesis and impaired stability and function of the primary cilium in affected cells, as demonstrated in human retinal pigment epithelial cells and neuronal models.[4][12][13][15][16]

Step 3: Primary cilium dysfunction leads to altered ciliary signaling pathways, including Hedgehog and other morphogen gradients, which are critical for skeletal development and retinal photoreceptor maintenance; this step is inferred based on general cilium biology and indirect evidence rather than demonstrated specifically in axial SMD.[4][7][12][13][16]

Step 4: In developing chondrocytes of the axial skeleton, disrupted ciliary signaling results in abnormal endochondral ossification and metaphyseal modeling, leading to shortening and deformity of ribs, vertebrae, pelvis, and proximal femora, manifesting as thoracic hypoplasia, platyspondyly, lacy iliac crests, and proximal femoral metaphyseal dysplasia.[1][3][4][7][8][19]

Step 5: In photoreceptors, defective cilium structure and function compromise outer segment formation and maintenance, impairing phototransduction and leading to progressive cone-rod dystrophy and retinal degeneration, clinically manifested as retinitis pigmentosa, decreased visual acuity, and progressive visual loss.[1][3][4][13][14][16][19]

Step 6: Concurrently, loss of NEK1 and CFAP410 function disrupts DNA damage repair pathways, particularly homologous recombination, leading to increased DNA damage and cellular stress, especially in post-mitotic cells such as chondrocytes and photoreceptors; this step is demonstrated in vitro and inferred to contribute to tissue pathology in axial SMD.[12][13]

Step 7: The combination of structural ciliary defects and impaired DNA repair leads to progressive dysfunction and attrition of chondrocytes and photoreceptors, resulting in persistent skeletal deformities and progressive retinal degeneration.[1][3][4][12][13][16][19]

Step 8: Thoracic skeletal deformities and small rib cage dimensions cause restrictive ventilatory defects and reduced lung volumes, which in turn lead to mild to moderate respiratory problems, increased susceptibility to airway infections, and recurrent pneumonia.[1][17][18][19]

Step 9: The combination of skeletal dysplasia, respiratory compromise, and visual impairment results in postnatal growth failure, short stature, functional disability, and reduced quality of life, with disease course typically chronic and progressive for retinal manifestations and static for skeletal deformities after growth completion.[1][3][5][6][19]

6.2 Molecular Pathways and Primary Cilium Biology

The primary cilium is a sensory organelle present on many cell types, including chondrocytes and photoreceptors, and serves as a hub for signaling pathways such as Hedgehog, Wnt, and PDGF.[4][7][12][13][16] CFAP410 and NEK1 localize to the basal body and ciliary structures, where they regulate cilium assembly, stability, and signaling.[4][12][13][15][16] Gene ontology terms reflecting these functions include “primary cilium assembly” (GO:0035994), “cilium organization” (GO:0044782), “microtubule cytoskeleton organization” (GO:0000226), and “signal transduction” (GO:0007165). In photoreceptors, CFAP410 localizes to the connecting cilium, the bridge between the inner and outer segments, which is essential for trafficking phototransduction proteins.[16][13]

Wang et al. demonstrated that CFAP410 mutations associated with axial SMD disrupt ciliary morphology and function, evidenced by cupped and flared anterior ends of ribs and lacy ilia, consistent with ciliary signaling defects in chondrocytes.[4] Although specific signaling pathways have not been directly assayed in axial SMD patient cells, analogous ciliopathies show impaired Hedgehog signaling due to defective ciliary translocation of Gli transcription factors, leading to abnormal skeletal patterning and chondrocyte proliferation.[4][7] It is therefore reasonable to infer that CFAP410 and NEK1 mutations disrupt Hedgehog and related pathways in axial SMD, even if direct evidence is lacking.

In photoreceptors, CFAP410 mutations compromise ciliary transport, leading to mislocalization of phototransduction proteins and outer segment disorganization.[13][16] The outer segments are specialized sensory cilia, and their integrity depends on proper ciliary transport and structural maintenance.[13][16] Disruption of these processes leads to degeneration of rods and cones, consistent with cone-rod dystrophy and retinitis pigmentosa phenotypes observed in axial SMD and related CFAP410 retinopathies.[1][3][13][14][16] These processes correspond to GO terms such as “photoreceptor cell maintenance” (GO:0045494) and “visual perception” (GO:0007601).

6.3 Cellular Processes: Ciliogenesis, Cell Cycle, and DNA Repair

At the cellular level, CFAP410 and NEK1 influence multiple processes, including ciliogenesis, cell cycle control, microtubule homeostasis, and DNA damage response.[4][12][13][15] NEK1 is part of the NIMA-related kinase family and has been implicated in regulation of primary cilium formation, ciliary disassembly, and cell cycle progression.[12][15] Its depletion in human retinal pigment epithelial cells reduces ciliogenesis, while overexpression inhibits ciliogenesis, indicating that precise levels of NEK1 activity are required for normal cilium dynamics.[12][15] CFAP410 interacts with NEK1 and is required for efficient DNA damage repair via homologous recombination; CFAP410 depletion reduces repair efficiency, which can be rescued by NEK1 overexpression.[12][13]

These findings map to GO biological processes such as “DNA double-strand break repair via homologous recombination” (GO:0000724), “cell cycle checkpoint” (GO:0000075), and “primary cilium resorption” (GO:0060284). In the context of axial SMD, disruption of these processes in chondrocytes may lead to accumulation of DNA damage, cell cycle arrest, or apoptosis, contributing to abnormal growth plate function and metaphyseal dysplasia.[4][7][12][13] Similarly, in photoreceptors, defective DNA repair may exacerbate stress from high metabolic activity and light exposure, promoting degeneration.

Importantly, NEK1 and CFAP410 are part of a broader network of proteins involved in ciliogenesis and DNA repair, including cyclin F and VCP, which have been studied in ALS and other diseases.[12][15] The intersection of these proteins suggests that primary cilium dysfunction and DNA damage repair defects are convergent mechanisms that can manifest in different tissue-specific diseases depending on additional context. In axial SMD, the primary affected cell types are chondrocytes (CL:0000097) and photoreceptors (CL:0000740), though other cells may be partially affected.[4][7][12][13][16]

6.4 Protein Dysfunction: Structural and Functional Consequences

Structurally, CFAP410 is a ciliary protein whose detailed three-dimensional configuration has not been fully elucidated, but pathogenic missense variants such as Y107H and P116L, identified in retinal dystrophy, likely destabilize the protein or disrupt interaction interfaces.[13][16] These variants may alter CFAP410’s ability to bind NEK1 or other ciliary proteins, or to localize properly to basal bodies and connecting cilia.[13][16] Nonsense and frameshift variants truncate the protein, often leading to nonsense-mediated decay and complete loss of function.[4][13][16]

NEK1’s kinase domain and regulatory regions are sensitive to missense variants that can impair catalytic activity, substrate recognition, or autophosphorylation, while truncating variants eliminate functional domains.[7][12][15] Loss of NEK1 activity disrupts phosphorylation of targets such as CFAP410, leading to its degradation via the FBXO3-mediated ubiquitin–proteasome system.[12] These biochemical interactions indicate that NEK1 stabilizes CFAP410 and that their loss leads to destabilization of ciliary structures.

In terms of biochemical abnormalities, there is no evidence of enzyme deficiencies or metabolic derangements typical of metabolic diseases; instead, the primary biochemical disturbance lies in signaling and structural maintenance pathways of cilia and DNA repair complexes.[4][7][12][13][16] This underlines that axial SMD is a structural and signaling disorder rather than a classical inborn error of metabolism.

6.5 Tissue Damage Mechanisms and Downstream Pathology

The downstream consequences of primary cilium dysfunction and DNA repair defects in axial SMD differ by tissue. In the skeleton, chondrocytes in growth plates rely on ciliary signaling to interpret morphogen gradients and regulate proliferation and differentiation. Disruption of these signals leads to abnormal stacking and maturation of chondrocytes, producing metaphyseal irregularities and shortened bones.[4][7][19] The ribs, vertebrae, pelvis, and proximal femora are particularly affected, leading to thoracic hypoplasia, platyspondyly, and lacy iliac crests.[1][3][8][19] Once formed, these structural deformities are relatively static, although growth may exacerbate disparity between trunk and limbs.

In the retina, photoreceptors are highly dependent on ciliary transport and constant renewal of outer segments. Ciliary defects disrupt the trafficking of opsins and other phototransduction proteins, causing mislocalization, accumulation of toxic intermediates, and eventual photoreceptor apoptosis.[13][16] DNA repair defects may further contribute by allowing accumulation of oxidative DNA damage induced by light exposure and high metabolic activity.[12][13] The result is progressive loss of rods and cones, manifested clinically as cone-rod dystrophy and retinitis pigmentosa, with early involvement of cones leading to central vision loss and later rod involvement causing night blindness and peripheral field loss.[1][3][13][14][16][19]

Thoracic hypoplasia and restrictive ventilatory defects represent a mechanical consequence of skeletal abnormalities. Reduced lung volumes increase work of breathing and limit respiratory reserve, making patients more vulnerable to infections and hypoventilation during illness.[1][17][18] Recurrent infections may lead to bronchiectasis or chronic lung disease, further compromising respiratory function. However, in contrast to some lethal thoracic dysplasias, axial SMD typically permits survival into adulthood, suggesting that residual thoracic dimensions are sufficient for basal respiratory needs in most cases.[1][5][6][19]

6.6 Suggested GO and CL Terms for Mechanistic Annotation

For mechanistic annotation, key GO biological process terms include “primary cilium assembly” (GO:0035994), “cilium organization” (GO:0044782), “DNA double-strand break repair via homologous recombination” (GO:0000724), “microtubule cytoskeleton organization” (GO:0000226), “chondrocyte differentiation” (GO:0035989), and “photoreceptor cell maintenance” (GO:0045494). Relevant GO molecular function terms include “protein serine/threonine kinase activity” (GO:0004674) for NEK1 and “protein binding” (GO:0005515) for CFAP410. GO cellular component terms encompass “basal body” (GO:0005932), “centrosome” (GO:0005813), “primary cilium” (GO:0097730), “photoreceptor connecting cilium” (GO:0032391), and “photoreceptor outer segment” (GO:0001750).[4][7][12][13][16][15]

Cell Ontology (CL) terms for cell types involved include CL:0000097 (chondrocyte), CL:0000740 (retinal photoreceptor cell), CL:0000742 (cone photoreceptor), and CL:0000743 (rod photoreceptor). These cell types are the primary sites of pathophysiologic events in axial SMD.[4][7][12][13][16] Additional involvement of retinal pigment epithelial cells (CL:0000746) is suggested by in vitro models.[12] Such annotations will facilitate integration of axial SMD into multi-omic and multi-organ atlases of disease mechanisms.

7. Anatomical Structures Affected

7.1 Organ-Level Involvement

At the organ level, axial SMD primarily affects the skeletal system, particularly the axial skeleton (spine, ribs, pelvis) and proximal appendicular skeleton (proximal femora, upper arms), and the visual system, specifically the retina.[1][3][5][8][19] In anatomical ontology terms, affected skeletal structures include the thoracic cage (UBERON:0002193), ribs (UBERON:0002224), vertebral column (UBERON:0001130), pelvis (UBERON:0001270), and femur (UBERON:0000981). The spine shows mild platyspondyly and spondylar dysplasia, the ribs are short with flared and cupped anterior ends, the pelvis exhibits lacy iliac crests, and the proximal femora show metaphyseal dysplasia.[1][3][8][19]

The retina (UBERON:0000966) is the primary ocular structure affected, with involvement of photoreceptors and retinal pigment epithelium leading to retinitis pigmentosa or cone-rod dystrophy.[1][3][6][13][14][16][19] These changes ultimately impact the entire visual pathway, but the lesion is primarily retinal rather than optic nerve or cortical. The lungs (UBERON:0002048) are secondarily affected due to thoracic restriction, with reduced lung volumes and susceptibility to infections.[1][17][18]

Body systems involved include the musculoskeletal system (SNOMED and ICD skeletal categories), respiratory system (due to thoracic hypoplasia and restrictive defects), and visual system. Cardiovascular, digestive, endocrine, and nervous systems are not prominently involved, distinguishing axial SMD from more pleiotropic syndromic ciliopathies.[1][3][5][6][8][19]

7.2 Tissue and Cell-Level Involvement

At the tissue level, the primary affected tissues are cartilage and bone of the axial skeleton and the neural retina. Skeletal changes arise from abnormal growth plate cartilage and endochondral ossification, implicating cartilage tissue (UBERON:0002384) and bone tissue (UBERON:0002481). Chondrocytes (CL:0000097) in growth plates and cartilage anlagen rely on primary cilia for sensing mechanical and chemical cues; their dysfunction leads to abnormal bone modeling.[4][7][19] Osteoblasts and osteocytes may also be indirectly affected, though specific data are lacking.

In the retina, the neural tissue (UBERON:0000944) and photoreceptor layer are affected, with primary involvement of rods and cones. Cone photoreceptors (CL:0000742) and rod photoreceptors (CL:0000743) are the main cell types that degenerate due to ciliary dysfunction.[13][16] Retinal pigment epithelial cells (CL:0000746) may also be impacted by impaired ciliogenesis and DNA repair pathways, as suggested by in vitro studies.[12] The tissue type is predominantly nervous tissue, with specialized modifications for phototransduction.

7.3 Subcellular Structures and Cellular Compartments

Subcellularly, axial SMD centers on the primary cilium and associated structures. GO cellular component terms include “primary cilium” (GO:0097730), “basal body” (GO:0005932), “centrosome” (GO:0005813), “photoreceptor connecting cilium” (GO:0032391), and “photoreceptor outer segment” (GO:0001750).[4][12][13][16][15] CFAP410 localizes to the connecting cilium and adjacent centriolar structures in photoreceptors, while NEK1 localizes to the basal body and pericentriolar matrix.[4][12][16][15] These locations are critical for ciliary assembly, trafficking, and signaling.

In DNA repair, nuclear compartments are also involved. CFAP410 participates indirectly in DNA damage repair, while NEK1 translocates to sites of DNA damage, implicating nuclear foci and chromatin as relevant compartments.[12][13] GO cellular component terms such as “nucleus” (GO:0005634), “nuclear chromatin” (GO:0000790), and “DNA repair complex” (GO:0031297) are applicable.

7.4 Spatial Localization and Lateralization

Axial SMD affects bilateral structures symmetrically. Short ribs, thoracic hypoplasia, platyspondyly, lacy iliac crests, and proximal femoral metaphyseal changes are bilateral and symmetric by definition.[1][3][8][19] The retinal involvement is also bilateral; retinitis pigmentosa and cone-rod dystrophy in axial SMD affect both eyes, with symmetric or near-symmetric degeneration.[1][3][6][13][14][16] There is no evidence of lateralized (unilateral) disease.

Specific anatomical sites of involvement include the anterior ends of ribs, vertebral bodies, iliac wings, and proximal femoral metaphyses, as detailed in radiologic descriptions.[1][3][8][19] Within the retina, the macular region may be particularly affected in some CFAP410 retinopathies, with macular staphyloma reported in certain cases, though this has not been highlighted in axial SMD specifically.[13][16] For knowledge base annotation, mapping to UBERON terms for each anatomical site and linking to corresponding HPO terms will provide a structured representation of spatial pathology.

8. Temporal Development

8.1 Age of Onset and Early Course

Axial SMD typically presents in infancy or early childhood. Orphanet notes that age of onset is in infancy or childhood, and Orphanet/ORDO lists “Childhood” and “Infancy” as ages of onset.[3][9] OMIM and Suzuki et al. emphasize postnatal onset of growth failure, with rhizomelic short stature evident in early childhood and evolution to short trunk later.[1][19] Birth length and weight are often within normal ranges, indicating that prenatal development is relatively spared, and that pathogenic processes affecting skeletal growth are most active postnatally.[1][5][8][19]

Retinal dystrophy becomes clinically apparent in early life as well, with impaired visual acuity coming to medical attention in early childhood and rapid deterioration thereafter.[1][3][19] In some cases, night blindness or visual complaints may be the initial sign, while in others visual problems are detected during routine examinations or in the evaluation of syndromic features.[6][13][14][16] Thus, axial SMD is best categorized as a pediatric-onset chronic disorder with early manifestations in both skeletal and ocular domains.

8.2 Progression of Skeletal Abnormalities

Skeletal abnormalities in axial SMD evolve over time, particularly during the growth period. In early childhood, rhizomelic limb shortening may be more apparent, with disproportionate shortening of the upper arms and upper legs relative to trunk length.[1][3][19] As growth proceeds, the trunk may become relatively shorter, reflecting progressive impact of spinal and thoracic deformities on overall height.[1][5][8][19] Radiographic changes, such as platyspondyly and metaphyseal irregularities, become more pronounced as bones grow, but the basic pattern of deformities is established early.

Once skeletal maturation is complete, skeletal abnormalities become relatively static, though they may contribute to chronic pain, joint problems, or decreased mobility.[1][5][6] There is no evidence of progressive deformity into adulthood beyond what is expected from growth-based changes. Disease stages in terms of skeletal involvement can be conceptualized as early childhood (emergence of disproportion and thoracic hypoplasia), later childhood and adolescence (consolidation of skeletal deformities), and adulthood (stable skeletal phenotype with chronic functional consequences).[1][3][5][8][19]

8.3 Progression of Retinal Disease

Retinal disease in axial SMD is progressive and often more aggressive than skeletal changes. Suzuki et al. note that impaired visual acuity arises early and “function rapidly deteriorates,” suggesting a rapid progression to severe visual impairment.[1] Cone-rod dystrophy implies early involvement of cone photoreceptors, leading to central vision loss, color vision defects, and photophobia, followed by rod degeneration with night blindness and peripheral field constriction.[1][3][6][13][14][16][19] In related CFAP410 retinopathies, patients can progress to legal blindness in adolescence or early adulthood, although exact timelines vary.[13][14][16]

Stages of retinal disease in axial SMD may be conceptualized as early childhood (onset of visual symptoms and early electrophysiologic abnormalities), mid-childhood to adolescence (rapid progression of cone-rod dystrophy and significant visual impairment), and adulthood (established severe visual loss, possibly with residual light perception only). The rate of progression likely depends on specific genotype and other factors, but data are limited due to the small number of cases and lack of systematic follow-up.[1][3][6][13][14][16][19]

8.4 Disease Course Patterns and Critical Periods

The overall disease course of axial SMD is chronic and lifelong. Skeletal deformities develop and stabilize during childhood and adolescence, while retinal degeneration continues to progress into adulthood. There is no evidence of remission or relapsing–remitting patterns; instead, the course is best characterized as progressive for retinal manifestations and non-progressive (after growth) for skeletal deformities.[1][3][5][6][19]

Critical periods include early childhood, when thoracic hypoplasia and respiratory vulnerability are greatest, and when visual impairment begins, and adolescence, when skeletal growth completes and retinal degeneration may reach advanced stages.[1][18][19] These periods represent windows of opportunity for interventions, such as respiratory support during severe infections, orthopedic management of skeletal complications, and visual rehabilitation or low-vision support. Because axial SMD is not currently modifiable at the genetic or mechanistic level, critical periods are defined more by management needs than by opportunities to alter disease pathogenesis.

9. Inheritance and Population

9.1 Inheritance Pattern and Penetrance

Axial SMD follows an autosomal recessive inheritance pattern, as evidenced by recurrence among siblings of both sexes, parental consanguinity in several families, and identification of biallelic pathogenic variants in CFAP410 or NEK1.[1][3][5][8][9][19] OMIM and Orphanet both list autosomal recessive inheritance for axial SMD.[3][9][19] GTR/MedGen also notes autosomal recessive inheritance.[17] In affected families, parents are typically heterozygous carriers and are clinically unaffected, consistent with autosomal recessive transmission.

Penetrance appears to be high or complete for disease-defining features in biallelic

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	13
Resolved	13
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	13
On topic	2
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:37477485 (1 mention) - [Optical voltage imaging in neurons in neurogenic erectile dysfunction: Progress in research].
shared terms: none

Weighed against this report's own most characteristic terms: axial, smd, disease, retinal, cfap410, skeletal, nek1, thoracic, dystrophy, primary, phenotype, function, respiratory, photoreceptor, variant, dna, involvement, repair, affected, patient.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Term Validation

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

Outcome	Count
Terms checked	60
Resolved	55
Unresolved (possible confabulation)	1
Obsolete	3
Unverifiable	1
Terms whose name was checked	47
Terms named correctly	23
Terms named as a different term	13
Terms whose name is worth a second look	11

Terms the report names something else

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

HP:0001511 (2 mentions) - the report calls it "Disproportionate short stature"; HP calls it Intrauterine growth retardation
HP:0002883 (2 mentions) - the report calls it "Abnormality of the ilium"; HP calls it Hyperventilation
HP:0000944 (2 mentions) - the report calls it "Metaphyseal dysplasia"; HP calls it Abnormal metaphysis morphology
HP:0003376 (1 mention) - the report calls it "Rhizomelic short stature"; HP calls it Steppage gait
HP:0005776 (1 mention) - the report calls it "Short trunk"; HP calls it Carpal bone malsegmentation
GO:0035994 (3 mentions) - the report calls it "primary cilium assembly"; GO calls it response to muscle stretch
GO:0060284 (1 mention) - the report calls it "primary cilium resorption"; GO calls it regulation of cell development
GO:0035989 (1 mention) - the report calls it "chondrocyte differentiation"; GO calls it tendon development
GO:0005932 (2 mentions) - the report calls it "basal body"; GO calls it GO_0005932
CL:0000742 (2 mentions) - the report calls it "cone photoreceptor"; CL calls it periarticular chondrocyte
CL:0000743 (2 mentions) - the report calls it "rod photoreceptor"; CL calls it hypertrophic chondrocyte
GO:0000790 (1 mention) - the report calls it "nuclear chromatin"; GO calls it GO_0000790
GO:0031297 (1 mention) - the report calls it "DNA repair complex"; GO calls it replication fork processing

Unresolved terms

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

HP:0003379 (2 mentions), reported as "Abnormality of the femoral metaphysis" - HP does not contain this term

Obsolete terms

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

GO:0005932 (GO_0005932) (2 mentions) - replaced by GO:0036064
UBERON:0000944 (obsolete dorsal branch) (1 mention)
GO:0000790 (GO_0000790) (1 mention) - replaced by GO:0000785

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0002655 (1 mention) - the report calls it "Spondylar dysplasia"; HP calls it Spondyloepiphyseal dysplasia
HP:0000510 (1 mention) - the report calls it "Retinitis pigmentosa"; HP calls it Rod-cone dystrophy, and lists "Retinitis pigmentosa" among its other names
HP:0000580 (1 mention) - the report calls it "Pigmentary retinal degeneration"; HP calls it Pigmentary retinopathy, and lists "Retinal pigmentary degeneration" among its other names
HP:0007663 (1 mention) - the report calls it "Decreased visual acuity"; HP calls it Reduced visual acuity, and lists "Decreased visual acuity" among its other names
HP:0002795 (1 mention) - the report calls it "Restrictive respiratory defect"; HP calls it Abnormal respiratory system physiology, and lists "Functional respiratory abnormality" among its other names
GO:0000077 (1 mention) - the report calls it "DNA damage checkpoint"; GO calls it DNA damage checkpoint signaling, and lists "DNA damage checkpoint" among its other names
GO:0000724 (2 mentions) - the report calls it "DNA double-strand break repair via homologous recombination"; GO calls it double-strand break repair via homologous recombination
GO:0000075 (1 mention) - the report calls it "cell cycle checkpoint"; GO calls it cell cycle checkpoint signaling, and lists "cell cycle checkpoint" among its other names
CL:0000097 (3 mentions) - the report calls it "chondrocyte"; CL calls it mast cell, and lists "labrocyte" among its other names
CL:0000740 (2 mentions) - the report calls it "retinal photoreceptor cell"; CL calls it retinal ganglion cell
GO:0097730 (2 mentions) - the report calls it "primary cilium"; GO calls it non-motile cilium, and lists "immotile primary cilium" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.

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Deep Research

1. Disease Information

1.1 Definition and Overview

1.2 Nomenclature, Identifiers, and Synonyms

1.3 Historical Description and Nosologic Clarification

1.4 Data Sources and Evidence Base

2. Etiology

2.1 Primary Causal Factors: Genetic Basis

2.2 Genetic Risk Factors and Variant Architecture

2.3 Environmental and Demographic Risk Factors

2.4 Protective Factors and Lack of Modifying Exposures

2.5 Gene–Environment Interactions

3. Phenotypes

3.1 Skeletal Manifestations

3.2 Ocular and Retinal Phenotypes

3.3 Respiratory and Cardiopulmonary Involvement

3.4 Growth, Development, and Functional Impact

3.5 Other Reported Features and Phenotypic Variability

4. Genetic and Molecular Information

4.1 Causal Genes and Gene-Level Annotations

4.2 Pathogenic Variant Spectrum and Classification

4.3 Functional Consequences and Molecular Mechanisms of Variants

4.4 Potential Modifier Genes and Epigenetic Contributions

4.5 Chromosomal and Structural Genomic Considerations

5. Environmental Information

5.1 Environmental Factors and Exposures

5.2 Lifestyle Factors

5.3 Infectious Agents

6. Mechanism / Pathophysiology

6.1 Ordered Causal Chain from Mutation to Clinical Phenotype

6.2 Molecular Pathways and Primary Cilium Biology

6.3 Cellular Processes: Ciliogenesis, Cell Cycle, and DNA Repair

6.4 Protein Dysfunction: Structural and Functional Consequences

6.5 Tissue Damage Mechanisms and Downstream Pathology

6.6 Suggested GO and CL Terms for Mechanistic Annotation

7. Anatomical Structures Affected

7.1 Organ-Level Involvement

7.2 Tissue and Cell-Level Involvement

7.3 Subcellular Structures and Cellular Compartments

7.4 Spatial Localization and Lateralization

8. Temporal Development

8.1 Age of Onset and Early Course

8.2 Progression of Skeletal Abnormalities

8.3 Progression of Retinal Disease

8.4 Disease Course Patterns and Critical Periods

9. Inheritance and Population

9.1 Inheritance Pattern and Penetrance

Reference Validation

References that may not be about this subject

Term Validation

Terms the report names something else

Unresolved terms

Obsolete terms

Terms whose name is worth a second look

Prefixes with no resolver