Spermatogenic failure 98

🏷

Classifications

Harrison's Part

👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Biallelic CFAP54 variants were identified in three unrelated men from a cohort of 334 probands: one homozygous frameshift and two compound heterozygous genotypes. All identified variants were absent or extremely rare in public genome databases.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:36593121 SUPPORT Human Clinical

"Biallelic variants of CFAP54 were identified in three unrelated men, including one homozygous frameshift variant (c.3317del, p.Phe1106Serfs*19) and two compound heterozygous variants (c.878G>A, p.Arg293His; c.955C>T, p.Arg319Cys and c.4885C>T, p.Arg1629Cys; c.937G>A, p.Gly313Arg)."

Documents biallelic genotypes, including homozygous and compound heterozygous forms, establishing recessive inheritance.

PMID:36593121 SUPPORT Human Clinical

"All of the identified variants were absent or extremely rare in the public human genome databases and predicted to be damaging by bioinformatic tools."

Supports pathogenicity by population frequency and in silico prediction.

?

Discussions and Knowledge Gaps

1

Is CFAP54-related spermatogenic failure a distinct entity from CFAP54-related primary ciliary dyskinesia, or are the infertility probands simply PCD patients whose airway disease was never looked for?

KNOWLEDGE GAP OPEN spgf98_isolated_infertility_versus_pcd_spectrum

Attached to

pathophysiology#CFAP54 Loss of Function pathophysiology#Male Infertility

This is the central nosological question for this entry and it is deliberately left open. CFAP54 causes both isolated spermatogenic failure and PCD, and the Cfap54 mouse has full PCD — hydrocephalus, mucus accumulation and male infertility together — rather than infertility alone. The men in the infertility cohort were ascertained through a reproductive clinic, so a respiratory phenotype would not necessarily have been sought or recorded. What makes this more than a bookkeeping question is that C1d-defective PCD is specifically invisible to the standard diagnostic algorithm: normal situs, normal nasal nitric oxide, normal transmission electron microscopy, normal high-speed videomicroscopy, and unreliable PICADAR scoring. A man could therefore be correctly diagnosed with CFAP54 infertility while having genuinely undetected airway disease. The alternative explanation — that specific alleles or residual function separate an infertility-only phenotype from full PCD — is equally untested. ClinGen's Motile Ciliopathy Gene Curation Expert Panel went further than leaving this open, and this entry diverges from them deliberately rather than silently. Applying the ClinGen Lumping & Splitting criteria, the panel found the molecular mechanism and mode of inheritance consistent across unrelated patients and the phenotypic variability to represent a spectrum rather than separate entities, and therefore lumped all inherited CFAP54 disease into a single entity, Primary Ciliary Dyskinesia 54 (MONDO:0100607, OMIM:621125). dismech nonetheless curates SPGF98 as its own entry, for three reasons. First, MONDO retains both terms — MONDO:0700290 for SPGF98 and MONDO:0100607 for PCD54 — and dismech entries are keyed to MONDO concepts, so curating SPGF98 is not an assertion that ClinGen is wrong about gene-disease validity, which is a different question from disease-concept granularity. Second, ClinGen's own narrative on the same record leaves the specific sub-question this discussion asks unresolved (quoted below), so the lumping conclusion and the open boundary question coexist in one document. Third, the differential diagnosis and `distinguishing_features` on this entry point explicitly at PCD54, so a reader who accepts ClinGen's lumping can traverse to it; the split costs nothing in navigability. If MONDO merges the two terms, this entry should be merged with them. Their leaving the sub-question open is the strongest available evidence that it is genuinely unresolved rather than merely unexamined here. Their review adds one fact that partly cuts against the undiagnosed-PCD reading: the proband in the study this entry is built on was examined carefully, including CT scanning, and had no obvious PCD symptoms. That is a real negative finding, though the panel notes respiratory ciliary structure and function were not investigated in either infertility study, so a subtle phenotype is not excluded.

Proposed experiments

Respiratory phenotyping of CFAP54 infertility probands

exp_spgf98_respiratory_phenotyping_of_infertility_probands

Systematically assess reported and newly identified CFAP54 infertility probands for airway disease using methods that work in C1d-defective PCD — ciliary transport assays and clinical history — rather than the standard algorithm that is known to return normal results in this PCD type.

Genotype comparison between infertility-only and PCD cohorts

exp_spgf98_genotype_stratified_comparison

Compare the CFAP54 alleles reported in infertility-only probands against those in PCD probands, testing whether allele class or predicted residual function separates the two presentations or whether the genotypes overlap.

Show evidence (4 references)

CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z SUPPORT Other

"It remains unclear if these patients might have subtle respiratory phenotypes or if spermatogenic failure alone may be part of the spectrum of disease seen in CFAP54 patients."

ClinGen's expert panel states this exact question as unresolved, confirming it is a genuine open question rather than a gap local to this entry.

CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z SUPPORT Human Clinical

"One of these studies reports on a patient that underwent careful examination, including CT scanning and had no obvious PCD symptoms such as sinusitis, bronchitis, pneumonia or otitis media (PMID: 36593121)."

Evidence against the undiagnosed-PCD reading for at least one proband; marked PARTIAL because respiratory ciliary structure and function were still not investigated.

CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z REFUTE Other

"Therefore, cases caused by inherited CFAP54 variants have been lumped into a single disease entity, Primary Ciliary Dyskinesia 54 (MONDO:0100607, OMIM:621125)."

ClinGen's formal conclusion, which argues against curating SPGF98 as a separate entity. Recorded as REFUTE against the split rather than omitted, so the divergence stated in the rationale is visible in the evidence rather than only asserted in prose.

+ 1 more reference

⚙

Pathophysiology

4

CFAP54 Loss of Function

Biallelic loss-of-function variants remove or impair CFAP54, a component of the C1d projection of the central microtubule apparatus. The C1d complex is conserved from Chlamydomonas, where the orthologue FAP54 occupies the same position, and mouse work established that C1d assembly requires CFAP54 specifically.

CFAP54 hgnc:26456

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Germline biallelic frameshift, missense and compound heterozygous variants, absent or extremely rare in population databases.

axoneme GO:0005930

Downstream

Flagellar Axoneme Disorganisation and Assembly Protein Depletion

Show evidence (2 references)

PMID:26224312 SUPPORT Model Organism

"Motile cilia have a structural defect in the C1d projection, indicating that the C1d assembly mechanism requires CFAP54."

Establishes that CFAP54 is specifically required for C1d assembly.

PMID:36593121 SUPPORT Human Clinical

"Biallelic variants of CFAP54 were identified in three unrelated men, including one homozygous frameshift variant (c.3317del, p.Phe1106Serfs*19) and two compound heterozygous variants (c.878G>A, p.Arg293His; c.955C>T, p.Arg319Cys and c.4885C>T, p.Arg1629Cys; c.937G>A, p.Gly313Arg)."

Documents the causative biallelic genotypes in affected men.

Flagellar Axoneme Disorganisation and Assembly Protein Depletion

Sperm from affected men show significant axonemal disorganisation on ultrastructural examination. The lesion is not confined to the C1d projection itself: immunofluorescence showed markedly reduced staining of four flagellar-assembly-associated proteins — IFT20, IFT52, IFT122 and SPEF2 — in the spermatozoa of CFAP54-deficient men, indicating that losing this central apparatus component destabilises the wider flagellar assembly machinery rather than deleting one projection in isolation.

Sperm CL:0000019

sperm axoneme assembly GO:0007288 ↓ DECREASED

axoneme GO:0005930

Animal models

Cfap54 gene-trap mouse Mouse recapitulates Reproduces the specific C1d projection structural defect that defines the molecular lesion, with functional consequences for ciliary beating.

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella

Show evidence (4 references)

PMID:36593121 SUPPORT Human Clinical

"Significant axoneme disorganisation and other ultrastructure abnormities were also detected inside the sperm cells from men harbouring CFAP54 mutations."

Direct ultrastructural demonstration of axonemal disorganisation in patient sperm.

PMID:36593121 SUPPORT Human Clinical

"Furthermore, immunofluorescence assays showed remarkably reduced staining of four flagellar assembly-associated proteins (IFT20, IFT52, IFT122 and SPEF2) in the spermatozoa of CFAP54-deficient men."

Shows the defect extends to the wider flagellar assembly machinery, not only the C1d projection.

PMID:32704025 SUPPORT Model Organism

"These findings identify genetic interactions between CPA genes and genetic mechanisms regulating the CPA and motile cilia function."

A genetic interaction between the central-pair-apparatus genes is established, which is the mechanistic underpinning for reading the reduced SPEF2 staining in patient sperm as part of a shared central-apparatus dependency rather than an isolated observation.

+ 1 more reference

Multiple Morphological Abnormalities of the Sperm Flagella

The disorganised axoneme yields the MMAF phenotype: abnormal sperm morphology with reduced motility. This is the sperm-flagellar instance of the same motile-axoneme failure that produces impaired ciliary beating in airway cilia, which is why this node conforms to the motile cilia arm of the ciliopathy module.

Sperm CL:0000019

cilium movement GO:0003341 ↓ DECREASED

Downstream

Male Infertility

Show evidence (2 references)

PMID:36593121 SUPPORT Human Clinical

"The men harbouring CFAP54 mutations exhibited abnormal sperm morphology, reduced sperm concentration and motility in ejaculated semen."

Documents the morphological and motility abnormalities in patient semen.

PMID:26224312 SUPPORT Model Organism

"This structural defect results in decreased ciliary beat frequency and perturbed cilia-driven flow."

Establishes that the same C1d structural defect impairs motile ciliary beating, supporting the shared motile-axoneme mechanism.

Male Infertility

The clinical endpoint. Affected men present with infertility spanning severe MMAF through to non-obstructive azoospermia — that is, the defect can manifest either as dysfunctional sperm or as an apparent failure to produce them. In the mouse, infertility was shown to result from defects in spermatogenesis rather than from obstruction.

Animal models

Cfap54 gene-trap mouse Mouse partially recapitulates Homozygous mice are infertile through defects in spermatogenesis, matching the human infertility. But they also have hydrocephalus and mucus accumulation — full PCD — whereas the men in the human infertility cohort were ascertained for infertility alone.

Cfap54 in-frame variant knock-in mouse Mouse partially recapitulates Reproduces the infertility endpoint of this entry, but as one component of a full PCD phenotype rather than in isolation.

Show evidence (2 references)

PMID:36593121 SUPPORT Human Clinical

"Our genetic analyses and experimental observations revealed that biallelic deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans."

States the causal relationship and the two clinical forms it produces.

PMID:26224312 SUPPORT Model Organism

"The infertility results from defects in spermatogenesis."

Establishes a spermatogenic rather than obstructive basis for the infertility in the model.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

5

Genitourinary 1

Male Infertility HP:0003251

Show evidence (1 reference)

PMID:36593121 SUPPORT Human Clinical

"Our genetic analyses and experimental observations revealed that biallelic deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans."

Establishes male infertility as the clinical consequence.

Other 4

Abnormal Sperm Morphology HP:0012864

Show evidence (1 reference)

PMID:36593121 SUPPORT Human Clinical

"The men harbouring CFAP54 mutations exhibited abnormal sperm morphology, reduced sperm concentration and motility in ejaculated semen."

Documents abnormal sperm morphology in affected men.

Reduced Sperm Motility HP:0012207

Show evidence (1 reference)

PMID:36593121 SUPPORT Human Clinical

"The men harbouring CFAP54 mutations exhibited abnormal sperm morphology, reduced sperm concentration and motility in ejaculated semen."

Documents reduced sperm motility.

Non-Obstructive Azoospermia HP:0011961

Show evidence (1 reference)

PMID:36593121 SUPPORT Human Clinical

"Our genetic analyses and experimental observations revealed that biallelic deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans."

Establishes non-obstructive azoospermia as part of the phenotypic spectrum.

Reduced Sperm Concentration Oligozoospermia HP:0000798

Show evidence (1 reference)

PMID:36593121 SUPPORT Human Clinical

"The men harbouring CFAP54 mutations exhibited abnormal sperm morphology, reduced sperm concentration and motility in ejaculated semen."

Documents reduced sperm concentration.

🧬

Genetic Associations

1

CFAP54

Gene: CFAP54 hgnc:26456 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (4 references)

PMID:36593121 SUPPORT Human Clinical

"Here, we performed genetic analyses through whole-exome sequencing in a cohort of 334 Han Chinese probands with severe MMAF or NOA."

Establishes the cohort size against which the three probands should be read.

PMID:37725231 SUPPORT Human Clinical

"The identification of PCD-causing variants of CFAP54 in two unrelated patients with PCD for the first time provides strong supportive evidence that CFAP54 is a new PCD-causing gene."

Establishes that the same gene also causes primary ciliary dyskinesia, the basis for the phenotypic-boundary discussion in this entry.

PMID:39267058 SUPPORT Human Clinical

"Accordingly, variants of 17 known causative (five X-linked and twelve autosomal) genes, including ACTRT1, ADAD2, AR, BCORL1, CFAP47, CFAP54, DNAH17, DNAH6, DNAH7, DNAH8, DNAH9, FSIP2, MSH4, SLC9C1, TDRD9, TTC21A, and WNK3, were identified in 23 patients."

A second independent cohort, unrelated to the founding series, in which CFAP54 is identified among the known causative genes for spermatogenic failure.

+ 1 more reference

💊

Medical Actions

1

Intracytoplasmic Sperm Injection

Action: intracytoplasmic sperm injection Ontology label: Intracytoplasmic Sperm Injection NCIT:C185482

ICSI bypasses the motility and morphology defect by injecting a single spermatozoon directly into the oocyte. Favourable clinical pregnancy outcomes have been reported using sperm from men carrying CFAP54 mutations, so a CFAP54 diagnosis carries a genuinely useful prognostic message rather than only an explanatory one.

Show evidence (1 reference)

PMID:36593121 SUPPORT Human Clinical

"Notably, favourable clinical pregnancy outcomes were achieved with sperm from men carrying CFAP54 mutations after intracytoplasmic sperm injection treatment."

Direct evidence that ICSI achieves pregnancy despite the flagellar defect.

🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Spermatogenic failure 98:

CFAP54-related primary ciliary dyskinesia Not Yet Curated MONDO:0100607

Overlapping Features Not merely a differential but the same gene. Biallelic CFAP54 variants also cause primary ciliary dyskinesia, and C1d-defective PCD is notoriously hard to detect: it presents with normal situs, normal nasal nitric oxide, normal ciliary ultrastructure on transmission electron microscopy and normal high-speed videomicroscopy, and the PICADAR clinical prediction tool does not reliably identify it. A man diagnosed with CFAP54 spermatogenic failure could therefore have unrecognised airway disease that every standard PCD test would have called normal.

Distinguishing Features

Chronic upper and lower airway disease — recurrent sinusitis, bronchitis, otitis media, bronchiectasis — with or without hydrocephalus. None of this is part of the infertility presentation.
Situs is normal in both, so situs inversus does not separate them.
The usual discriminating ciliary tests do not separate them either: nasal nitric oxide, transmission electron microscopy and high-speed videomicroscopy are all normal in C1d-defective PCD, and PICADAR scoring is unreliable. The distinction therefore rests on clinical respiratory history rather than on any ciliary assay.

Show evidence (2 references)

PMID:39362668 SUPPORT Human Clinical

"Careful evaluation revealed that C1d-defective primary ciliary dyskinesia is associated with normal situs composition, normal nasal nitric oxide production rates, normal ciliary ultrastructure by transmission electron microscopy and normal ciliary beating by high-speed videomicroscopy analysis."

Documents that every standard PCD diagnostic modality is normal in C1d-defective disease.

PMID:39362668 SUPPORT Human Clinical

"Overall, this study extends the spectrum of primary ciliary dyskinesia genes and highlights that individuals with C1d-defective primary ciliary dyskinesia elude diagnosis when using the current diagnostic algorithm."

States that these patients evade the standard diagnostic algorithm, the clinically actionable point of this differential.

🐁

Animal Models

2

Cfap54 gene-trap mouse

Mouse line carrying a gene-trapped Cfap54 allele, established by its authors as a new model of primary ciliary dyskinesia.

Species

Mouse

Genotype

Cfap54 gene-trapped allele, homozygous

Publication

PMID:26224312

Pathograph links

Flagellar Axoneme Disorganisation and Assembly Protein Depletion recapitulates fidelity: moderate Reproduces the specific C1d projection structural defect that defines the molecular lesion, with functional consequences for ciliary beating.

Limitations: The structural and functional characterisation is of motile cilia rather than of the sperm flagellum, so the flagellar readout is inferred from the shared axonemal architecture; a gene trap is also not equivalent to the human missense alleles.

Readouts

C1d projection structure

Direction: ALTERED

Interpretation: Structural defect in the C1d projection of the central apparatus.

Show evidence (1 reference)

PMID:26224312 SUPPORT Model Organism

"Motile cilia have a structural defect in the C1d projection, indicating that the C1d assembly mechanism requires CFAP54."

The ultrastructural measurement underlying this readout.

Ciliary beat frequency

Direction: DECREASED

Interpretation: Reduced beat frequency with perturbed cilia-driven flow.

Show evidence (1 reference)

PMID:26224312 SUPPORT Model Organism

"This structural defect results in decreased ciliary beat frequency and perturbed cilia-driven flow."

The functional measurement underlying this readout.

Show evidence (1 reference)

PMID:26224312 SUPPORT Model Organism

"The requirement for one of these C1d complex members, CFAP54, was identified in a mouse line with a gene-trapped allele."

Establishes the model used to define the CFAP54 requirement.

Male Infertility partially recapitulates fidelity: moderate Homozygous mice are infertile through defects in spermatogenesis, matching the human infertility. But they also have hydrocephalus and mucus accumulation — full PCD — whereas the men in the human infertility cohort were ascertained for infertility alone.

Limitations: The mouse phenotype is broader than the curated human phenotype: it includes hydrocephalus and mucus accumulation not reported in the infertility probands. The model therefore cannot be used to argue that isolated spermatogenic failure is the expected consequence of CFAP54 loss, and this mismatch is the substance of the open phenotypic-boundary discussion.

Readouts

Male fertility

Direction: DECREASED

Interpretation: Homozygous males are infertile, with the infertility attributed to defective spermatogenesis.

Show evidence (1 reference)

PMID:26224312 SUPPORT Model Organism

"Homozygous mice have PCD characterized by hydrocephalus, male infertility, and mucus accumulation."

Documents male infertility in the model, alongside the other PCD features.

Show evidence (1 reference)

PMID:26224312 SUPPORT Model Organism

"Homozygous mice have PCD characterized by hydrocephalus, male infertility, and mucus accumulation."

Supports the infertility phenotype while making explicit that the model manifests full PCD rather than isolated spermatogenic failure.

Cfap54 in-frame variant knock-in mouse

Knock-in mouse carrying a human CFAP54 pathogenic variant rather than a gene trap, so it tests the specific allele class found in patients. Its relevance to this entry cuts in a particular direction: the mouse develops full PCD — hydrocephalus and nasal mucus accumulation as well as infertility — so on the closest available allele-matched model, CFAP54 loss does not produce isolated infertility.

Species

Mouse

Genotype

Cfap54 in-frame variant knock-in, modelling a human pathogenic allele

Publication

PMID:37725231

Pathograph links

Male Infertility partially recapitulates fidelity: moderate Reproduces the infertility endpoint of this entry, but as one component of a full PCD phenotype rather than in isolation.

Limitations: The human probands curated here have infertility without recognised airway disease, whereas this mouse has both. Whether that is a species difference, an allele difference, or undetected airway disease in the men is exactly the question left open in this entry's discussion, so the model cannot be read as settling it. The variant is in-frame, which need not match the frameshift and missense alleles in the infertility cohort.

Readouts

Fertility

Direction: DECREASED

Interpretation: Infertility observed alongside the other PCD manifestations.

Show evidence (1 reference)

PMID:37725231 SUPPORT Model Organism

"In addition, a CFAP54 in-frame variant knock-in mouse model was established, which recapitulated the typical symptoms of PCD, including hydrocephalus, infertility, and mucus accumulation in nasal sinuses."

The measurement behind this readout, and the reason the model is recorded as partially rather than fully recapitulating an infertility-only entity.

Show evidence (1 reference)

PMID:37725231 SUPPORT Model Organism

"In addition, a CFAP54 in-frame variant knock-in mouse model was established, which recapitulated the typical symptoms of PCD, including hydrocephalus, infertility, and mucus accumulation in nasal sinuses."

Supports treating this allele-matched model as informative for the infertility node while recording that it manifests the wider PCD phenotype.

{ }

Source YAML

click to show

name: Spermatogenic failure 98
creation_date: "2026-08-22T00:00:00Z"
description: >-
  Spermatogenic failure 98 is male infertility caused by biallelic variants in
  CFAP54, which encodes a cilia- and flagella-associated protein of the C1d
  projection of the central microtubule apparatus. The sperm flagellum and the
  motile cilium share that axonemal architecture, so loss of CFAP54 disorganises
  the flagellar axoneme and depletes flagellar assembly proteins, producing
  multiple morphological abnormalities of the sperm flagella (MMAF) together
  with reduced sperm concentration and motility, extending in some men to
  non-obstructive azoospermia. Importantly, CFAP54 is not an infertility-only
  gene: the same gene causes primary ciliary dyskinesia, and the Cfap54 mouse
  has full PCD with hydrocephalus and mucus accumulation as well as male
  infertility. Whether isolated spermatogenic failure and CFAP54-related PCD are
  distinct entities or one spectrum is unresolved and is curated here as an open
  question rather than assumed. Fertility is achievable: favourable pregnancy
  outcomes have been reported using these men's sperm for intracytoplasmic sperm
  injection.
category: Mendelian
parents:
- hereditary disease
synonyms:
- SPGF98
- CFAP54-related spermatogenic failure
- CFAP54-related male infertility
disease_term:
  preferred_term: Spermatogenic failure 98
  term:
    id: MONDO:0700290
    label: spermatogenic failure 98
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:36593121
      reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Our genetic analyses and experimental observations revealed that biallelic
        deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans.
      explanation: >-
        Establishes a single-gene recessive Mendelian basis for the phenotype.
references:
- reference: PMID:36593121
  title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
- reference: PMID:26224312
  title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
- reference: PMID:37725231
  title: "Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients."
- reference: PMID:39362668
  title: "Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus."
- reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
  title: "CFAP54 / ciliary dyskinesia, primary, 54 (Strong)"
- reference: PMID:39267058
  title: "Whole exome sequencing analysis of 167 men with primary infertility."
- reference: PMID:32704025
  title: "Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia."
- reference: PMID:41393159
  title: "Exome sequencing reanalysis identifies a novel likely pathogenic CFAP54 variant and expands the phenotypic and genotypic spectrum of primary ciliary dyskinesia."
- reference: PMID:20301301
  title: "Primary Ciliary Dyskinesia."
  tags: [GeneReviews]
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic CFAP54 variants were identified in three unrelated men from a
    cohort of 334 probands: one homozygous frameshift and two compound
    heterozygous genotypes. All identified variants were absent or extremely rare
    in public genome databases.
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic variants of CFAP54 were identified in three unrelated men,
      including one homozygous frameshift variant (c.3317del, p.Phe1106Serfs*19)
      and two compound heterozygous variants (c.878G>A, p.Arg293His; c.955C>T,
      p.Arg319Cys and c.4885C>T, p.Arg1629Cys; c.937G>A, p.Gly313Arg).
    explanation: >-
      Documents biallelic genotypes, including homozygous and compound
      heterozygous forms, establishing recessive inheritance.
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All of the identified variants were absent or extremely rare in the public
      human genome databases and predicted to be damaging by bioinformatic tools.
    explanation: >-
      Supports pathogenicity by population frequency and in silico prediction.
pathophysiology:
- name: CFAP54 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic loss-of-function variants remove or impair CFAP54, a component of
    the C1d projection of the central microtubule apparatus. The C1d complex is
    conserved from Chlamydomonas, where the orthologue FAP54 occupies the same
    position, and mouse work established that C1d assembly requires CFAP54
    specifically.
  genes:
  - preferred_term: CFAP54
    term:
      id: hgnc:26456
      label: CFAP54
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Germline biallelic frameshift, missense and compound heterozygous variants,
      absent or extremely rare in population databases.
  cellular_components:
  - preferred_term: axoneme
    term:
      id: GO:0005930
      label: axoneme
  evidence:
  - reference: PMID:26224312
    reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Motile cilia have a structural defect in the C1d projection, indicating that
      the C1d assembly mechanism requires CFAP54.
    explanation: >-
      Establishes that CFAP54 is specifically required for C1d assembly.
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biallelic variants of CFAP54 were identified in three unrelated men,
      including one homozygous frameshift variant (c.3317del, p.Phe1106Serfs*19)
      and two compound heterozygous variants (c.878G>A, p.Arg293His; c.955C>T,
      p.Arg319Cys and c.4885C>T, p.Arg1629Cys; c.937G>A, p.Gly313Arg).
    explanation: >-
      Documents the causative biallelic genotypes in affected men.
  downstream:
  - target: Flagellar Axoneme Disorganisation and Assembly Protein Depletion
- name: Flagellar Axoneme Disorganisation and Assembly Protein Depletion
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Sperm from affected men show significant axonemal disorganisation on
    ultrastructural examination. The lesion is not confined to the C1d projection
    itself: immunofluorescence showed markedly reduced staining of four
    flagellar-assembly-associated proteins — IFT20, IFT52, IFT122 and SPEF2 — in
    the spermatozoa of CFAP54-deficient men, indicating that losing this central
    apparatus component destabilises the wider flagellar assembly machinery
    rather than deleting one projection in isolation.
  biological_processes:
  - preferred_term: sperm axoneme assembly
    modifier: DECREASED
    term:
      id: GO:0007288
      label: sperm axoneme assembly
  cellular_components:
  - preferred_term: axoneme
    term:
      id: GO:0005930
      label: axoneme
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Significant axoneme disorganisation and other ultrastructure abnormities
      were also detected inside the sperm cells from men harbouring CFAP54
      mutations.
    explanation: >-
      Direct ultrastructural demonstration of axonemal disorganisation in patient
      sperm.
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, immunofluorescence assays showed remarkably reduced staining of
      four flagellar assembly-associated proteins (IFT20, IFT52, IFT122 and SPEF2)
      in the spermatozoa of CFAP54-deficient men.
    explanation: >-
      Shows the defect extends to the wider flagellar assembly machinery, not only
      the C1d projection.
  - reference: PMID:32704025
    reference_title: "Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings identify genetic interactions between CPA genes and genetic
      mechanisms regulating the CPA and motile cilia function.
    explanation: >-
      A genetic interaction between the central-pair-apparatus genes is
      established, which is the mechanistic
      underpinning for reading the reduced SPEF2 staining in patient sperm as
      part of a shared central-apparatus dependency rather than an isolated
      observation.
  - reference: PMID:32704025
    reference_title: "Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Spermiogenesis is aborted in double homozygotes, with an absence of mature
      flagella on elongating spermatids and epididymal sperm.
    explanation: >-
      The CFAP54-SPEF2 double homozygote aborts spermiogenesis, supporting the
      node's claim that loss of this central apparatus component destabilises the
      wider flagellar assembly machinery. Two caveats travel with this evidence.
      SPEF2 localises to the C1b projection, not C1d, so the interaction is
      between distinct projections of the same central apparatus rather than
      within one complex. And the double homozygote's sperm phenotype is not more
      severe than the single mutants' - the paper states it "is not dissimilar to
      the spermatogenesis phenotype observed in single nm1054, bgh, or
      Cfap54gt/gt mutants". The paper's severity language concerns mortality,
      hydrocephalus and airway disease, which are not this entry's node.
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  conforms_to: "ciliopathy_dysfunction#Motile Cilia Beat Dysfunction"
  description: >-
    The disorganised axoneme yields the MMAF phenotype: abnormal sperm morphology
    with reduced motility. This is the sperm-flagellar instance of the same
    motile-axoneme failure that produces impaired ciliary beating in airway cilia,
    which is why this node conforms to the motile cilia arm of the ciliopathy
    module.
  biological_processes:
  - preferred_term: cilium movement
    modifier: DECREASED
    term:
      id: GO:0003341
      label: cilium movement
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The men harbouring CFAP54 mutations exhibited abnormal sperm morphology,
      reduced sperm concentration and motility in ejaculated semen.
    explanation: >-
      Documents the morphological and motility abnormalities in patient semen.
  - reference: PMID:26224312
    reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This structural defect results in decreased ciliary beat frequency and
      perturbed cilia-driven flow.
    explanation: >-
      Establishes that the same C1d structural defect impairs motile ciliary
      beating, supporting the shared motile-axoneme mechanism.
  downstream:
  - target: Male Infertility
- name: Male Infertility
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical endpoint. Affected men present with infertility spanning severe
    MMAF through to non-obstructive azoospermia — that is, the defect can
    manifest either as dysfunctional sperm or as an apparent failure to produce
    them. In the mouse, infertility was shown to result from defects in
    spermatogenesis rather than from obstruction.
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our genetic analyses and experimental observations revealed that biallelic
      deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans.
    explanation: >-
      States the causal relationship and the two clinical forms it produces.
  - reference: PMID:26224312
    reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The infertility results from defects in spermatogenesis.
    explanation: >-
      Establishes a spermatogenic rather than obstructive basis for the
      infertility in the model.
phenotypes:
- category: Reproductive
  name: Male Infertility
  description: >-
    The presenting feature, through which these men are ascertained.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our genetic analyses and experimental observations revealed that biallelic
      deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans.
    explanation: >-
      Establishes male infertility as the clinical consequence.
- category: Reproductive
  name: Abnormal Sperm Morphology
  description: >-
    Multiple morphological abnormalities of the sperm flagella: absent, short,
    bent, coiled and irregular-calibre tails, the MMAF pattern.
  phenotype_term:
    preferred_term: Abnormal sperm morphology
    term:
      id: HP:0012864
      label: Abnormal sperm morphology
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The men harbouring CFAP54 mutations exhibited abnormal sperm morphology,
      reduced sperm concentration and motility in ejaculated semen.
    explanation: >-
      Documents abnormal sperm morphology in affected men.
- category: Reproductive
  name: Reduced Sperm Motility
  description: >-
    Motility is reduced as a direct consequence of the disorganised flagellar
    axoneme.
  phenotype_term:
    preferred_term: Reduced sperm motility
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The men harbouring CFAP54 mutations exhibited abnormal sperm morphology,
      reduced sperm concentration and motility in ejaculated semen.
    explanation: >-
      Documents reduced sperm motility.
- category: Reproductive
  name: Non-Obstructive Azoospermia
  description: >-
    At the severe end of the spectrum, sperm are absent from the ejaculate
    without obstruction. That the same gene produces both MMAF and NOA is
    notable — it means a normal-looking azoospermia workup should not exclude a
    flagellar gene.
  phenotype_term:
    preferred_term: Non-obstructive azoospermia
    term:
      id: HP:0011961
      label: Non-obstructive azoospermia
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our genetic analyses and experimental observations revealed that biallelic
      deleterious mutations of CFAP54 can induce severe MMAF and NOA in humans.
    explanation: >-
      Establishes non-obstructive azoospermia as part of the phenotypic spectrum.
- category: Reproductive
  name: Reduced Sperm Concentration
  description: >-
    Oligozoospermia accompanies the morphological and motility defects in
    affected men.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The men harbouring CFAP54 mutations exhibited abnormal sperm morphology,
      reduced sperm concentration and motility in ejaculated semen.
    explanation: >-
      Documents reduced sperm concentration.
genetic:
- name: CFAP54
  gene_term:
    preferred_term: CFAP54
    term:
      id: hgnc:26456
      label: CFAP54
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  frequency: 3 of 334 MMAF/NOA probands; separately 1 of 167 primary-infertility probands
  notes: >-
    CFAP54 encodes a C1d projection component of the ciliary and flagellar
    central microtubule apparatus; its Chlamydomonas orthologue is FAP54. Three
    unrelated men were found among 334 Han Chinese probands with severe MMAF or
    NOA, giving a genotype yield of roughly 1%. Reported alleles include a
    homozygous frameshift and two compound heterozygous combinations of missense
    variants. The same gene causes primary ciliary dyskinesia, so a CFAP54
    genotype found in an infertility workup should prompt a respiratory history.

    A second, independent cohort supports the relationship: whole-exome
    sequencing of 167 men with primary infertility identified CFAP54 among the
    known causative genes, in patient M827, who carried the compound
    heterozygous combination c.1540-4C>T and c.8642_8643del p.(Leu2882Phefs*7).
    That proband is worth noting for a second reason — his semen phenotype was
    oligoasthenozoospermia rather than the severe MMAF or NOA that defined the
    original cohort, so the reported genotype-phenotype range for CFAP54
    infertility is wider than the founding series alone suggests.
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we performed genetic analyses through whole-exome sequencing in a
      cohort of 334 Han Chinese probands with severe MMAF or NOA.
    explanation: >-
      Establishes the cohort size against which the three probands should be read.
  - reference: PMID:37725231
    reference_title: "Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The identification of PCD-causing variants of CFAP54 in two unrelated
      patients with PCD for the first time provides strong supportive evidence
      that CFAP54 is a new PCD-causing gene.
    explanation: >-
      Establishes that the same gene also causes primary ciliary dyskinesia, the
      basis for the phenotypic-boundary discussion in this entry.
  - reference: PMID:39267058
    reference_title: "Whole exome sequencing analysis of 167 men with primary infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Accordingly, variants of 17 known causative (five X-linked and twelve
      autosomal) genes, including ACTRT1, ADAD2, AR, BCORL1, CFAP47, CFAP54,
      DNAH17, DNAH6, DNAH7, DNAH8, DNAH9, FSIP2, MSH4, SLC9C1, TDRD9, TTC21A, and
      WNK3, were identified in 23 patients.
    explanation: >-
      A second independent cohort, unrelated to the founding series, in which
      CFAP54 is identified among the known causative genes for spermatogenic
      failure.
  - reference: PMID:39267058
    reference_title: "Whole exome sequencing analysis of 167 men with primary infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, it has been shown that biallelic deleterious mutations of
      CFAP54 can induce severe MMAF and NOA in humans
    explanation: >-
      The authors' own reading of the CFAP54 gene-disease relationship in the
      context of their cohort finding.
animal_models:
- name: Cfap54 gene-trap mouse
  species: Mouse
  genotype: Cfap54 gene-trapped allele, homozygous
  publication: PMID:26224312
  description: >-
    Mouse line carrying a gene-trapped Cfap54 allele, established by its authors
    as a new model of primary ciliary dyskinesia.
  modeled_mechanisms:
  - target: Flagellar Axoneme Disorganisation and Assembly Protein Depletion
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the specific C1d projection structural defect that defines the
      molecular lesion, with functional consequences for ciliary beating.
    limitations: >-
      The structural and functional characterisation is of motile cilia rather
      than of the sperm flagellum, so the flagellar readout is inferred from the
      shared axonemal architecture; a gene trap is also not equivalent to the
      human missense alleles.
    readouts:
    - name: C1d projection structure
      target: Flagellar Axoneme Disorganisation and Assembly Protein Depletion
      direction: ALTERED
      interpretation: >-
        Structural defect in the C1d projection of the central apparatus.
      evidence:
      - reference: PMID:26224312
        reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Motile cilia have a structural defect in the C1d projection, indicating
          that the C1d assembly mechanism requires CFAP54.
        explanation: >-
          The ultrastructural measurement underlying this readout.
    - name: Ciliary beat frequency
      target: Flagellar Axoneme Disorganisation and Assembly Protein Depletion
      direction: DECREASED
      interpretation: >-
        Reduced beat frequency with perturbed cilia-driven flow.
      evidence:
      - reference: PMID:26224312
        reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          This structural defect results in decreased ciliary beat frequency and
          perturbed cilia-driven flow.
        explanation: >-
          The functional measurement underlying this readout.
    evidence:
    - reference: PMID:26224312
      reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The requirement for one of these C1d complex members, CFAP54, was
        identified in a mouse line with a gene-trapped allele.
      explanation: >-
        Establishes the model used to define the CFAP54 requirement.
  - target: Male Infertility
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygous mice are infertile through defects in spermatogenesis, matching
      the human infertility. But they also have hydrocephalus and mucus
      accumulation — full PCD — whereas the men in the human infertility cohort
      were ascertained for infertility alone.
    limitations: >-
      The mouse phenotype is broader than the curated human phenotype: it
      includes hydrocephalus and mucus accumulation not reported in the
      infertility probands. The model therefore cannot be used to argue that
      isolated spermatogenic failure is the expected consequence of CFAP54 loss,
      and this mismatch is the substance of the open phenotypic-boundary
      discussion.
    readouts:
    - name: Male fertility
      target: Male Infertility
      direction: DECREASED
      interpretation: >-
        Homozygous males are infertile, with the infertility attributed to
        defective spermatogenesis.
      evidence:
      - reference: PMID:26224312
        reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Homozygous mice have PCD characterized by hydrocephalus, male
          infertility, and mucus accumulation.
        explanation: >-
          Documents male infertility in the model, alongside the other PCD
          features.
    evidence:
    - reference: PMID:26224312
      reference_title: "CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Homozygous mice have PCD characterized by hydrocephalus, male
        infertility, and mucus accumulation.
      explanation: >-
        Supports the infertility phenotype while making explicit that the model
        manifests full PCD rather than isolated spermatogenic failure.
- name: Cfap54 in-frame variant knock-in mouse
  species: Mouse
  genotype: Cfap54 in-frame variant knock-in, modelling a human pathogenic allele
  publication: PMID:37725231
  description: >-
    Knock-in mouse carrying a human CFAP54 pathogenic variant rather than a gene
    trap, so it tests the specific allele class found in patients. Its relevance
    to this entry cuts in a particular direction: the mouse develops full PCD —
    hydrocephalus and nasal mucus accumulation as well as infertility — so on the
    closest available allele-matched model, CFAP54 loss does not produce isolated
    infertility.
  modeled_mechanisms:
  - target: Male Infertility
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the infertility endpoint of this entry, but as one component of
      a full PCD phenotype rather than in isolation.
    limitations: >-
      The human probands curated here have infertility without recognised airway
      disease, whereas this mouse has both. Whether that is a species difference,
      an allele difference, or undetected airway disease in the men is exactly
      the question left open in this entry's discussion, so the model cannot be
      read as settling it. The variant is in-frame, which need not match the
      frameshift and missense alleles in the infertility cohort.
    readouts:
    - name: Fertility
      target: Male Infertility
      direction: DECREASED
      interpretation: >-
        Infertility observed alongside the other PCD manifestations.
      evidence:
      - reference: PMID:37725231
        reference_title: "Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In addition, a CFAP54 in-frame variant knock-in mouse model was
          established, which recapitulated the typical symptoms of PCD, including
          hydrocephalus, infertility, and mucus accumulation in nasal sinuses.
        explanation: >-
          The measurement behind this readout, and the reason the model is
          recorded as partially rather than fully recapitulating an
          infertility-only entity.
    evidence:
    - reference: PMID:37725231
      reference_title: "Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, a CFAP54 in-frame variant knock-in mouse model was
        established, which recapitulated the typical symptoms of PCD, including
        hydrocephalus, infertility, and mucus accumulation in nasal sinuses.
      explanation: >-
        Supports treating this allele-matched model as informative for the
        infertility node while recording that it manifests the wider PCD
        phenotype.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility and morphology defect by injecting a single
    spermatozoon directly into the oocyte. Favourable clinical pregnancy outcomes
    have been reported using sperm from men carrying CFAP54 mutations, so a
    CFAP54 diagnosis carries a genuinely useful prognostic message rather than
    only an explanatory one.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: intracytoplasmic sperm injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  evidence:
  - reference: PMID:36593121
    reference_title: "Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, favourable clinical pregnancy outcomes were achieved with sperm
      from men carrying CFAP54 mutations after intracytoplasmic sperm injection
      treatment.
    explanation: >-
      Direct evidence that ICSI achieves pregnancy despite the flagellar defect.
differential_diagnoses:
- name: CFAP54-related primary ciliary dyskinesia
  disease_term:
    preferred_term: primary ciliary dyskinesia 54
    term:
      id: MONDO:0100607
      label: ciliary dyskinesia, primary, 54
  distinguishing_features:
  - >-
    Chronic upper and lower airway disease — recurrent sinusitis, bronchitis,
    otitis media, bronchiectasis — with or without hydrocephalus. None of this
    is part of the infertility presentation.
  - >-
    Situs is normal in both, so situs inversus does not separate them.
  - >-
    The usual discriminating ciliary tests do not separate them either: nasal
    nitric oxide, transmission electron microscopy and high-speed
    videomicroscopy are all normal in C1d-defective PCD, and PICADAR scoring is
    unreliable. The distinction therefore rests on clinical respiratory history
    rather than on any ciliary assay.
  description: >-
    Not merely a differential but the same gene. Biallelic CFAP54 variants also
    cause primary ciliary dyskinesia, and C1d-defective PCD is notoriously hard
    to detect: it presents with normal situs, normal nasal nitric oxide, normal
    ciliary ultrastructure on transmission electron microscopy and normal
    high-speed videomicroscopy, and the PICADAR clinical prediction tool does not
    reliably identify it. A man diagnosed with CFAP54 spermatogenic failure could
    therefore have unrecognised airway disease that every standard PCD test would
    have called normal.
  evidence:
  - reference: PMID:39362668
    reference_title: "Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Careful evaluation revealed that C1d-defective primary ciliary dyskinesia is
      associated with normal situs composition, normal nasal nitric oxide
      production rates, normal ciliary ultrastructure by transmission electron
      microscopy and normal ciliary beating by high-speed videomicroscopy
      analysis.
    explanation: >-
      Documents that every standard PCD diagnostic modality is normal in
      C1d-defective disease.
  - reference: PMID:39362668
    reference_title: "Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Overall, this study extends the spectrum of primary ciliary dyskinesia genes
      and highlights that individuals with C1d-defective primary ciliary
      dyskinesia elude diagnosis when using the current diagnostic algorithm.
    explanation: >-
      States that these patients evade the standard diagnostic algorithm, the
      clinically actionable point of this differential.
discussions:
- discussion_id: spgf98_isolated_infertility_versus_pcd_spectrum
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is CFAP54-related spermatogenic failure a distinct entity from CFAP54-related
    primary ciliary dyskinesia, or are the infertility probands simply
    PCD patients whose airway disease was never looked for?
  attaches_to:
  - "pathophysiology#CFAP54 Loss of Function"
  - "pathophysiology#Male Infertility"
  rationale: >-
    This is the central nosological question for this entry and it is
    deliberately left open. CFAP54 causes both isolated spermatogenic failure and
    PCD, and the Cfap54 mouse has full PCD — hydrocephalus, mucus accumulation
    and male infertility together — rather than infertility alone. The men in the
    infertility cohort were ascertained through a reproductive clinic, so a
    respiratory phenotype would not necessarily have been sought or recorded.
    What makes this more than a bookkeeping question is that C1d-defective PCD is
    specifically invisible to the standard diagnostic algorithm: normal situs,
    normal nasal nitric oxide, normal transmission electron microscopy, normal
    high-speed videomicroscopy, and unreliable PICADAR scoring. A man could
    therefore be correctly diagnosed with CFAP54 infertility while having
    genuinely undetected airway disease. The alternative explanation — that
    specific alleles or residual function separate an infertility-only phenotype
    from full PCD — is equally untested.

    ClinGen's Motile Ciliopathy Gene Curation Expert Panel went further than
    leaving this open, and this entry diverges from them deliberately rather than
    silently. Applying the ClinGen Lumping & Splitting criteria, the panel found
    the molecular mechanism and mode of inheritance consistent across unrelated
    patients and the phenotypic variability to represent a spectrum rather than
    separate entities, and therefore lumped all inherited CFAP54 disease into a
    single entity, Primary Ciliary Dyskinesia 54 (MONDO:0100607, OMIM:621125).
    dismech nonetheless curates SPGF98 as its own entry, for three reasons. First,
    MONDO retains both terms — MONDO:0700290 for SPGF98 and MONDO:0100607 for
    PCD54 — and dismech entries are keyed to MONDO concepts, so curating SPGF98
    is not an assertion that ClinGen is wrong about gene-disease validity, which
    is a different question from disease-concept granularity. Second, ClinGen's
    own narrative on the same record leaves the specific sub-question this
    discussion asks unresolved (quoted below), so the lumping conclusion and the
    open boundary question coexist in one document. Third, the differential
    diagnosis and `distinguishing_features` on this entry point explicitly at
    PCD54, so a reader who accepts ClinGen's lumping can traverse to it; the
    split costs nothing in navigability. If MONDO merges the two terms, this
    entry should be merged with them.

    Their leaving the sub-question open is the strongest available
    evidence that it is genuinely unresolved rather than merely unexamined here.
    Their review adds one fact that partly cuts against the
    undiagnosed-PCD reading: the proband in the study this entry is built on was
    examined carefully, including CT scanning, and had no obvious PCD symptoms.
    That is a real negative finding, though the panel notes respiratory ciliary
    structure and function were not investigated in either infertility study, so
    a subtle phenotype is not excluded.
  evidence:
  - reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
    reference_title: "CFAP54 / ciliary dyskinesia, primary, 54 (Strong)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It remains unclear if these patients might have subtle respiratory
      phenotypes or if spermatogenic failure alone may be part of the spectrum of
      disease seen in CFAP54 patients.
    explanation: >-
      ClinGen's expert panel states this exact question as unresolved, confirming
      it is a genuine open question rather than a gap local to this entry.
  - reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
    reference_title: "CFAP54 / ciliary dyskinesia, primary, 54 (Strong)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One of these studies reports on a patient that underwent careful
      examination, including CT scanning and had no obvious PCD symptoms such as
      sinusitis, bronchitis, pneumonia or otitis media (PMID: 36593121).
    explanation: >-
      Evidence against the undiagnosed-PCD reading for at least one proband;
      marked PARTIAL because respiratory ciliary structure and function were still
      not investigated.
  - reference: CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z
    reference_title: "CFAP54 / ciliary dyskinesia, primary, 54 (Strong)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Therefore, cases caused by inherited CFAP54 variants have been lumped into
      a single disease entity, Primary Ciliary Dyskinesia 54 (MONDO:0100607,
      OMIM:621125).
    explanation: >-
      ClinGen's formal conclusion, which argues against curating SPGF98 as a
      separate entity. Recorded as REFUTE against the split rather than omitted,
      so the divergence stated in the rationale is visible in the evidence rather
      than only asserted in prose.
  - reference: PMID:41393159
    reference_title: "Exome sequencing reanalysis identifies a novel likely pathogenic CFAP54 variant and expands the phenotypic and genotypic spectrum of primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This finding brings the total number of CFAP54-associated PCD patients to
      eight and the number of distinct CFAP54 mutations to twelve, thereby
      enriching the phenotypic and genotypic spectrum of this gene.
    explanation: >-
      The CFAP54 PCD arm is still only eight patients, which bounds how firmly
      the infertility-versus-PCD boundary can be drawn from either side. The
      proband reported here is a 35-year-old woman with bronchiectasis, so the
      PCD arm is not male-restricted and the two presentations cannot be
      separated by sex.
  proposed_experiments:
  - experiment_id: exp_spgf98_respiratory_phenotyping_of_infertility_probands
    name: Respiratory phenotyping of CFAP54 infertility probands
    description: >-
      Systematically assess reported and newly identified CFAP54 infertility
      probands for airway disease using methods that work in C1d-defective PCD —
      ciliary transport assays and clinical history — rather than the standard
      algorithm that is known to return normal results in this PCD type.
  - experiment_id: exp_spgf98_genotype_stratified_comparison
    name: Genotype comparison between infertility-only and PCD cohorts
    description: >-
      Compare the CFAP54 alleles reported in infertility-only probands against
      those in PCD probands, testing whether allele class or predicted residual
      function separates the two presentations or whether the genotypes overlap.
notes: >-
  Scope. This entry curates SPGF98 (MONDO:0700290), the male infertility
  presentation of biallelic CFAP54 disease. It does not curate CFAP54-related
  primary ciliary dyskinesia, which is a separate clinical entity carried here as
  a differential diagnosis; the relationship between the two is an open question
  recorded in the discussions rather than a settled split.

  Cross-reference. `Primary_Ciliary_Dyskinesia.yaml` carries CFAP54 as an
  established PCD gene with a defective-C1d mechanism, including a
  `Caveat - C1d-Defective PCD Evades the Standard Diagnostic Algorithm` node
  recording that nasal nitric oxide, transmission electron microscopy and
  high-speed video microscopy can all read normal in this PCD type. Between
  them the two entries document the range of one gene: the airway presentation
  there, the male-infertility presentation here. Read together they are the
  evidence base for the open lump/split question in the discussions below.

  Why the MMAF node conforms to the ciliopathy module. The sperm flagellum and
  the motile cilium share axonemal architecture, so a C1d defect impairs both.
  The conformance to `ciliopathy_dysfunction#Motile Cilia Beat Dysfunction` is
  therefore a claim about shared mechanism, not about the patient having airway
  disease — that separate question is the subject of the open discussion.

  Evidence base. Three probands from a 334-proband MMAF/NOA cohort, plus a fourth
  from an independent 167-proband primary-infertility cohort; two mouse models (a
  gene trap and an allele-matched knock-in); a mouse genetic-interaction study
  placing CFAP54 in a central-apparatus dependency with SPEF2 and CFAP221; and
  independent human PCD reports of the same gene, now totalling eight PCD
  patients and twelve distinct alleles. Small for the infertility phenotype, but
  the mechanism is well supported across species and the C1d requirement was
  established independently in mouse and Chlamydomonas.

  Why the PCD GeneReviews chapter is listed but not mined. PMID:20301301 is the
  authoritative clinical source for the diagnostic algorithm this entry's
  differential and open discussion both turn on, so it is listed in `references:`
  and tagged GeneReviews for navigability. It is not cited as evidence anywhere:
  the cached record is `content_type: abstract_only` — 448 characters of purpose
  statement, with no Clinical Characteristics, Diagnosis or Management content —
  so the only quotable text in it is the title, and quoting a title as a finding
  is the anti-pattern the evidence SOP forbids.

  Divergence from ClinGen on disease granularity. ClinGen's Motile Ciliopathy
  GCEP formally lumped all inherited CFAP54 disease into Primary Ciliary
  Dyskinesia 54. This entry nevertheless exists as a separate SPGF98 record,
  because MONDO retains both concepts and dismech entries are keyed to MONDO;
  the reasoning, and the ClinGen sentence that argues against it, are curated in
  the `spgf98_isolated_infertility_versus_pcd_spectrum` discussion rather than
  left implicit.

📚

References & Deep Research

References

9

PMID:36593121

Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA.

No top-level findings curated for this source.

PMID:26224312

CFAP54 is required for proper ciliary motility and assembly of the central pair apparatus in mice.

No top-level findings curated for this source.

PMID:37725231

Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients.

No top-level findings curated for this source.

PMID:39362668

Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.

No top-level findings curated for this source.

CGGV:assertion_f16ea0ce-7d5d-4bdc-92fe-52d111913161-2025-07-16T070000.000Z

CFAP54 / ciliary dyskinesia, primary, 54 (Strong)

No top-level findings curated for this source.

PMID:39267058

Whole exome sequencing analysis of 167 men with primary infertility.

No top-level findings curated for this source.

PMID:32704025

Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia.

No top-level findings curated for this source.

PMID:41393159

Exome sequencing reanalysis identifies a novel likely pathogenic CFAP54 variant and expands the phenotypic and genotypic spectrum of primary ciliary dyskinesia.

No top-level findings curated for this source.

PMID:20301301

Primary Ciliary Dyskinesia.

No top-level findings curated for this source.

Spermatogenic failure 98

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Differential Diagnoses

Animal Models

Source YAML

References & Deep Research

References