Spermatogenic failure 43

Mendelian MONDO:0032898 Pathograph 13 Show in embeddings browser hereditary disease

Spermatogenic failure 43 is male infertility caused by biallelic variants in SPEF2, which encodes sperm flagellar protein 2, a component of the C1b projection of the central pair apparatus that also acts as a linker for dynein-1-dependent cargo transport along the spermatid manchette. Loss of SPEF2 delays delivery of flagellar cargo — IFT20 among it — to the growing tail, so the central pair fails to assemble and the sperm flagellum is built wrong: patient spermatozoa show multiple morphological abnormalities of the sperm flagella (MMAF) with a 9+0 rather than 9+2 axoneme, severely reduced motility, and disorganised mitochondrial sheath and accessory structures. SPEF2 is not an infertility-only gene. The same biallelic loss of function causes primary ciliary dyskinesia, ClinGen classifies the SPEF2-PCD relationship as Definitive, and in the one cohort that took a respiratory history systematically every SPEF2-biallelic man had PCD-like airway symptoms. Whether isolated spermatogenic failure and SPEF2-related PCD are distinct entities or one spectrum is unresolved; this entry curates the reproductive presentation and records the boundary as an open question rather than assuming it. Fertility is achievable: intracytoplasmic sperm injection has produced healthy live births using these men's sperm.

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1
Inheritance
5
Pathophys.
5
Phenotypes
1
Gaps
13
Pathograph
1
Genes
2
Medical Actions
1
Differentials
2
Models
17
References
1
Deep Research
🏷

Classifications

Harrison's Part
GENETICS ENVIRONMENT DISEASE
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Affected men carry biallelic SPEF2 variants — homozygous in consanguineous families and compound heterozygous in outbred ones — with heterozygous parents. The reported alleles are truncating (nonsense, frameshift), splice or deleterious missense, and are absent or extremely rare in population databases.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:31048344 SUPPORT Human Clinical
"Two homozygous stop-gain variants (c.910C>T (p.Arg304*) and c.3400delA (p.Ile1134Serfs*13)) of the SPEF2 (sperm flagellar 2) gene were identified in two unrelated consanguineous families."
Documents homozygous truncating genotypes segregating in consanguineous pedigrees.
PMID:31151990 SUPPORT Human Clinical
"By screening gene variants in 42 patients with MMAF using whole exome sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and c. 4323dupA mutations in the SPEF2 gene from two patients."
Documents the compound heterozygous allele combinations in the founding cohort, showing the disorder also occurs outside consanguineous families.
CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z SUPPORT Other
"SPEF2 | HGNC:26293 | primary ciliary dyskinesia | MONDO:0016575 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-01-09T17:00:00.000Z"
ClinGen's Motile Ciliopathy expert panel records autosomal recessive inheritance for biallelic SPEF2 disease. Note the disease entity on that record is primary ciliary dyskinesia, not spermatogenic failure 43 — the reason is curated in the open discussion on this entry.
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Discussions and Knowledge Gaps

1
Is SPEF2-related spermatogenic failure a distinct entity from SPEF2-related primary ciliary dyskinesia, or is every biallelic SPEF2 man a PCD patient whose airway disease was or was not looked for?
KNOWLEDGE GAP OPEN spgf43_reproductive_versus_pcd_spectrum
Attached to
pathophysiology#SPEF2 Loss of Function pathophysiology#Male Infertility
This is the central nosological question for the entry and it is left open deliberately. The evidence points both ways and the two directions are not symmetrical in strength. Toward one spectrum. In the cohort that took a respiratory history systematically, all six biallelic SPEF2 men had PCD-like symptoms — recurrent airway infections, bronchitis and rhinosinusitis — and the authors explicitly framed their result as bridging MMAF and PCD. That cohort is the load-bearing one, because it was ascertained on severe asthenozoospermia alone; a later series in which all three men had infertility with PCD or likely PCD was ascertained on both features together, so its 3/3 is a description of who was recruited rather than an independent frequency. The whole-animal bgh mouse has full PCD, not isolated infertility. ClinGen's Motile Ciliopathy expert panel applied the Lumping and Splitting criteria and lumped all SPEF2 disease into primary ciliary dyskinesia. And the standard PCD diagnostic algorithm cannot exclude airway disease in a central pair defect, so an infertility proband called PCD-negative on nasal nitric oxide, electron microscopy and high-speed videomicroscopy has not really been cleared. Toward two entities. At least one proband was reported in the confirmed absence of respiratory features rather than merely without them being looked for. There is also a genuine tissue-level dissociation: in the same men, respiratory cilia keep a normal 9+2 axoneme while sperm flagella are 9+0, which the authors read as SPEF2 having different roles in the two tissues. A transcript explanation has been proposed — that alleles hitting only the long testis-expressed transcripts give isolated infertility while alleles hitting broadly expressed isoforms add airway disease — and it is not hand-waving: the naturally occurring immotile short-tail sperm defect of Finnish Yorkshire pigs is exactly that, an intronic SPEF2/KPL2 insertion whose aberrantly spliced exon is expressed predominantly in testis, giving a sperm-restricted disease with cilia elsewhere unaffected. What has not been done is testing it against the human genotypes, so it is cited here as a plausible and precedented mechanism rather than curated as this disease's mechanism. What this entry does about it. dismech curates SPGF43 as its own record while recording the divergence from ClinGen rather than leaving it implicit. MONDO retains both concepts — MONDO:0032898 for SPGF43 and MONDO:0016575 for PCD — and dismech entries are keyed to MONDO concepts, so curating SPGF43 is not an assertion that ClinGen is wrong about gene-disease validity, which is a different question from disease-concept granularity. The same call was made for CFAP54 in Spermatogenic_Failure_98, on the same reasoning. If MONDO merges the two terms, this entry should be merged with them.
Proposed experiments
Respiratory phenotyping of SPEF2 infertility probands
exp_spgf43_respiratory_phenotyping_of_infertility_probands
Systematically assess reported and newly identified SPEF2 infertility probands for airway disease using methods that work in central pair defects — structured respiratory history, high-speed video microscopy and immunofluorescence for SPEF2 in respiratory cells — rather than the standard algorithm, which returns normal nasal nitric oxide and normal electron microscopy in this defect class.
Transcript-stratified comparison of infertility-only and PCD genotypes
exp_spgf43_transcript_stratified_genotype_comparison
Test the proposed transcript explanation directly: map every reported SPEF2 allele onto the long testis-specific and the broadly expressed transcripts, and ask whether transcript coverage separates probands with isolated infertility from those with airway disease, or whether the genotypes overlap.
Show evidence (8 references)
PMID:31942643 SUPPORT Human Clinical
"Notably, all six patients exhibited PCD-like symptoms, including recurrent airway infections, bronchitis, and rhinosinusitis."
The strongest evidence for one spectrum: when respiratory history was taken systematically in a SPEF2 infertility cohort, every man had airway symptoms.
PMID:31942643 SUPPORT Human Clinical
"Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory cilia but consistently abnormal 9 + 0 axoneme or disordered accessory structures of sperm flagella, indicating different roles of SPEF2 in sperm flagella and respiratory cilia."
Evidence in the other direction, from the same study: the two tissues are not affected identically, so the shared genotype does not imply an identical lesion.
PMID:31942643 SUPPORT Human Clinical
"Recent studies have revealed that SPEF2 mutations lead to multiple morphological abnormalities of the sperm flagella (MMAF) without primary ciliary dyskinesia (PCD) symptoms in males, but PCD phenotype was also found in one female individual."
States the position of the field before this study: SPEF2 infertility had been reported without PCD symptoms in men, which is the observation the study then complicated.
+ 5 more references
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Pathophysiology

5
SPEF2 Loss of Function
Biallelic loss-of-function variants remove or truncate SPEF2, a component of the C1b projection of the ciliary and flagellar central pair apparatus. The variants reported in affected men fall in the long, testis-expressed SPEF2 transcripts that encode the IFT20-binding domain, and patient spermatozoa show markedly reduced or absent SPEF2 protein on western blot and immunofluorescence.
SPEF2 hgnc:26293 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SPEF2 (hgnc:26293). hgnc:26293 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Germline biallelic nonsense, frameshift, canonical-splice and deleterious missense variants, absent or extremely rare in population databases.
axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology.
Downstream
Impaired Manchette and Intraflagellar Cargo Transport SPEF2 is the linker; losing it is what removes the transport function.
Show evidence (3 references)
PMID:31151990 SUPPORT Human Clinical
"The SPEF2 protein level was significantly decreased in the spermatozoa of the patients revealed by Western blot (WB) and immunofluorescence (IF) analyses."
Demonstrates that the variants produce loss of SPEF2 protein in the affected cell, rather than only a predicted consequence.
PMID:31048344 SUPPORT Human Clinical
"All these variants affected the long SPEF2 transcripts that are expressed in the testis and encode the IFT20 (intraflagellar transport 20) binding domain, important for sperm tail development."
Localises the reported alleles to the testis-expressed transcripts carrying the IFT20-binding domain, which is what connects the lesion to the transport step downstream.
PMID:31278745 SUPPORT Human Clinical
"The expression of truncated SPEF2 protein was reduced significantly in the patient's spermatozoa."
Independent replication of reduced SPEF2 protein in patient spermatozoa.
Impaired Manchette and Intraflagellar Cargo Transport
SPEF2 binds the intraflagellar transport protein IFT20 and cytoplasmic dynein 1, and localises to the Golgi complex, manchette and basal body of differentiating spermatids. In the male-germ-cell-specific Spef2 knockout mouse, IFT20 transport from the Golgi to the manchette is delayed and the manchette fails to migrate, so SPEF2 acts as a cargo linker for dynein-1-mediated transport along the microtubule tracks that build the tail. The human evidence for this step is the IFT20 and RSPH9 binding shown in a heterologous assay plus the transcript localisation of the patient alleles; the transport defect itself has been demonstrated in mouse rather than in human spermatids, which is why this node is marked PROVISIONAL rather than ESTABLISHED.
spermatid CL:0000018 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves spermatid (CL:0000018). CL:0000018 is a cell type from the Cell Ontology.
intraciliary transport GO:0042073 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased intraciliary transport (GO:0042073). GO:0042073 is a biological process from the Gene Ontology. ↓ DECREASED
sperm flagellum GO:0036126 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves sperm flagellum (GO:0036126). GO:0036126 is a cellular component from the Gene Ontology.
Animal models
Male germ cell-specific Spef2 conditional knockout mouse Mouse recapitulates Loss of SPEF2 in male germ cells delays IFT20 transport from the Golgi complex to the manchette and causes the manchette to fail to migrate, which is the transport failure this node asserts.
Downstream
Sperm Flagellar Central Pair Apparatus Failure Cargo that is not delivered to the growing tail cannot be built into the axoneme.
Show evidence (4 references)
PMID:19889948 SUPPORT INDIRECT Model Organism
"Using yeast two-hybrid assay and coimmunoprecipitation experiments, we identified an interaction between SPEF2 and the intraflagellar transport protein IFT20 in the testis."
Establishes the SPEF2-IFT20 interaction in testis, the molecular basis of the transport role. Indirect because the experiment is in mouse testis.
PMID:28619825 SUPPORT INDIRECT Model Organism
"Furthermore, the transport of a known SPEF2-binding protein, IFT20, from the Golgi complex to the manchette was delayed in the absence of SPEF2."
The direct functional demonstration that losing SPEF2 delays cargo transport. Indirect because it is a mouse germ-cell conditional knockout.
PMID:28619825 SUPPORT INDIRECT Model Organism
"We identified cytoplasmic dynein 1 and GOLGA3 as novel interaction partners for SPEF2."
Identifies the motor SPEF2 links cargo to, which is why the node is described as a transport-linker failure rather than a structural one.
+ 1 more reference
Sperm Flagellar Central Pair Apparatus Failure
The sperm axoneme is assembled without its central pair. Transmission electron microscopy of patient spermatozoa shows a 9+0 rather than the normal 9+2 configuration and disorganised accessory structures, and immunofluorescence shows loss of SPEF2 itself together with other central pair and axonemal proteins, including the MMAF-associated CFAP69. Sperm proteomics from three SPEF2-mutant men found over a thousand differentially expressed proteins, so the lesion propagates well beyond the C1b projection.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
sperm axoneme assembly GO:0007288 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased sperm axoneme assembly (GO:0007288). GO:0007288 is a biological process from the Gene Ontology. ↓ DECREASED
axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella An axoneme assembled without its central pair produces a malformed flagellum.
Absent Sperm Axoneme Central Pair Complex The clinical expression of this node: the missing central pair is what a pathologist sees on transmission electron microscopy of patient sperm.
Show evidence (5 references)
PMID:38568462 SUPPORT Human Clinical
"Ultrastructural analyses of the spermatozoa of the patients revealed the absence of the central pair complex in the sperm flagella."
Direct ultrastructural demonstration that the central pair is missing from patient sperm flagella.
PMID:31942643 SUPPORT Human Clinical
"Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory cilia but consistently abnormal 9 + 0 axoneme or disordered accessory structures of sperm flagella, indicating different roles of SPEF2 in sperm flagella and respiratory cilia."
Names the 9+0 configuration in sperm, and in the same measurement shows the respiratory cilia of the same men are ultrastructurally normal — the tissue-level dissociation this entry's scope note turns on.
PMID:31048344 SUPPORT Human Clinical
"Our further functional studies using immunofluorescence assays showed the absence or a remarkably reduced staining of SPEF2 and of the MMAF-associated CFAP69 protein in the spermatozoa from SPEF2-affected subjects."
Shows the defect extends to other axonemal proteins, not only to SPEF2 itself.
+ 2 more references
Multiple Morphological Abnormalities of the Sperm Flagella
The malformed axoneme yields the MMAF phenotype — absent, short, coiled, bent and irregular-calibre tails with severely reduced motility — together with mitochondrial-sheath and accessory-structure disorganisation. This is the sperm-flagellar instance of the motile-axoneme beat failure that produces impaired ciliary beating in the airway, which is why the node conforms to the motile-cilia arm of the ciliopathy module. The conformance is a claim about shared mechanism, not about the patient having airway disease; note also that in SPEF2 disease the two tissues are not affected identically, since respiratory cilia of the same men retain a normal 9+2 ultrastructure while their sperm flagella do not.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
cilium movement GO:0003341 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cilium movement (GO:0003341). GO:0003341 is a biological process from the Gene Ontology. ↓ DECREASED
Animal models
Spef2 big giant head (bgh) mouse Mouse recapitulates Homozygous males are infertile with shortened flagella and disorganised axonemal and accessory structures in elongating spermatids and mature sperm, matching the human flagellar phenotype.
Downstream
Male Infertility Flagella built this way cannot propel the spermatozoon.
Abnormal Sperm Morphology The clinical expression of this node in a routine semen analysis.
Abnormal Sperm Tail Morphology The same finding localised to the flagellum on detailed tail morphology scoring.
Reduced Sperm Motility A flagellum that cannot beat normally is a spermatozoon that cannot swim.
Show evidence (3 references)
PMID:31151990 SUPPORT Human Clinical
"Our experimental findings indicate that loss-of-function mutations in the SPEF2 gene can cause the MMAF phenotype in human."
States the causal relationship between SPEF2 loss of function and the MMAF phenotype in patients.
PMID:31278745 SUPPORT Human Clinical
"The spermatozoa harbored biallelic mutations and showed severe ultrastructural defects in the axoneme and mitochondrial sheath."
Documents that the defect includes the mitochondrial sheath and accessory structures, not the axoneme alone.
PMID:31151990 SUPPORT Human Clinical
"Transmission electron microscope (TEM) analysis showed a disrupted axonemal structure with mitochondrial sheath defects in the patients' spermatozoa."
The ultrastructural measurement behind the morphological claim.
Male Infertility
The clinical endpoint, and the route by which these men are ascertained. Affected men present in a reproductive clinic with severe asthenoteratozoospermia; the underlying failure is of spermiogenesis rather than of transport out of the tract.
Animal models
Spef2 big giant head (bgh) mouse Mouse partially recapitulates Homozygous males are infertile, matching the human endpoint. But they are infertile as one component of full PCD — hydrocephalus and sinusitis alongside — rather than in isolation.
Show evidence (2 references)
PMID:34755699 SUPPORT Human Clinical
"Previous studies have reported that sperm flagellar 2 (SPEF2) deficiency causes severe asthenoteratozoospermia owing to spermiogenesis failure, but the underlying molecular mechanism in humans remains unclear."
States that the infertility arises from failed spermiogenesis, which is what makes this node the endpoint of the assembly chain above it.
CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z SUPPORT Human Clinical
"Probands diagnosed with spermatogenic failure displayed male infertility and reduced sperm motility, often without reported details of respiratory examinations, but sometimes in the confirmed absence of respiratory features"
ClinGen's summary of the reproductive presentation across the published probands, including the observation that respiratory examination was often not reported — which is the substance of the open boundary discussion.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spermatogenic failure 43 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

5
Genitourinary 1
Male Infertility HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38568462 SUPPORT Human Clinical
"All the patients presented with male infertility and PCD/likely PCD."
Documents male infertility in every proband of this series. The same sentence also records the co-occurring airway phenotype, which this entry deliberately does not curate as an SPGF43 feature — see the scope note.
Other 4
Abnormal Sperm Morphology HP:0012864 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal sperm morphology (HP:0012864). HP:0012864 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31151990 SUPPORT Human Clinical
"Our experimental findings indicate that loss-of-function mutations in the SPEF2 gene can cause the MMAF phenotype in human."
MMAF is by definition a set of morphological abnormalities of the sperm flagellum, so establishing the MMAF phenotype establishes this one.
Abnormal Sperm Tail Morphology HP:0012868 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal sperm tail morphology (HP:0012868). HP:0012868 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:31278745 SUPPORT Human Clinical
"Our data suggest that biallelic mutations in SPEF2 can cause severe sperm flagellum defects, thus providing a novel candidate genetic pathogen for the human MMAF phenotype."
Localises the severe defect to the sperm flagellum specifically.
Absent Sperm Axoneme Central Pair Complex HP:0033525 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent sperm axoneme central pair complex (HP:0033525). HP:0033525 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38568462 SUPPORT Human Clinical
"Ultrastructural analyses of the spermatozoa of the patients revealed the absence of the central pair complex in the sperm flagella."
Direct ultrastructural observation of the absent central pair in patient spermatozoa.
PMID:31942643 SUPPORT Human Clinical
"Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory cilia but consistently abnormal 9 + 0 axoneme or disordered accessory structures of sperm flagella, indicating different roles of SPEF2 in sperm flagella and respiratory cilia."
Independent cohort reporting the 9+0 sperm axoneme, and in the same measurement showing the finding is specific to the flagellum rather than shared with respiratory cilia.
Reduced Sperm Motility HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z SUPPORT Human Clinical
"Probands diagnosed with spermatogenic failure displayed male infertility and reduced sperm motility, often without reported details of respiratory examinations, but sometimes in the confirmed absence of respiratory features"
ClinGen's summary of the reproductive presentation across published SPEF2 spermatogenic-failure probands records reduced sperm motility.
PMID:34755699 SUPPORT Human Clinical
"Previous studies have reported that sperm flagellar 2 (SPEF2) deficiency causes severe asthenoteratozoospermia owing to spermiogenesis failure, but the underlying molecular mechanism in humans remains unclear."
Asthenoteratozoospermia is by definition reduced motility together with abnormal morphology.
🧬

Genetic Associations

1
SPEF2
Gene: SPEF2 hgnc:26293 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SPEF2 (hgnc:26293). hgnc:26293 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (5 references)
PMID:31151990 SUPPORT Human Clinical
"By screening gene variants in 42 patients with MMAF using whole exome sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and c. 4323dupA mutations in the SPEF2 gene from two patients."
Establishes the founding cohort size against which the two probands should be read.
PMID:31048344 SUPPORT Human Clinical
"We conducted genetic analyses using whole-exome sequencing in 50 Han Chinese probands with MMAF."
The denominator for the second independent cohort.
PMID:31942643 SUPPORT Human Clinical
"We identified four novel biallelic mutations in SPEF2 (8.9%, 4/45) in six affected individuals (12.8%, 6/47), while no deleterious biallelic variants in SPEF2 were detected in 637 controls"
A third independent cohort with an explicit denominator and a control series in which no biallelic SPEF2 genotype was found.
+ 2 more references
💊

Medical Actions

2
Intracytoplasmic Sperm Injection
Action: intracytoplasmic sperm injectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is intracytoplasmic sperm injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. Ontology label: Intracytoplasmic Sperm Injection NCIT:C185482
ICSI bypasses the motility and morphology defect by injecting a single spermatozoon directly into the oocyte. Every man in the largest reported SPEF2 series to undergo ICSI achieved a live birth, so a SPEF2 diagnosis carries a usable prognostic message and not only an explanatory one. The series is three men, so this is a favourable signal rather than a success rate.
Mechanism Target:
BYPASSES Male Infertility — ICSI does not repair the flagellum. It circumvents the requirement for sperm propulsion, so it acts on the clinical endpoint rather than on any upstream assembly node.
Show evidence (1 reference)
PMID:38568462 SUPPORT Human Clinical
"All patients carrying SPEF2 variants underwent one ICSI cycle and delivered healthy infants."
Direct evidence that ICSI achieves live birth despite the flagellar defect.
Show evidence (1 reference)
PMID:39753944 SUPPORT Human Clinical
"The infertility caused by FSIP2 and SPEF2 variants can be mitigated through ICSI or even IVF."
A second series reaching the same conclusion. Its quantitative outcome rates are pooled across FSIP2 and SPEF2 probands, so only the qualitative conclusion is curated here.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal recessive recurrence counselling for the couple, cascade carrier testing for relatives, and — because the same genotype causes primary ciliary dyskinesia — an explicit discussion of respiratory risk for the proband and for any biallelic relative of either sex. Once the familial alleles are known, preimplantation genetic testing for monogenic disease (PGT-M) and prenatal diagnosis become available options alongside the ICSI cycle, subject to local regulation and the couple's preferences.
Show evidence (1 reference)
PMID:38568462 SUPPORT Human Clinical
"Our study reported four novel pathogenic variants of SPEF2 in three male patients with infertility and PCD/PCD-like phenotypes, which not only extend the spectrum of SPEF2 mutations but also provide information for genetic counseling and treatment of such conditions."
The authors state genetic counselling as the application of the molecular diagnosis, and in the same sentence tie it to the PCD-overlapping phenotype.
🔬

Diagnosis

3
Molecular Genetic Testing
The primary diagnostic modality, and the only one that establishes the diagnosis. Every reported proband was ascertained by whole-exome sequencing or a targeted MMAF/PCD panel that includes SPEF2, with biallelic status and parental phase confirmed by Sanger sequencing. Splice-aware and copy-number-aware analysis matters here, because reported alleles include canonical splice variants and the founding pig disease is an intronic insertion acting through aberrant splicing. Semen analysis and ultrastructure raise the suspicion of a flagellar gene; they do not name it, since MMAF is genetically heterogeneous and more than twenty other genes produce the same semen picture.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:31048344 SUPPORT Human Clinical
"We conducted genetic analyses using whole-exome sequencing in 50 Han Chinese probands with MMAF."
Whole-exome sequencing of an MMAF cohort is the route by which these probands were identified.
PMID:36873931 SUPPORT Human Clinical
"Here, we performed genetic testing by next generation sequencing techniques, PCD diagnostics including immunofluorescence-, transmission electron-, and high-speed video microscopy on sperm flagella and andrological work up including semen analyses."
Describes the combined workup in which next-generation sequencing is the genetic arm, alongside the sperm immunofluorescence curated below.
Immunofluorescence Staining of SPEF2 in Sperm Flagella
Immunofluorescence microscopy of ejaculated spermatozoa for SPEF2 and its axonemal partners is a practical adjunct to sequencing. It converts an uncertain variant into a demonstrated protein defect, which matters here because several reported alleles are missense.
Show evidence (1 reference)
PMID:36873931 SUPPORT Human Clinical
"Our findings demonstrate that immunofluorescence microscopy in sperm cells is a valuable tool to identify flagellar defects related to the axonemal ruler, radial spoke head and the central pair apparatus, thus aiding the diagnosis of male infertility."
States the diagnostic utility of sperm immunofluorescence for central pair apparatus defects, the class SPEF2 belongs to.
Caveat - Central Pair Defects Evade the Standard PCD Diagnostic Algorithm
Recorded here because it bears directly on this entry's scope rather than on its own diagnosis. A man given a SPEF2 spermatogenic-failure diagnosis cannot be cleared of airway disease by the usual ciliary tests: in central pair defects the ciliary beating abnormality is very subtle, the ciliary ultrastructure is normal and situs is normal, so the standard PCD algorithm returns normal results. In SPEF2 disease specifically, the respiratory cilia of affected men have a normal 9+2 axoneme even while their sperm flagella do not. Assessing for PCD therefore rests on respiratory history and on immunofluorescence for SPEF2 in respiratory cells, not on electron microscopy.
Show evidence (2 references)
PMID:31545650 SUPPORT Human Clinical
"However, it is difficult to establish a diagnosis in individuals with PCD and central pair (CP) defects, and alternative strategies are required because of very subtle ciliary beating abnormalities, a normal ciliary ultrastructure, and normal situs composition."
Documents that the standard PCD diagnostic modalities read normal in central pair defects.
PMID:31545650 SUPPORT Human Clinical
"We conclude that SPEF2 IF analyses can facilitate the detection of CP defects and evaluation of the pathogenicity of HYDIN variants, thus aiding the molecular diagnosis of CP defects."
Names the alternative that does work — immunofluorescence for SPEF2 in respiratory cells.
🔀

Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Spermatogenic failure 43:

🐁

Animal Models

2
Spef2 big giant head (bgh) mouse
A spontaneous mouse mutant positionally cloned to a nonsense variant in Spef2. It is the model that established SPEF2 as a motile-ciliopathy gene, and it is informative for this entry in two directions: it reproduces the flagellar assembly defect, and it demonstrates that whole-animal loss of SPEF2 produces full primary ciliary dyskinesia rather than isolated infertility.
Species
Mouse
Genotype
Spef2 bgh, homozygous nonsense
Publication
PMID:21715716
Pathograph links
Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: moderate Homozygous males are infertile with shortened flagella and disorganised axonemal and accessory structures in elongating spermatids and mature sperm, matching the human flagellar phenotype.
Limitations: A nonsense allele in mouse is not equivalent to the compound heterozygous and missense genotypes reported in men, and the mouse also has hydrocephalus and sinusitis, which are not part of the curated human reproductive phenotype.
Readouts
Sperm flagellar structure in elongating spermatids and mature sperm
Direction: ALTERED
Interpretation: Shortened flagella with disorganised axonemal and accessory structures.
Show evidence (1 reference)
PMID:21715716 SUPPORT Model Organism
"Histopathological, immunofluorescence, and electron microscopic analyses demonstrate that the male infertility results from shortened flagella and disorganized axonemal and accessory structures in elongating spermatids and mature sperm."
The histological and ultrastructural measurement behind this readout.
Elongating spermatid and epididymal sperm number
Direction: DECREASED
Interpretation: Fewer elongating spermatids during spermatogenesis and fewer mature sperm in the epididymis.
Show evidence (1 reference)
PMID:21715716 SUPPORT Model Organism
"In addition, there is a reduced number of elongating spermatids during spermatogenesis and mature sperm in the epididymis."
The quantitative germ-cell measurement behind this readout.
Show evidence (1 reference)
PMID:21715716 SUPPORT Model Organism
"Through a positional cloning approach, we identified two sequence variants in the gene encoding sperm flagellar protein 2 (SPEF2), which has been postulated to play an important role in spermatogenesis and flagellar assembly."
Establishes that the bgh phenotype is caused by loss of the same gene, which is what makes the model informative for this node.
Male Infertility partially recapitulates fidelity: moderate Homozygous males are infertile, matching the human endpoint. But they are infertile as one component of full PCD — hydrocephalus and sinusitis alongside — rather than in isolation.
Limitations: The mouse phenotype is broader than the curated human phenotype. It cannot be used to argue that isolated spermatogenic failure is the expected consequence of SPEF2 loss; that mismatch is the substance of the open phenotypic-boundary discussion on this entry.
Readouts
Male fertility
Direction: DECREASED
Interpretation: Homozygous males are infertile, alongside hydrocephalus and sinusitis.
Show evidence (1 reference)
PMID:21715716 SUPPORT Model Organism
"Mice homozygous for the mutation big giant head (bgh) have several abnormalities commonly associated with PCD, including hydrocephalus, male infertility, and sinusitis."
Documents infertility in the model while making explicit that it occurs as part of full PCD.
Show evidence (1 reference)
PMID:21715716 SUPPORT Model Organism
"Taken together, the data in this study demonstrate that SPEF2 is required for cilia function and identify a new genetic cause of PCD in mice."
The authors' own conclusion, which frames the model as a PCD model rather than an isolated-infertility model.
Male germ cell-specific Spef2 conditional knockout mouse
A germ-cell-restricted Spef2 knockout, which isolates the spermiogenesis phenotype from the hydrocephalus and airway disease of the whole-animal mutant. It is the model that demonstrated the transport function of SPEF2.
Species
Mouse
Genotype
Spef2 conditional knockout, male germ cell-specific
Publication
PMID:28619825
Pathograph links
Impaired Manchette and Intraflagellar Cargo Transport recapitulates fidelity: moderate Loss of SPEF2 in male germ cells delays IFT20 transport from the Golgi complex to the manchette and causes the manchette to fail to migrate, which is the transport failure this node asserts.
Limitations: The transport measurements are in mouse spermatids; the equivalent experiment has not been done in human germ cells, where the evidence is limited to protein-protein interaction in a heterologous cell line and to the transcript position of the patient alleles. A complete germ-cell knockout also does not model the hypomorphic missense alleles seen in some men.
Readouts
IFT20 transport from Golgi complex to manchette
Direction: DECREASED
Interpretation: Delivery of the SPEF2 cargo IFT20 to the manchette is delayed when SPEF2 is absent.
Show evidence (1 reference)
PMID:28619825 SUPPORT Model Organism
"Furthermore, the transport of a known SPEF2-binding protein, IFT20, from the Golgi complex to the manchette was delayed in the absence of SPEF2."
The transport measurement behind this readout.
Manchette migration and basal body number
Direction: ALTERED
Interpretation: Failure of manchette migration with basal body duplication and abnormal spermatid head shape.
Show evidence (1 reference)
PMID:28619825 SUPPORT Model Organism
"In addition to defects in sperm tail development, we observed a duplication of the basal body and failure in manchette migration resulting in an abnormal head shape."
The structural measurement behind this readout.
Show evidence (1 reference)
PMID:28619825 SUPPORT Model Organism
"In this study we investigated the function of SPEF2 during spermatogenesis using a male germ cell-specific Spef2 knockout mouse model."
Establishes the model and its germ-cell restriction, which is what makes it informative for the spermiogenesis transport node specifically.
{ }

Source YAML

click to show 
name: Spermatogenic failure 43
creation_date: "2026-09-03T00:00:00Z"
description: >-
  Spermatogenic failure 43 is male infertility caused by biallelic variants in
  SPEF2, which encodes sperm flagellar protein 2, a component of the C1b
  projection of the central pair apparatus that also acts as a linker for
  dynein-1-dependent cargo transport along the spermatid manchette. Loss of
  SPEF2 delays delivery of flagellar cargo — IFT20 among it — to the growing
  tail, so the central pair fails to assemble and the sperm flagellum is built
  wrong: patient spermatozoa show multiple morphological abnormalities of the
  sperm flagella (MMAF) with a 9+0 rather than 9+2 axoneme, severely reduced
  motility, and disorganised mitochondrial sheath and accessory structures.
  SPEF2 is not an infertility-only gene. The same biallelic loss of function
  causes primary ciliary dyskinesia, ClinGen classifies the SPEF2-PCD
  relationship as Definitive, and in the one cohort that took a respiratory
  history systematically every SPEF2-biallelic man had PCD-like airway symptoms.
  Whether isolated spermatogenic failure and SPEF2-related PCD are distinct
  entities or one spectrum is unresolved; this entry curates the reproductive
  presentation and records the boundary as an open question rather than assuming
  it. Fertility is achievable: intracytoplasmic sperm injection has produced
  healthy live births using these men's sperm.
category: Mendelian
parents:
- hereditary disease
synonyms:
- SPGF43
- SPEF2-related spermatogenic failure
- SPEF2-related male infertility
- SPEF2-associated MMAF
disease_term:
  preferred_term: Spermatogenic failure 43
  term:
    id: MONDO:0032898
    label: spermatogenic failure 43
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:31048344
      reference_title: "Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We identified SPEF2 as a novel gene for human MMAF across the populations.
      explanation: >-
        Establishes a single-gene recessive Mendelian basis for the phenotype,
        placing the entry in Harrison's genetics Part.
references:
- reference: PMID:31151990
  title: "Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)."
- reference: PMID:31278745
  title: "Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype."
- reference: PMID:31048344
  title: "Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility."
- reference: PMID:31942643
  title: "Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD."
- reference: PMID:34755699
  title: "Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans."
- reference: PMID:36873931
  title: "Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility."
- reference: PMID:38568462
  title: "Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia."
- reference: PMID:39753944
  title: "Novel variants of FSIP2 and SPEF2 cause varying degrees of spermatozoa damage in MMAF patients and favorable ART outcomes."
- reference: PMID:31545650
  title: "SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics."
- reference: PMID:36615117
  title: "Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review."
- reference: PMID:21715716
  title: "Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia."
- reference: PMID:28619825
  title: "SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation."
- reference: PMID:19889948
  title: "Expression of SPEF2 during mouse spermatogenesis and identification of IFT20 as an interacting protein."
- reference: PMID:32704025
  title: "Genetic interaction between central pair apparatus genes CFAP221, CFAP54, and SPEF2 in mouse models of primary ciliary dyskinesia."
- reference: PMID:16549801
  title: "An intronic insertion in KPL2 results in aberrant splicing and causes the immotile short-tail sperm defect in the pig."
- reference: PMID:20301301
  title: "Primary Ciliary Dyskinesia."
  tags: [GeneReviews]
- reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
  title: "SPEF2 / primary ciliary dyskinesia (Definitive)"
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Affected men carry biallelic SPEF2 variants — homozygous in consanguineous
    families and compound heterozygous in outbred ones — with heterozygous
    parents. The reported alleles are truncating (nonsense, frameshift), splice
    or deleterious missense, and are absent or extremely rare in population
    databases.
  evidence:
  - reference: PMID:31048344
    reference_title: "Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Two homozygous stop-gain variants (c.910C>T (p.Arg304*) and c.3400delA
      (p.Ile1134Serfs*13)) of the SPEF2 (sperm flagellar 2) gene were identified
      in two unrelated consanguineous families.
    explanation: >-
      Documents homozygous truncating genotypes segregating in consanguineous
      pedigrees.
  - reference: PMID:31151990
    reference_title: "Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By screening gene variants in 42 patients with MMAF using whole exome
      sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and
      c. 4323dupA mutations in the SPEF2 gene from two patients.
    explanation: >-
      Documents the compound heterozygous allele combinations in the founding
      cohort, showing the disorder also occurs outside consanguineous families.
  - reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
    reference_title: "SPEF2 / primary ciliary dyskinesia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SPEF2 | HGNC:26293 | primary ciliary dyskinesia | MONDO:0016575 | AR | Definitive | SOP11 | Motile Ciliopathy Gene Curation Expert Panel | 2025-01-09T17:00:00.000Z"
    explanation: >-
      ClinGen's Motile Ciliopathy expert panel records autosomal recessive
      inheritance for biallelic SPEF2 disease. Note the disease entity on that
      record is primary ciliary dyskinesia, not spermatogenic failure 43 — the
      reason is curated in the open discussion on this entry.
pathophysiology:
- name: SPEF2 Loss of Function
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    Biallelic loss-of-function variants remove or truncate SPEF2, a component of
    the C1b projection of the ciliary and flagellar central pair apparatus. The
    variants reported in affected men fall in the long, testis-expressed SPEF2
    transcripts that encode the IFT20-binding domain, and patient spermatozoa
    show markedly reduced or absent SPEF2 protein on western blot and
    immunofluorescence.
  genes:
  - preferred_term: SPEF2
    term:
      id: hgnc:26293
      label: SPEF2
  genetic_context:
    functional_impact_category: LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    description: >-
      Germline biallelic nonsense, frameshift, canonical-splice and deleterious
      missense variants, absent or extremely rare in population databases.
  cellular_components:
  - preferred_term: axoneme
    term:
      id: GO:0005930
      label: axoneme
  evidence:
  - reference: PMID:31151990
    reference_title: "Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The SPEF2 protein level was significantly decreased in the spermatozoa of
      the patients revealed by Western blot (WB) and immunofluorescence (IF)
      analyses.
    explanation: >-
      Demonstrates that the variants produce loss of SPEF2 protein in the
      affected cell, rather than only a predicted consequence.
  - reference: PMID:31048344
    reference_title: "Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All these variants affected the long SPEF2 transcripts that are expressed
      in the testis and encode the IFT20 (intraflagellar transport 20) binding
      domain, important for sperm tail development.
    explanation: >-
      Localises the reported alleles to the testis-expressed transcripts carrying
      the IFT20-binding domain, which is what connects the lesion to the transport
      step downstream.
  - reference: PMID:31278745
    reference_title: "Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The expression of truncated SPEF2 protein was reduced significantly in the
      patient's spermatozoa.
    explanation: >-
      Independent replication of reduced SPEF2 protein in patient spermatozoa.
  downstream:
  - target: Impaired Manchette and Intraflagellar Cargo Transport
    causal_link_type: DIRECT
    description: >-
      SPEF2 is the linker; losing it is what removes the transport function.
- name: Impaired Manchette and Intraflagellar Cargo Transport
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: PROVISIONAL
  description: >-
    SPEF2 binds the intraflagellar transport protein IFT20 and cytoplasmic
    dynein 1, and localises to the Golgi complex, manchette and basal body of
    differentiating spermatids. In the male-germ-cell-specific Spef2 knockout
    mouse, IFT20 transport from the Golgi to the manchette is delayed and the
    manchette fails to migrate, so SPEF2 acts as a cargo linker for
    dynein-1-mediated transport along the microtubule tracks that build the
    tail. The human evidence for this step is the IFT20 and RSPH9 binding shown
    in a heterologous assay plus the transcript localisation of the patient
    alleles; the transport defect itself has been demonstrated in mouse rather
    than in human spermatids, which is why this node is marked PROVISIONAL
    rather than ESTABLISHED.
  cell_types:
  - preferred_term: spermatid
    term:
      id: CL:0000018
      label: spermatid
  biological_processes:
  - preferred_term: intraciliary transport
    modifier: DECREASED
    term:
      id: GO:0042073
      label: intraciliary transport
  cellular_components:
  - preferred_term: sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  evidence:
  - reference: PMID:19889948
    reference_title: "Expression of SPEF2 during mouse spermatogenesis and identification of IFT20 as an interacting protein."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Using yeast two-hybrid assay and coimmunoprecipitation experiments, we
      identified an interaction between SPEF2 and the intraflagellar transport
      protein IFT20 in the testis.
    explanation: >-
      Establishes the SPEF2-IFT20 interaction in testis, the molecular basis of
      the transport role. Indirect because the experiment is in mouse testis.
  - reference: PMID:28619825
    reference_title: "SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Furthermore, the transport of a known SPEF2-binding protein, IFT20, from
      the Golgi complex to the manchette was delayed in the absence of SPEF2.
    explanation: >-
      The direct functional demonstration that losing SPEF2 delays cargo
      transport. Indirect because it is a mouse germ-cell conditional knockout.
  - reference: PMID:28619825
    reference_title: "SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      We identified cytoplasmic dynein 1 and GOLGA3 as novel interaction partners
      for SPEF2.
    explanation: >-
      Identifies the motor SPEF2 links cargo to, which is why the node is
      described as a transport-linker failure rather than a structural one.
  - reference: PMID:34755699
    reference_title: "Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: >-
      Furthermore, we showed that SPEF2 interacts with radial spoke head
      component 9 (RSPH9) and IFT20 in vitro, which are well-studied components
      of radial spokes or intra-flagellar transport and are essential for
      flagellar assembly.
    explanation: >-
      Confirms the IFT20 interaction for the human protein. Indirect because the
      co-immunoprecipitation was performed in transfected HEK293T cells, not in
      spermatids.
  downstream:
  - target: Sperm Flagellar Central Pair Apparatus Failure
    causal_link_type: DIRECT
    description: >-
      Cargo that is not delivered to the growing tail cannot be built into the
      axoneme.
- name: Sperm Flagellar Central Pair Apparatus Failure
  biological_scale: CELLULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The sperm axoneme is assembled without its central pair. Transmission
    electron microscopy of patient spermatozoa shows a 9+0 rather than the
    normal 9+2 configuration and disorganised accessory structures, and
    immunofluorescence shows loss of SPEF2 itself together with other central
    pair and axonemal proteins, including the MMAF-associated CFAP69. Sperm
    proteomics from three SPEF2-mutant men found over a thousand differentially
    expressed proteins, so the lesion propagates well beyond the C1b projection.
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  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
  evidence:
  - reference: PMID:38568462
    reference_title: "Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrastructural analyses of the spermatozoa of the patients revealed the
      absence of the central pair complex in the sperm flagella.
    explanation: >-
      Direct ultrastructural demonstration that the central pair is missing from
      patient sperm flagella.
  - reference: PMID:31942643
    reference_title: "Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory
      cilia but consistently abnormal 9 + 0 axoneme or disordered accessory
      structures of sperm flagella, indicating different roles of SPEF2 in sperm
      flagella and respiratory cilia.
    explanation: >-
      Names the 9+0 configuration in sperm, and in the same measurement shows the
      respiratory cilia of the same men are ultrastructurally normal — the
      tissue-level dissociation this entry's scope note turns on.
  - reference: PMID:31048344
    reference_title: "Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our further functional studies using immunofluorescence assays showed the
      absence or a remarkably reduced staining of SPEF2 and of the
      MMAF-associated CFAP69 protein in the spermatozoa from SPEF2-affected
      subjects.
    explanation: >-
      Shows the defect extends to other axonemal proteins, not only to SPEF2
      itself.
  - reference: PMID:36873931
    reference_title: "Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We show absence or severe reduction of CCDC39 and SPEF2 in sperm flagella
      of CCDC39- and CCDC40-mutant individuals and HYDIN- and SPEF2-mutant
      individuals, respectively.
    explanation: >-
      Independent cohort confirming loss of SPEF2 from the sperm flagellum, and
      placing it in a dependency with HYDIN in the central pair apparatus.
  - reference: PMID:34755699
    reference_title: "Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A total of 1262 differentially expressed proteins were detected, including
      486 upregulated and 776 downregulated.
    explanation: >-
      Quantifies how far the proteomic disturbance in patient spermatozoa extends
      beyond the C1b projection itself.
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
    description: >-
      An axoneme assembled without its central pair produces a malformed
      flagellum.
  - target: Absent Sperm Axoneme Central Pair Complex
    causal_link_type: DIRECT
    description: >-
      The clinical expression of this node: the missing central pair is what a
      pathologist sees on transmission electron microscopy of patient sperm.
- 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 malformed axoneme yields the MMAF phenotype — absent, short, coiled,
    bent and irregular-calibre tails with severely reduced motility — together
    with mitochondrial-sheath and accessory-structure disorganisation. This is
    the sperm-flagellar instance of the motile-axoneme beat failure that
    produces impaired ciliary beating in the airway, which is why the node
    conforms to the motile-cilia arm of the ciliopathy module. The conformance
    is a claim about shared mechanism, not about the patient having airway
    disease; note also that in SPEF2 disease the two tissues are not affected
    identically, since respiratory cilia of the same men retain a normal 9+2
    ultrastructure while their sperm flagella do not.
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: cilium movement
    modifier: DECREASED
    term:
      id: GO:0003341
      label: cilium movement
  evidence:
  - reference: PMID:31151990
    reference_title: "Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our experimental findings indicate that loss-of-function mutations in the
      SPEF2 gene can cause the MMAF phenotype in human.
    explanation: >-
      States the causal relationship between SPEF2 loss of function and the MMAF
      phenotype in patients.
  - reference: PMID:31278745
    reference_title: "Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The spermatozoa harbored biallelic mutations and showed severe
      ultrastructural defects in the axoneme and mitochondrial sheath.
    explanation: >-
      Documents that the defect includes the mitochondrial sheath and accessory
      structures, not the axoneme alone.
  - reference: PMID:31151990
    reference_title: "Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Transmission electron microscope (TEM) analysis showed a disrupted axonemal
      structure with mitochondrial sheath defects in the patients' spermatozoa.
    explanation: >-
      The ultrastructural measurement behind the morphological claim.
  downstream:
  - target: Male Infertility
    causal_link_type: DIRECT
    description: >-
      Flagella built this way cannot propel the spermatozoon.
  - target: Abnormal Sperm Morphology
    causal_link_type: DIRECT
    description: >-
      The clinical expression of this node in a routine semen analysis.
  - target: Abnormal Sperm Tail Morphology
    causal_link_type: DIRECT
    description: >-
      The same finding localised to the flagellum on detailed tail morphology
      scoring.
  - target: Reduced Sperm Motility
    causal_link_type: DIRECT
    description: >-
      A flagellum that cannot beat normally is a spermatozoon that cannot swim.
- name: Male Infertility
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical endpoint, and the route by which these men are ascertained.
    Affected men present in a reproductive clinic with severe
    asthenoteratozoospermia; the underlying failure is of spermiogenesis rather
    than of transport out of the tract.
  evidence:
  - reference: PMID:34755699
    reference_title: "Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous studies have reported that sperm flagellar 2 (SPEF2) deficiency
      causes severe asthenoteratozoospermia owing to spermiogenesis failure, but
      the underlying molecular mechanism in humans remains unclear.
    explanation: >-
      States that the infertility arises from failed spermiogenesis, which is
      what makes this node the endpoint of the assembly chain above it.
  - reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
    reference_title: "SPEF2 / primary ciliary dyskinesia (Definitive)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probands diagnosed with spermatogenic failure displayed male infertility
      and reduced sperm motility, often without reported details of respiratory
      examinations, but sometimes in the confirmed absence of respiratory
      features
    explanation: >-
      ClinGen's summary of the reproductive presentation across the published
      probands, including the observation that respiratory examination was often
      not reported — which is the substance of the open boundary discussion.
phenotypes:
- category: Reproductive
  name: Male Infertility
  description: >-
    The presenting feature. Men are ascertained through infertility clinics
    after failure to conceive, with normal genital examination.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:38568462
    reference_title: "Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the patients presented with male infertility and PCD/likely PCD.
    explanation: >-
      Documents male infertility in every proband of this series. The same
      sentence also records the co-occurring airway phenotype, which this entry
      deliberately does not curate as an SPGF43 feature — see the scope note.
- category: Reproductive
  name: Abnormal Sperm Morphology
  description: >-
    Multiple morphological abnormalities of the sperm flagella: absent, short,
    coiled, bent and irregular-calibre tails, the MMAF pattern, with
    disorganised axonemal and accessory structures on electron microscopy.
  phenotype_term:
    preferred_term: Abnormal sperm morphology
    term:
      id: HP:0012864
      label: Abnormal sperm morphology
  evidence:
  - reference: PMID:31151990
    reference_title: "Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our experimental findings indicate that loss-of-function mutations in the
      SPEF2 gene can cause the MMAF phenotype in human.
    explanation: >-
      MMAF is by definition a set of morphological abnormalities of the sperm
      flagellum, so establishing the MMAF phenotype establishes this one.
- category: Reproductive
  name: Abnormal Sperm Tail Morphology
  description: >-
    The morphological defect is localised to the flagellum. Patient spermatozoa
    show a 9+0 axoneme lacking the central pair, together with disorganised
    mitochondrial sheath and other accessory structures.
  phenotype_term:
    preferred_term: Abnormal sperm tail morphology
    term:
      id: HP:0012868
      label: Abnormal sperm tail morphology
  evidence:
  - reference: PMID:31278745
    reference_title: "Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that biallelic mutations in SPEF2 can cause severe sperm
      flagellum defects, thus providing a novel candidate genetic pathogen for
      the human MMAF phenotype.
    explanation: >-
      Localises the severe defect to the sperm flagellum specifically.
- category: Reproductive
  name: Absent Sperm Axoneme Central Pair Complex
  description: >-
    The specific ultrastructural lesion. Transmission electron microscopy of
    patient spermatozoa shows the central pair of singlet microtubules missing
    from the flagellar axoneme, leaving a 9+0 rather than a 9+2 configuration.
  phenotype_term:
    preferred_term: Absent sperm axoneme central pair complex
    term:
      id: HP:0033525
      label: Absent sperm axoneme central pair complex
  evidence:
  - reference: PMID:38568462
    reference_title: "Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrastructural analyses of the spermatozoa of the patients revealed the
      absence of the central pair complex in the sperm flagella.
    explanation: >-
      Direct ultrastructural observation of the absent central pair in patient
      spermatozoa.
  - reference: PMID:31942643
    reference_title: "Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory
      cilia but consistently abnormal 9 + 0 axoneme or disordered accessory
      structures of sperm flagella, indicating different roles of SPEF2 in sperm
      flagella and respiratory cilia.
    explanation: >-
      Independent cohort reporting the 9+0 sperm axoneme, and in the same
      measurement showing the finding is specific to the flagellum rather than
      shared with respiratory cilia.
- category: Reproductive
  name: Reduced Sperm Motility
  description: >-
    Severe asthenozoospermia is the functional counterpart of the flagellar
    defect; men are ascertained through severe asthenozoospermia or
    asthenoteratozoospermia rather than through azoospermia.
  phenotype_term:
    preferred_term: Reduced sperm motility
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
    reference_title: "SPEF2 / primary ciliary dyskinesia (Definitive)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probands diagnosed with spermatogenic failure displayed male infertility
      and reduced sperm motility, often without reported details of respiratory
      examinations, but sometimes in the confirmed absence of respiratory
      features
    explanation: >-
      ClinGen's summary of the reproductive presentation across published SPEF2
      spermatogenic-failure probands records reduced sperm motility.
  - reference: PMID:34755699
    reference_title: "Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Previous studies have reported that sperm flagellar 2 (SPEF2) deficiency
      causes severe asthenoteratozoospermia owing to spermiogenesis failure, but
      the underlying molecular mechanism in humans remains unclear.
    explanation: >-
      Asthenoteratozoospermia is by definition reduced motility together with
      abnormal morphology.
genetic:
- name: SPEF2
  gene_term:
    preferred_term: SPEF2
    term:
      id: hgnc:26293
      label: SPEF2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  frequency: 2 of 42 MMAF probands in the founding cohort; separately 4 of 45 families with severe asthenozoospermia
  notes: >-
    SPEF2 (5p13.2) encodes a component of the C1b projection of the ciliary and
    flagellar central pair apparatus that also links cargo to cytoplasmic dynein
    1 during spermiogenesis. Reported yields are 2 of 42 Han Chinese MMAF
    probands in the founding cohort, 2 of 50 in a second Han Chinese MMAF cohort
    plus one Iranian proband from a separate cohort, and 4 of 45 unrelated
    Chinese families ascertained for severe asthenozoospermia.

    Read those denominators carefully: none of them is SPGF43. They are the
    fraction of MMAF or severe-asthenozoospermia probands in whom SPEF2 was the
    cause, not the prevalence of SPGF43 and not a share of SPGF43 cases —
    SPGF43 is by definition entirely SPEF2, so no per-gene case fraction applies
    here.

    The alleles reported to date are truncating (nonsense and frameshift),
    canonical splice, and deleterious missense, and the ones characterised in
    detail fall in the long testis-expressed transcripts that carry the
    IFT20-binding domain. One report suggests missense alleles may produce
    milder spermatozoal damage than truncating ones, but that observation is
    drawn from a series covering FSIP2 and SPEF2 together and is not
    SPEF2-specific.

    The same gene causes primary ciliary dyskinesia, where ClinGen classifies
    the relationship as Definitive. A SPEF2 genotype found in an infertility
    workup should therefore prompt a respiratory history.
  evidence:
  - reference: PMID:31151990
    reference_title: "Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      By screening gene variants in 42 patients with MMAF using whole exome
      sequencing, we identified the c. 12delC, c. 1745-2A > G, c. 4102 G > T and
      c. 4323dupA mutations in the SPEF2 gene from two patients.
    explanation: >-
      Establishes the founding cohort size against which the two probands should
      be read.
  - reference: PMID:31048344
    reference_title: "Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conducted genetic analyses using whole-exome sequencing in 50 Han
      Chinese probands with MMAF.
    explanation: >-
      The denominator for the second independent cohort.
  - reference: PMID:31942643
    reference_title: "Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified four novel biallelic mutations in SPEF2 (8.9%, 4/45) in six
      affected individuals (12.8%, 6/47), while no deleterious biallelic variants
      in SPEF2 were detected in 637 controls
    explanation: >-
      A third independent cohort with an explicit denominator and a control
      series in which no biallelic SPEF2 genotype was found.
  - reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
    reference_title: "SPEF2 / primary ciliary dyskinesia (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Variants in SPEF2 had also been previously identified in individuals
      affected with multiple morphologic abnormalities of the flagella
    explanation: >-
      ClinGen's own record of the SPEF2-MMAF relationship, on the gene-disease
      validity curation that classifies SPEF2 as Definitive for the motile
      ciliopathy phenotype.
  - reference: PMID:39753944
    reference_title: "Novel variants of FSIP2 and SPEF2 cause varying degrees of spermatozoa damage in MMAF patients and favorable ART outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our work revealed that missense variations of FSIP2 or SPEF2 might cause a
      milder spermatozoa damage.
    explanation: >-
      Suggests an allele-class effect on severity. The claim is made across FSIP2
      and SPEF2 jointly rather than for SPEF2 alone, which is why the notes on
      this entry state it as a suggestion and not as a SPEF2 genotype-phenotype
      rule.
animal_models:
- name: Spef2 big giant head (bgh) mouse
  species: Mouse
  genotype: Spef2 bgh, homozygous nonsense
  publication: PMID:21715716
  description: >-
    A spontaneous mouse mutant positionally cloned to a nonsense variant in
    Spef2. It is the model that established SPEF2 as a motile-ciliopathy gene,
    and it is informative for this entry in two directions: it reproduces the
    flagellar assembly defect, and it demonstrates that whole-animal loss of
    SPEF2 produces full primary ciliary dyskinesia rather than isolated
    infertility.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygous males are infertile with shortened flagella and disorganised
      axonemal and accessory structures in elongating spermatids and mature
      sperm, matching the human flagellar phenotype.
    limitations: >-
      A nonsense allele in mouse is not equivalent to the compound heterozygous
      and missense genotypes reported in men, and the mouse also has
      hydrocephalus and sinusitis, which are not part of the curated human
      reproductive phenotype.
    readouts:
    - name: Sperm flagellar structure in elongating spermatids and mature sperm
      target: Multiple Morphological Abnormalities of the Sperm Flagella
      direction: ALTERED
      interpretation: >-
        Shortened flagella with disorganised axonemal and accessory structures.
      evidence:
      - reference: PMID:21715716
        reference_title: "Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Histopathological, immunofluorescence, and electron microscopic
          analyses demonstrate that the male infertility results from shortened
          flagella and disorganized axonemal and accessory structures in
          elongating spermatids and mature sperm.
        explanation: >-
          The histological and ultrastructural measurement behind this readout.
    - name: Elongating spermatid and epididymal sperm number
      target: Multiple Morphological Abnormalities of the Sperm Flagella
      direction: DECREASED
      interpretation: >-
        Fewer elongating spermatids during spermatogenesis and fewer mature sperm
        in the epididymis.
      evidence:
      - reference: PMID:21715716
        reference_title: "Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In addition, there is a reduced number of elongating spermatids during
          spermatogenesis and mature sperm in the epididymis.
        explanation: >-
          The quantitative germ-cell measurement behind this readout.
    evidence:
    - reference: PMID:21715716
      reference_title: "Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Through a positional cloning approach, we identified two sequence
        variants in the gene encoding sperm flagellar protein 2 (SPEF2), which
        has been postulated to play an important role in spermatogenesis and
        flagellar assembly.
      explanation: >-
        Establishes that the bgh phenotype is caused by loss of the same gene,
        which is what makes the model informative for this node.
  - target: Male Infertility
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Homozygous males are infertile, matching the human endpoint. But they are
      infertile as one component of full PCD — hydrocephalus and sinusitis
      alongside — rather than in isolation.
    limitations: >-
      The mouse phenotype is broader than the curated human phenotype. It cannot
      be used to argue that isolated spermatogenic failure is the expected
      consequence of SPEF2 loss; that mismatch is the substance of the open
      phenotypic-boundary discussion on this entry.
    readouts:
    - name: Male fertility
      target: Male Infertility
      direction: DECREASED
      interpretation: >-
        Homozygous males are infertile, alongside hydrocephalus and sinusitis.
      evidence:
      - reference: PMID:21715716
        reference_title: "Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Mice homozygous for the mutation big giant head (bgh) have several
          abnormalities commonly associated with PCD, including hydrocephalus,
          male infertility, and sinusitis.
        explanation: >-
          Documents infertility in the model while making explicit that it occurs
          as part of full PCD.
    evidence:
    - reference: PMID:21715716
      reference_title: "Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Taken together, the data in this study demonstrate that SPEF2 is required
        for cilia function and identify a new genetic cause of PCD in mice.
      explanation: >-
        The authors' own conclusion, which frames the model as a PCD model rather
        than an isolated-infertility model.
- name: Male germ cell-specific Spef2 conditional knockout mouse
  species: Mouse
  genotype: Spef2 conditional knockout, male germ cell-specific
  publication: PMID:28619825
  description: >-
    A germ-cell-restricted Spef2 knockout, which isolates the spermiogenesis
    phenotype from the hydrocephalus and airway disease of the whole-animal
    mutant. It is the model that demonstrated the transport function of SPEF2.
  modeled_mechanisms:
  - target: Impaired Manchette and Intraflagellar Cargo Transport
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Loss of SPEF2 in male germ cells delays IFT20 transport from the Golgi
      complex to the manchette and causes the manchette to fail to migrate,
      which is the transport failure this node asserts.
    limitations: >-
      The transport measurements are in mouse spermatids; the equivalent
      experiment has not been done in human germ cells, where the evidence is
      limited to protein-protein interaction in a heterologous cell line and to
      the transcript position of the patient alleles. A complete germ-cell
      knockout also does not model the hypomorphic missense alleles seen in some
      men.
    readouts:
    - name: IFT20 transport from Golgi complex to manchette
      target: Impaired Manchette and Intraflagellar Cargo Transport
      direction: DECREASED
      interpretation: >-
        Delivery of the SPEF2 cargo IFT20 to the manchette is delayed when SPEF2
        is absent.
      evidence:
      - reference: PMID:28619825
        reference_title: "SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Furthermore, the transport of a known SPEF2-binding protein, IFT20,
          from the Golgi complex to the manchette was delayed in the absence of
          SPEF2.
        explanation: >-
          The transport measurement behind this readout.
    - name: Manchette migration and basal body number
      target: Impaired Manchette and Intraflagellar Cargo Transport
      direction: ALTERED
      interpretation: >-
        Failure of manchette migration with basal body duplication and abnormal
        spermatid head shape.
      evidence:
      - reference: PMID:28619825
        reference_title: "SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In addition to defects in sperm tail development, we observed a
          duplication of the basal body and failure in manchette migration
          resulting in an abnormal head shape.
        explanation: >-
          The structural measurement behind this readout.
    evidence:
    - reference: PMID:28619825
      reference_title: "SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In this study we investigated the function of SPEF2 during
        spermatogenesis using a male germ cell-specific Spef2 knockout mouse
        model.
      explanation: >-
        Establishes the model and its germ-cell restriction, which is what makes
        it informative for the spermiogenesis transport node specifically.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    The primary diagnostic modality, and the only one that establishes the
    diagnosis. Every reported proband was ascertained by whole-exome sequencing
    or a targeted MMAF/PCD panel that includes SPEF2, with biallelic status and
    parental phase confirmed by Sanger sequencing. Splice-aware and
    copy-number-aware analysis matters here, because reported alleles include
    canonical splice variants and the founding pig disease is an intronic
    insertion acting through aberrant splicing. Semen analysis and ultrastructure
    raise the suspicion of a flagellar gene; they do not name it, since MMAF is
    genetically heterogeneous and more than twenty other genes produce the same
    semen picture.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31048344
    reference_title: "Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conducted genetic analyses using whole-exome sequencing in 50 Han
      Chinese probands with MMAF.
    explanation: >-
      Whole-exome sequencing of an MMAF cohort is the route by which these
      probands were identified.
  - reference: PMID:36873931
    reference_title: "Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we performed genetic testing by next generation sequencing
      techniques, PCD diagnostics including immunofluorescence-, transmission
      electron-, and high-speed video microscopy on sperm flagella and
      andrological work up including semen analyses.
    explanation: >-
      Describes the combined workup in which next-generation sequencing is the
      genetic arm, alongside the sperm immunofluorescence curated below.
- name: Immunofluorescence Staining of SPEF2 in Sperm Flagella
  description: >-
    Immunofluorescence microscopy of ejaculated spermatozoa for SPEF2 and its
    axonemal partners is a practical adjunct to sequencing. It converts an
    uncertain variant into a demonstrated protein defect, which matters here
    because several reported alleles are missense.
  evidence:
  - reference: PMID:36873931
    reference_title: "Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings demonstrate that immunofluorescence microscopy in sperm cells
      is a valuable tool to identify flagellar defects related to the axonemal
      ruler, radial spoke head and the central pair apparatus, thus aiding the
      diagnosis of male infertility.
    explanation: >-
      States the diagnostic utility of sperm immunofluorescence for central pair
      apparatus defects, the class SPEF2 belongs to.
- name: Caveat - Central Pair Defects Evade the Standard PCD Diagnostic Algorithm
  notes: >-
    Recorded here because it bears directly on this entry's scope rather than on
    its own diagnosis. A man given a SPEF2 spermatogenic-failure diagnosis cannot
    be cleared of airway disease by the usual ciliary tests: in central pair
    defects the ciliary beating abnormality is very subtle, the ciliary
    ultrastructure is normal and situs is normal, so the standard PCD algorithm
    returns normal results. In SPEF2 disease specifically, the respiratory cilia
    of affected men have a normal 9+2 axoneme even while their sperm flagella do
    not. Assessing for PCD therefore rests on respiratory history and on
    immunofluorescence for SPEF2 in respiratory cells, not on electron
    microscopy.
  evidence:
  - reference: PMID:31545650
    reference_title: "SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, it is difficult to establish a diagnosis in individuals with PCD
      and central pair (CP) defects, and alternative strategies are required
      because of very subtle ciliary beating abnormalities, a normal ciliary
      ultrastructure, and normal situs composition.
    explanation: >-
      Documents that the standard PCD diagnostic modalities read normal in
      central pair defects.
  - reference: PMID:31545650
    reference_title: "SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We conclude that SPEF2 IF analyses can facilitate the detection of CP
      defects and evaluation of the pathogenicity of HYDIN variants, thus aiding
      the molecular diagnosis of CP defects.
    explanation: >-
      Names the alternative that does work — immunofluorescence for SPEF2 in
      respiratory cells.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility and morphology defect by injecting a single
    spermatozoon directly into the oocyte. Every man in the largest reported
    SPEF2 series to undergo ICSI achieved a live birth, so a SPEF2 diagnosis
    carries a usable prognostic message and not only an explanatory one. The
    series is three men, so this is a favourable signal rather than a success
    rate.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: intracytoplasmic sperm injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Male Infertility
    treatment_effect: BYPASSES
    description: >-
      ICSI does not repair the flagellum. It circumvents the requirement for
      sperm propulsion, so it acts on the clinical endpoint rather than on any
      upstream assembly node.
    evidence:
    - reference: PMID:38568462
      reference_title: "Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        All patients carrying SPEF2 variants underwent one ICSI cycle and
        delivered healthy infants.
      explanation: >-
        Direct evidence that ICSI achieves live birth despite the flagellar
        defect.
  evidence:
  - reference: PMID:39753944
    reference_title: "Novel variants of FSIP2 and SPEF2 cause varying degrees of spermatozoa damage in MMAF patients and favorable ART outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The infertility caused by FSIP2 and SPEF2 variants can be mitigated through
      ICSI or even IVF.
    explanation: >-
      A second series reaching the same conclusion. Its quantitative outcome
      rates are pooled across FSIP2 and SPEF2 probands, so only the qualitative
      conclusion is curated here.
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence counselling for the couple, cascade carrier
    testing for relatives, and — because the same genotype causes primary
    ciliary dyskinesia — an explicit discussion of respiratory risk for the
    proband and for any biallelic relative of either sex. Once the familial
    alleles are known, preimplantation genetic testing for monogenic disease
    (PGT-M) and prenatal diagnosis become available options alongside the ICSI
    cycle, subject to local regulation and the couple's preferences.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38568462
    reference_title: "Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our study reported four novel pathogenic variants of SPEF2 in three male
      patients with infertility and PCD/PCD-like phenotypes, which not only
      extend the spectrum of SPEF2 mutations but also provide information for
      genetic counseling and treatment of such conditions.
    explanation: >-
      The authors state genetic counselling as the application of the molecular
      diagnosis, and in the same sentence tie it to the PCD-overlapping
      phenotype.
differential_diagnoses:
- name: SPEF2-related primary ciliary dyskinesia
  disease_term:
    preferred_term: primary ciliary dyskinesia
    term:
      id: MONDO:0016575
      label: primary ciliary dyskinesia
  distinguishing_features:
  - >-
    Chronic upper and lower airway disease — recurrent airway infection,
    bronchitis, rhinosinusitis, bronchiectasis. This is what separates the two
    presentations clinically, and it is not part of the reproductive phenotype
    curated here.
  - >-
    Situs is normal in both, so laterality does not separate them.
  - >-
    Neither does ciliary ultrastructure. Respiratory cilia in SPEF2 disease have
    a normal 9+2 axoneme even in men whose sperm flagella are 9+0, so
    transmission electron microscopy of respiratory cells cannot make the call.
  - >-
    The PCD presentation is not male-restricted: reported SPEF2 PCD patients
    include women, in whom the reproductive phenotype of this entry cannot
    arise at all.
  description: >-
    Not merely a differential but the same gene, and ClinGen classifies the
    SPEF2-PCD relationship as Definitive. The distinction rests on respiratory
    history rather than on any ciliary assay, and the standard PCD diagnostic
    algorithm is known to read normal in central pair defects, so a man
    diagnosed with SPEF2 spermatogenic failure may have unrecognised airway
    disease.
  evidence:
  - reference: PMID:31545650
    reference_title: "SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified a mutation of SPEF2 that is causative for PCD with a CP
      defect.
    explanation: >-
      The report that first established SPEF2 as a PCD gene, making this a
      same-gene differential rather than a coincidental one.
  - reference: PMID:36615117
    reference_title: "Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We performed whole-exome analysis and identified novel biallelic variants
      of SPEF2 in the homozygous state (c.1860_1861insCT).
    explanation: >-
      A biallelic SPEF2 genotype in a woman with severe progressive PCD, showing
      the PCD presentation occurs in patients for whom the spermatogenic
      phenotype is not applicable.
discussions:
- discussion_id: spgf43_reproductive_versus_pcd_spectrum
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is SPEF2-related spermatogenic failure a distinct entity from SPEF2-related
    primary ciliary dyskinesia, or is every biallelic SPEF2 man a PCD patient
    whose airway disease was or was not looked for?
  attaches_to:
  - "pathophysiology#SPEF2 Loss of Function"
  - "pathophysiology#Male Infertility"
  rationale: >-
    This is the central nosological question for the entry and it is left open
    deliberately. The evidence points both ways and the two directions are not
    symmetrical in strength.

    Toward one spectrum. In the cohort that took a respiratory history
    systematically, all six biallelic SPEF2 men had PCD-like symptoms —
    recurrent airway infections, bronchitis and rhinosinusitis — and the authors
    explicitly framed their result as bridging MMAF and PCD. That cohort is the
    load-bearing one, because it was ascertained on severe asthenozoospermia
    alone; a later series in which all three men had infertility with PCD or
    likely PCD was ascertained on both features together, so its 3/3 is a
    description of who was recruited rather than an independent frequency. The
    whole-animal bgh mouse has full PCD, not isolated infertility. ClinGen's
    Motile Ciliopathy expert panel applied the Lumping and Splitting criteria
    and lumped all SPEF2 disease into primary ciliary dyskinesia. And the
    standard PCD diagnostic algorithm cannot exclude airway disease in a central
    pair defect, so an infertility proband called PCD-negative on nasal nitric
    oxide, electron microscopy and high-speed videomicroscopy has not really
    been cleared.

    Toward two entities. At least one proband was reported in the confirmed
    absence of respiratory features rather than merely without them being
    looked for. There is also a genuine tissue-level dissociation: in the same
    men, respiratory cilia keep a normal 9+2 axoneme while sperm flagella are
    9+0, which the authors read as SPEF2 having different roles in the two
    tissues. A transcript explanation has been proposed — that alleles hitting
    only the long testis-expressed transcripts give isolated infertility while
    alleles hitting broadly expressed isoforms add airway disease — and it is
    not hand-waving: the naturally occurring immotile short-tail sperm defect of
    Finnish Yorkshire pigs is exactly that, an intronic SPEF2/KPL2 insertion
    whose aberrantly spliced exon is expressed predominantly in testis, giving a
    sperm-restricted disease with cilia elsewhere unaffected. What has not been
    done is testing it against the human genotypes, so it is cited here as a
    plausible and precedented mechanism rather than curated as this disease's
    mechanism.

    What this entry does about it. dismech curates SPGF43 as its own record
    while recording the divergence from ClinGen rather than leaving it implicit.
    MONDO retains both concepts — MONDO:0032898 for SPGF43 and MONDO:0016575 for
    PCD — and dismech entries are keyed to MONDO concepts, so curating SPGF43 is
    not an assertion that ClinGen is wrong about gene-disease validity, which is
    a different question from disease-concept granularity. The same call was made
    for CFAP54 in Spermatogenic_Failure_98, on the same reasoning. If MONDO
    merges the two terms, this entry should be merged with them.
  evidence:
  - reference: PMID:31942643
    reference_title: "Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Notably, all six patients exhibited PCD-like symptoms, including recurrent
      airway infections, bronchitis, and rhinosinusitis.
    explanation: >-
      The strongest evidence for one spectrum: when respiratory history was taken
      systematically in a SPEF2 infertility cohort, every man had airway
      symptoms.
  - reference: PMID:31942643
    reference_title: "Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ultrastructural analysis revealed normal 9 + 2 axonemes of respiratory
      cilia but consistently abnormal 9 + 0 axoneme or disordered accessory
      structures of sperm flagella, indicating different roles of SPEF2 in sperm
      flagella and respiratory cilia.
    explanation: >-
      Evidence in the other direction, from the same study: the two tissues are
      not affected identically, so the shared genotype does not imply an
      identical lesion.
  - reference: PMID:31942643
    reference_title: "Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Recent studies have revealed that SPEF2 mutations lead to multiple
      morphological abnormalities of the sperm flagella (MMAF) without primary
      ciliary dyskinesia (PCD) symptoms in males, but PCD phenotype was also
      found in one female individual.
    explanation: >-
      States the position of the field before this study: SPEF2 infertility had
      been reported without PCD symptoms in men, which is the observation the
      study then complicated.
  - reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
    reference_title: "SPEF2 / primary ciliary dyskinesia (Definitive)"
    supports: REFUTE
    evidence_source: OTHER
    snippet: >-
      Per the recommendations of the ClinGen Lumping & Splitting Working Group,
      the GCEP found consistencies between the mode of inheritance (autosomal
      recessive) and molecular mechanism (biallelic SPEF2 loss-of-function)
      between patients diagnosed with either infertility or primary ciliary
      dyskinesia, while their overlapping phenotypes formed a single spectrum
      that included both infertility and respiratory features.
    explanation: >-
      ClinGen's formal conclusion, which argues against curating SPGF43 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 and not
      only asserted in prose.
  - reference: CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
    reference_title: "SPEF2 / primary ciliary dyskinesia (Definitive)"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probands diagnosed with spermatogenic failure displayed male infertility
      and reduced sperm motility, often without reported details of respiratory
      examinations, but sometimes in the confirmed absence of respiratory
      features
    explanation: >-
      Evidence for two entities, and the reason the question is open rather than
      settled: at least one proband had respiratory features confirmed absent
      rather than merely unexamined, though most were simply not examined.
  - reference: PMID:21715716
    reference_title: "Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      In contrast to the sperm phenotype, electron microscopy demonstrates that
      mutant respiratory epithelial cilia are ultrastructurally normal, but video
      microscopic analysis shows that their beat frequency is lower than that of
      wild-type cilia.
    explanation: >-
      The mouse reproduces the human tissue dissociation exactly — normal
      respiratory ciliary ultrastructure with a functional beat defect — so the
      dissociation is a property of SPEF2 loss and not an artefact of how the
      human cohorts were examined.
  - reference: PMID:16549801
    reference_title: "An intronic insertion in KPL2 results in aberrant splicing and causes the immotile short-tail sperm defect in the pig."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      Further work revealed that the aberrantly spliced exon is expressed
      predominantly in testicular tissue, which explains the tissue-specificity
      of the immotile short-tail sperm defect.
    explanation: >-
      A naturally occurring SPEF2 allele that produces sperm-restricted disease
      through testis-predominant splicing. It does not settle the human
      question, but it shows the transcript explanation is a demonstrated
      mechanism for this gene rather than a speculation. Indirect because it is
      a pig disease.
  - reference: PMID:16549801
    reference_title: "An intronic insertion in KPL2 results in aberrant splicing and causes the immotile short-tail sperm defect in the pig."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: >-
      This disease specifically affects the axoneme structure of sperm flagella,
      whereas cilia in other tissues appear unaffected.
    explanation: >-
      States the tissue restriction directly: a SPEF2 genotype that damages the
      sperm flagellum and spares other cilia exists in nature, which is the
      strongest single argument that isolated spermatogenic failure is a real
      presentation of SPEF2 loss and not only an unexamined one.
  proposed_experiments:
  - experiment_id: exp_spgf43_respiratory_phenotyping_of_infertility_probands
    name: Respiratory phenotyping of SPEF2 infertility probands
    description: >-
      Systematically assess reported and newly identified SPEF2 infertility
      probands for airway disease using methods that work in central pair
      defects — structured respiratory history, high-speed video microscopy and
      immunofluorescence for SPEF2 in respiratory cells — rather than the
      standard algorithm, which returns normal nasal nitric oxide and normal
      electron microscopy in this defect class.
  - experiment_id: exp_spgf43_transcript_stratified_genotype_comparison
    name: Transcript-stratified comparison of infertility-only and PCD genotypes
    description: >-
      Test the proposed transcript explanation directly: map every reported SPEF2
      allele onto the long testis-specific and the broadly expressed transcripts,
      and ask whether transcript coverage separates probands with isolated
      infertility from those with airway disease, or whether the genotypes
      overlap.
notes: >-
  Scope, and what this entry deliberately does not claim. This entry curates
  SPGF43 (MONDO:0032898), the male reproductive presentation of biallelic SPEF2
  disease. It does not curate SPEF2-related primary ciliary dyskinesia, and it
  does not list airway phenotypes — recurrent airway infection, bronchitis,
  rhinosinusitis, bronchiectasis — among its `phenotypes`. That is an explicit
  decision, not an oversight, and it is the harder of the two calls available:
  in the one SPEF2 infertility cohort that took a respiratory history
  systematically, every affected man had PCD-like symptoms. Three things decided
  it. The airway mechanism is already curated in
  `Primary_Ciliary_Dyskinesia.yaml`, which carries SPEF2 as an established PCD
  gene, so listing it here would duplicate rather than add. MONDO keys the two
  concepts separately and dismech entries follow MONDO. And
  `Spermatogenic_Failure_98` made the same split for CFAP54, whose situation is
  structurally identical. The co-occurrence is not hidden by the decision: it is
  stated in the description, carried in the differential diagnosis, and the
  boundary itself is an OPEN knowledge gap in the discussions with the evidence
  from both sides attached.

  Cross-reference. `Primary_Ciliary_Dyskinesia.yaml` carries SPEF2 as a PCD gene
  with the ClinGen Definitive assertion and includes it among the central pair
  apparatus genes. Between them the two entries document the range of one gene:
  the airway presentation there, the male reproductive presentation here.

  Why the MMAF node conforms to the ciliopathy module. The sperm flagellum and
  the motile cilium share axonemal architecture, so loss of a central pair
  component impairs beating in both. The conformance to
  `ciliopathy_dysfunction#Motile Cilia Beat Dysfunction` is a claim about shared
  mechanism, not about the patient having airway disease. It is a weaker claim
  for SPEF2 than for a gene that damages both tissues identically, because
  respiratory cilia in SPEF2 disease retain a normal 9+2 ultrastructure while
  sperm flagella do not; what is shared is the beat defect, demonstrated in the
  bgh mouse, rather than the structural lesion.

  Evidence base. Two probands from a 42-proband MMAF cohort, two from a
  50-proband MMAF cohort plus one Iranian proband from a separate cohort, six
  affected men from 45 families ascertained for severe asthenozoospermia, three
  from a later series, and two within a ten-man axonemal-gene cohort. Add sperm
  proteomics from three mutant men, a spontaneous whole-animal mouse mutant, a
  male-germ-cell conditional knockout, and naturally occurring SPEF2 sperm-tail
  defects in pig and cattle. The human series are small and every one of them is
  ascertained through infertility or PCD clinics, so the reported phenotype
  range is bounded by how the probands were found.

  No prevalence record. No prevalence, incidence or carrier-frequency estimate
  exists for SPGF43, and the cohort yields reported in the `genetic` section are
  not substitutes: their denominators are MMAF and severe-asthenozoospermia
  cohorts, not the general population and not SPGF43. A prevalence record is
  omitted rather than filled with a number that would misstate what was
  measured.

  Oligozoospermia is not curated as a phenotype. Sperm concentration is reported
  for only three men (9.3, 10.4 and 21.0 million/mL), and the third of those is
  above the WHO lower reference limit, so the reported values do not support a
  claim that reduced sperm concentration is a feature of this disorder. The
  disorder as reported is one of sperm quality rather than sperm number; men are
  ascertained through severe asthenoteratozoospermia, not through oligozoospermia
  or azoospermia. If a larger series reports concentrations, this should be
  revisited.

  Why the PCD GeneReviews chapter is listed but not mined. PMID:20301301 is the
  authoritative clinical source for the PCD diagnostic algorithm that 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` and
  holds only a 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. It also
  does not mention SPEF2.

  Livestock SPEF2 disease is cited but not curated as a model. The Finnish
  Yorkshire pig immotile short-tail sperm defect is a naturally occurring
  SPEF2/KPL2 disease with a sperm-restricted phenotype and a demonstrated
  testis-predominant splicing mechanism, and it is cited in the open discussion
  because it bears directly on the boundary question. It is not entered as an
  `animal_model`, because it is a spontaneous disease of a farmed species rather
  than a model built to represent this disorder, and the two mouse models
  already carry every mechanism link the pathograph needs. A comparable cattle
  SPEF2 sperm defect exists but was not read in its primary sources here and is
  not cited.
📚

References & Deep Research

References

17
PMID:31151990
Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF).
No top-level findings curated for this source.
PMID:31278745
Biallelic mutations in Sperm flagellum 2 cause human multiple morphological abnormalities of the sperm flagella (MMAF) phenotype.
No top-level findings curated for this source.
PMID:31048344
Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility.
No top-level findings curated for this source.
PMID:31942643
Novel mutations in SPEF2 causing different defects between flagella and cilia bridge: the phenotypic link between MMAF and PCD.
No top-level findings curated for this source.
PMID:34755699
Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans.
No top-level findings curated for this source.
PMID:36873931
Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility.
No top-level findings curated for this source.
PMID:38568462
Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia.
No top-level findings curated for this source.
PMID:39753944
Novel variants of FSIP2 and SPEF2 cause varying degrees of spermatozoa damage in MMAF patients and favorable ART outcomes.
No top-level findings curated for this source.
PMID:31545650
SPEF2- and HYDIN-Mutant Cilia Lack the Central Pair-associated Protein SPEF2, Aiding Primary Ciliary Dyskinesia Diagnostics.
No top-level findings curated for this source.
PMID:36615117
Novel SPEF2 Variant in a Japanese Patient with Primary Ciliary Dyskinesia: A Case Report and Literature Review.
No top-level findings curated for this source.
PMID:21715716
Loss of SPEF2 function in mice results in spermatogenesis defects and primary ciliary dyskinesia.
No top-level findings curated for this source.
PMID:28619825
SPEF2 functions in microtubule-mediated transport in elongating spermatids to ensure proper male germ cell differentiation.
No top-level findings curated for this source.
PMID:19889948
Expression of SPEF2 during mouse spermatogenesis and identification of IFT20 as an interacting protein.
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:16549801
An intronic insertion in KPL2 results in aberrant splicing and causes the immotile short-tail sperm defect in the pig.
No top-level findings curated for this source.
PMID:20301301
Primary Ciliary Dyskinesia.
No top-level findings curated for this source.
CGGV:assertion_e137eed5-fcd8-4497-a6dc-6651062d1cf3-2025-01-09T170000.000Z
SPEF2 / primary ciliary dyskinesia (Definitive)
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 31 citations 2026-09-03T13:20:27.581560

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

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

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

Disease Characteristics Research Template

Target Disease

  • Disease Name: Spermatogenic failure 43 (SPGF43, biallelic SPEF2 variants)
  • MONDO ID: MONDO:0032898 (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Spermatogenic failure 43 (SPGF43, biallelic SPEF2 variants) covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

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

1. Disease Information

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

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

2. Etiology

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

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

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

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

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

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

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

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

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

4. Genetic/Molecular Information

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

5. Environmental Information

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

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

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

    Search first: CDC databases, WHO, PubMed, NHANES

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

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

6. Mechanism / Pathophysiology

Present this section as an ordered causal chain first, then the detail below. Open with a numbered sequence of mechanistic steps running from the initiating lesion (mutation, exposure, infection) to the clinical manifestation, one step per line, each naming what it causes next. State the causal verb explicitly ("leads to", "results in") and say where a step is inferred rather than demonstrated. Where the mechanism branches, show the branch. The categories below are a checklist of what to cover within those steps, not the organizing structure — a step may draw on several of them, and a category may contribute to several steps.

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

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

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

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

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

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

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

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

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

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

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

    Search first: PubMed, Gene Ontology, Reactome

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

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

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

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

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

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

7. Anatomical Structures Affected

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

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

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

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

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

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

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

8. Temporal Development

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

    Search first: OMIM, Orphanet, HPO, PubMed

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

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

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

9. Inheritance and Population

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

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

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

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Citation Requirements

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

Output Format

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

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

Spermatogenic failure 43 (SPGF43; biallelic SPEF2 variants)

Executive summary

SPGF43 is an ultra-rare, autosomal-recessive male-infertility disorder caused by biallelic pathogenic variants in SPEF2. Its defining laboratory phenotype is severe asthenoteratozoospermia—usually multiple morphological abnormalities of the sperm flagella (MMAF)—with absent, short, coiled, bent, or irregular-calibre tails and nearly absent progressive motility. Human ultrastructural and protein studies place SPEF2 in assembly and function of the sperm axonemal central-pair apparatus, particularly the C1b projection, and implicate defective intraflagellar/intramanchette cargo transport. Some individuals also have chronic upper- or lower-airway symptoms compatible with primary ciliary dyskinesia (PCD), whereas others have isolated infertility; this likely reflects variant- and transcript-dependent expressivity. The current practical applications are molecular diagnosis, reproductive counseling, assessment for PCD, and intracytoplasmic sperm injection (ICSI). There is no established pharmacologic, gene, RNA, or cell therapy and no SPEF2-specific registered clinical trial identified in the search.

The evidence base remains small: the principal reports comprise individual patients or small families ascertained through infertility/MMAF or PCD cohorts. Consequently, prevalence, penetrance, natural history, genotype–phenotype correlations, and treatment-response estimates are not yet population-level quantities.

1. Disease information

Definition. SPGF43 is the disease-level designation for recessive SPEF2-associated spermatogenic failure. The observable reproductive phenotype overlaps MMAF, a severe form of teratozoospermia in which sperm show a mosaic of absent, short, bent, coiled, and irregular-calibre flagella, accompanied by severe asthenozoospermia or complete immotility. The initial 2019 study identified SPEF2 variants in 2 of 42 Han Chinese men selected for MMAF and experimentally demonstrated reduced SPEF2 and disrupted axonemal/mitochondrial-sheath architecture. The authors’ abstract conclusion was: “loss-of-function mutations in the SPEF2 gene can cause the MMAF phenotype in human.” (liu2019lossoffunctionmutationsin pages 1-2)

Identifiers and terminology. The supplied disease identifier is MONDO:0032898. Common labels include spermatogenic failure 43, SPGF43, SPEF2-related male infertility, SPEF2-associated MMAF, and male infertility due to multiple morphological abnormalities of the sperm flagella. SPEF2 is also historically called KPL2 in animal literature. A distinct, broader phenotype may be described as SPEF2-related PCD or PCD-like disease. Disease-specific Orphanet, MeSH, ICD-10, and ICD-11 entries were not established in the retrieved literature; coding generally occurs under male infertility, abnormal sperm motility/morphology, or PCD rather than a dedicated SPGF43 code. The precise OMIM disease-number/gene-number pair and HGNC numeric identifier should be validated directly against the live OMIM/HGNC records before database ingestion rather than inferred from secondary papers.

Data provenance. Clinical findings come from individual patients and families recruited into research infertility/PCD cohorts. MONDO/OMIM-style entries are aggregated disease-level interpretations of those reports—not EHR-derived population surveillance.

2. Etiology, risk, and protective factors

The necessary cause is biallelic germline SPEF2 dysfunction, usually rare truncating, frameshift, canonical splice, or deleterious missense alleles. Homozygous disease is enriched in consanguineous pedigrees, while compound heterozygosity also occurs. The 2020 study reported three homozygous truncating alleles in two Han Chinese and one Iranian consanguineous family, inherited under a recessive model. Their frequencies in gnomAD were approximately 8×10⁻⁶, 4×10⁻⁶, and absent, respectively. (liu2020homozygousmutationsin pages 2-2, liu2020homozygousmutationsin pages 3-4)

No validated susceptibility loci, modifier genes, protective alleles, environmental causes, infectious triggers, or gene–environment interactions are known specifically for SPGF43. Smoking, heat, toxins, infection, varicocele, and age can impair semen quality generally, but they neither cause the Mendelian disorder nor explain its characteristic central-pair defect. No diet or lifestyle intervention has been shown to restore SPEF2-dependent flagellar assembly. Avoidance of general gonadotoxic exposures is reasonable reproductive care but is not disease-specific prevention.

Potential molecular modifiers include HYDIN, CFAP69, IFT20, RSPH9, and other central-pair/transport proteins, based on interaction or localization data, but none has been demonstrated to alter penetrance in human SPGF43. Mouse double-mutant experiments indicate interactions among central-pair genes, but extrapolation to human modifier effects remains experimental.

3. Phenotypes

Core reproductive phenotype

  • Male infertility—usually recognized in reproductive adulthood after failure to conceive; suggested HPO: HP:0003251 Male infertility.
  • Severe asthenozoospermia or complete sperm immotility—progressive motility was 0% in all three men in one study and total motility was 0–0.6%; suggested HPO: HP:0011961 Asthenozoospermia.
  • Teratozoospermia/MMAF—absent, short, coiled, bent/angulated, and irregular-calibre flagella; suggested HPO: HP:0012864 Teratozoospermia and, where supported by the current HPO release, the specific MMAF concept.
  • Oligozoospermia may coexist. In three subjects, concentrations were 9.3, 10.4, and 21.0×10⁶/mL; suggested HPO: HP:0000798 Oligospermia. Semen volumes were normal-range at 2.9–4.0 mL. (liu2020homozygousmutationsin pages 4-5)
  • Axonemal central-pair absence—TEM may show a 9+0 rather than normal 9+2 configuration; this is a pathology/ultrastructural finding rather than a conventional symptom HPO term. (liu2020homozygousmutationsin pages 3-4)
  • Mitochondrial-sheath and peri-axonemal disorganization occur in some cases. (liu2019lossoffunctionmutationsin pages 1-2, li2022spermflagellar2 pages 4-6)

In the 2020 three-patient series, normal flagella represented only 13.5%, 30%, and 35% of counted sperm; short tails occurred in 48%, 25%, and 35%; absent tails in 28%, 18%, and 13%; coiled tails in 10%, 24%, and 7%; angulation in 0.5%, 2%, and 5%; and irregular calibre in 0%, 1%, and 5%. These are patient-level observations, not population frequencies. (liu2020homozygousmutationsin pages 4-5)

Extra-reproductive phenotype

Earlier cohorts reported no bronchitis, sinusitis, pneumonia, or evident PCD; one subject had normal chest radiography and olfactory testing. (liu2019lossoffunctionmutationsin pages 1-2, liu2020homozygousmutationsin pages 5-6) In contrast, three 2024 patients had chronic wet cough, chronic sinusitis, and/or nasal congestion and were described as having likely PCD/PCD-like disease despite preserved respiratory-cilium ultrastructure. Suggested HPO terms include HP:0032223 Chronic wet cough, HP:0011109 Chronic sinusitis, and HP:0000458 Anosmia only when present. (lu2024novelspef2variants pages 1-2)

There is no established neurologic, behavioral, immune, metabolic, or endocrine syndrome in reported human SPGF43. Hydrocephalus and growth/bone abnormalities are prominent in some global Spef2-null mice but have not been established as human SPGF43 manifestations.

Severity/course. Reproductive severity is usually high and stable because malformed mature flagella cannot be repaired. Respiratory expressivity is variable. Quantified health-related quality-of-life data—EQ-5D, SF-36, PROMIS, or infertility-specific scores—are unavailable. Likely impacts include involuntary childlessness, treatment burden, psychological distress, and, where PCD occurs, chronic respiratory morbidity; these are clinically plausible but not measured specifically in SPGF43 cohorts.

A study-level summary follows.

Study/date and URL/DOI Cohort SPEF2 variants Core phenotype/quantitative findings Respiratory/PCD findings ART outcome
Liu et al., May 2019, J Med Genet; doi:10.1136/jmedgenet-2018-105952 2 SPEF2-positive men among 42 infertile Han Chinese men with MMAF; 10 fertile controls P1: c.12delC and c.1745-2A>G; P2: c.4102G>T and c.4323dupA; reported as rare, potentially deleterious loss-of-function alleles Severe asthenozoospermia with absent, short, bent, coiled, and/or irregular-calibre flagella; TEM showed disrupted axonemes and mitochondrial-sheath defects; sperm SPEF2 was significantly reduced by immunofluorescence and western blot (liu2019lossoffunctionmutationsin pages 1-2, liu2019lossoffunctionmutationsin pages 6-6) No reported bronchitis, sinusitis, pneumonia, or other PCD-related symptoms; genital examination and bilateral testes were normal (liu2019lossoffunctionmutationsin pages 1-2) P1: two blastocysts after ICSI and one embryo transferred, but no pregnancy; maternal age was noted as a possible contributor (liu2019lossoffunctionmutationsin pages 6-6)
Liu et al., May 2020, J Med Genet; doi:10.1136/jmedgenet-2019-106011 3 affected men from unrelated consanguineous families: two Han Chinese and one Iranian Homozygous c.910C>T (p.Arg304*), c.3400delA (p.Ile1134Serfs*13), and c.3240delT (p.Phe1080Leufs*2). gnomAD frequencies: 8×10⁻⁶, 4×10⁻⁶, and 0, respectively (liu2020homozygousmutationsin pages 2-2, liu2020homozygousmutationsin pages 3-4) Semen volume 2.9–4.0 mL; concentration 9.3–21.0×10⁶/mL; total motility 0–0.6%; progressive motility 0%. Normal flagella occurred in only 13.5–35%; short flagella in 25–48%. TEM showed central-pair loss and a 9+0 rather than 9+2 axoneme; SPEF2 and CFAP69 staining was absent or markedly reduced (liu2020homozygousmutationsin pages 4-5, liu2020homozygousmutationsin pages 3-4, liu2020homozygousmutationsin pages 5-6) No obvious PCD-like manifestations documented; one subject had normal chest radiography and olfactory testing, without evident pulmonary or cardiac abnormality (liu2020homozygousmutationsin pages 5-6) Not reported in the available evidence
Li et al., online Nov 2021 / vol. 24, 2022, Asian J Androl; doi:10.4103/aja202154 Sperm proteomics from 3 SPEF2-mutant patients Previously identified pathogenic SPEF2 genotypes; individual variant notation was not restated in the extracted evidence 1,262 differentially expressed proteins: 486 upregulated and 776 downregulated. Reduced proteins included SPAG6, RSPH1/RSPH4A, DYNLT1, MNS1 and TOM20; IFT20 and other IFT proteins increased. SPEF2–IFT20 and SPEF2–RSPH9 interactions were experimentally supported, implicating central-pair, radial-spoke, mitochondrial-sheath, and cargo-transport defects (li2022spermflagellar2 pages 4-6, li2022spermflagellar2 pages 3-4, li2022spermflagellar2 pages 6-7) Not evaluated or not reported in the extracted proteomic evidence Not reported
Aprea et al., 3 Feb 2023, Front Genet; doi:10.3389/fgene.2023.1117821 2 SPEF2 cases within a 10-man cohort carrying defects in six axonemal genes; overall cohort comprised eight men diagnosed with PCD and two with MMAF-associated infertility Pathogenic SPEF2 variants were reported, but exact patient-level nomenclature and allele frequencies were not available in the extracted evidence Andrological assessment plus sperm high-speed video, immunofluorescence, and TEM demonstrated abnormal flagellar composition; SPEF2 was absent or severely reduced in SPEF2-mutant sperm. The study positioned SPEF2 in the central-pair C1b projection and supported sperm immunofluorescence as a variant-classification aid (aprea2023pathogenicgenevariants pages 2-3) Respiratory-cilia work-up was performed, but SPEF2-specific respiratory findings and definitive patient-level PCD classifications were not available in the extracted evidence Not reported
Lu et al., online 3 Apr 2024, J Assist Reprod Genet; doi:10.1007/s10815-024-03106-9 3 affected men from 3 unrelated Han Chinese families F1: homozygous c.4447+1G>A; F2: compound heterozygous c.1339C>T (p.Arg447*) and c.1645G>T (p.Glu549*); F3: homozygous c.2524G>A (p.Asp842Asn), transcript NM_024867.4. All four were novel/very rare and experimentally supported as deleterious; exact database frequencies and formal ACMG classes were not available in the extracted evidence (lu2024novelspef2variants pages 1-2) Male infertility with MMAF; mutant sperm had abnormal flagella and loss of the axonemal central-pair complex. Reported ICSI fertilization rates were 100%, 90%, and 82% (lu2024novelspef2variants pages 12-13, lu2024novelspef2variants pages 1-2) Chronic wet cough, chronic sinusitis, and/or nasal congestion supported likely PCD/PCD-like disease, although respiratory-cilium ultrastructure was reportedly unaffected; definitive PCD status therefore remains cautious (lu2024novelspef2variants pages 1-2) Each couple underwent one ICSI cycle; all three achieved healthy live births (lu2024novelspef2variants pages 1-2, lu2024novelspef2variants pages 12-13)

Table: Compact study-level evidence for biallelic SPEF2-associated SPGF43, spanning initial human discovery through 2024 clinical expansion. It highlights cohort sizes, variants, quantitative sperm findings, respiratory involvement, and reported ICSI outcomes while preserving uncertainty.

4. Genetic and molecular information

Gene. SPEF2, chromosome 5p13.2, encodes sperm flagellar protein 2, a large, evolutionarily conserved ciliary/flagellar protein. Full-length protein annotations include a calponin-homology region, P-loop NTPase-like fold, EF-hand region, and an IFT20-binding region. Several tissue-specific transcripts are expressed; disruption of long testis transcripts may produce isolated infertility, while alleles affecting broadly expressed isoforms may increase PCD risk. This transcript explanation is plausible and supported by expression observations, but genotype–phenotype rules remain incomplete. (liu2020homozygousmutationsin pages 2-2, li2022spermflagellar2 pages 4-6)

Reported pathogenic spectrum. Examples include:

  • Compound heterozygous c.12delC and c.1745-2A>G; compound heterozygous c.4102G>T and c.4323dupA (2019). (liu2019lossoffunctionmutationsin pages 1-2, liu2019lossoffunctionmutationsin pages 6-6)
  • Homozygous c.910C>T (p.Arg304), c.3400delA (p.Ile1134Serfs13), and c.3240delT (p.Phe1080Leufs*2) (2020). These were absent from 1000 Genomes; ExAC frequencies were approximately 8.2×10⁻⁶, 8.3×10⁻⁶, and zero, and gnomAD frequencies approximately 8×10⁻⁶, 4×10⁻⁶, and zero. (liu2020homozygousmutationsin pages 3-4)
  • Homozygous c.4447+1G>A; compound heterozygous c.1339C>T (p.Arg447) plus c.1645G>T (p.Glu549); and homozygous c.2524G>A (p.Asp842Asn), referenced to NM_024867.4 (2024). (lu2024novelspef2variants pages 1-2)

These are germline, not somatic, variants. Most demonstrated alleles act through loss of function, including nonsense-mediated decay, truncation, abnormal splicing, loss/reduction of protein, or disruption of functional domains. Formal ClinVar submissions and ACMG classifications should be assessed variant by variant; a published “pathogenic” assertion is not automatically equivalent to a current ClinVar expert-panel classification. The 2024 missense p.Asp842Asn has experimental support but warrants especially careful transcript, segregation, population-frequency, and functional review.

No recurrent chromosomal abnormality, repeat expansion, mitochondrial-DNA defect, pathogenic epimutation, or disease-specific methylation signature is established. No human modifier gene or somatic mosaic mechanism is proven.

5. Environmental information

SPGF43 is genetic. No toxin, pollutant, radiation exposure, occupation, diet, alcohol use, smoking pattern, or infectious agent has been linked specifically to its occurrence or penetrance. General semen-toxic exposures may add nonspecific impairment but have not been shown to interact with SPEF2. The disease is noninfectious and nontransmissible between persons.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic SPEF2 pathogenic variants lead to absent, truncated, mis-spliced, or dysfunctional SPEF2 in developing spermatids and mature sperm. (liu2019lossoffunctionmutationsin pages 1-2, liu2020homozygousmutationsin pages 3-4)
  2. SPEF2 deficiency leads to defective interaction/localization with IFT20 and central-pair/radial-spoke partners, including RSPH9; altered CFAP69 and HYDIN-dependent central-apparatus composition is also observed. (liu2020homozygousmutationsin pages 5-6, li2022spermflagellar2 pages 3-4, li2022spermflagellar2 pages 6-7, aprea2023pathogenicgenevariants pages 2-3)
  3. Defective SPEF2-dependent transport and scaffolding lead to impaired intraflagellar and probably intramanchette cargo delivery during spermiogenesis; the intramanchette contribution is mechanistically supported in models/proteomics but remains partly inferred in humans. (virtanen2016theroleofa pages 44-47, lehti2016microtubulemediatedproteintransport pages 31-34, li2022spermflagellar2 pages 6-7)
  4. Transport/scaffold failure results in incomplete assembly of the C1b/central-pair apparatus, radial spokes, dynein-associated components, fibrous sheath, outer dense fibres, and mitochondrial sheath. (liu2020homozygousmutationsin pages 4-4, li2022spermflagellar2 pages 4-6, li2022spermflagellar2 pages 3-4)
  5. Axonemal and peri-axonemal disorganization leads to absent, short, bent, coiled, or irregular sperm flagella and inefficient energy/mechanical coupling. (liu2019lossoffunctionmutationsin pages 1-2, liu2020homozygousmutationsin pages 4-5)
  6. Malformed flagella result in near-total loss of progressive sperm motility and inability to traverse the female reproductive tract, causing male infertility. (liu2020homozygousmutationsin pages 4-5, liu2020homozygousmutationsin pages 3-4)
  7. Branch—when respiratory motile-cilium function is sufficiently affected, SPEF2 dysfunction leads to impaired mucociliary clearance and chronic wet cough/sinusitis/nasal congestion; this branch is variably expressed and may occur without obvious TEM abnormalities. (lu2024novelspef2variants pages 1-2)

Molecular and cellular detail

Normal sperm axonemes contain nine outer doublet microtubules around two central singlets. SPEF2 is associated with the central-pair C1b projection and is also detected during spermatid development in the Golgi, manchette, basal body, and forming tail. Human mutant sperm can lose the central pair completely, generating a 9+0 arrangement. (liu2020homozygousmutationsin pages 3-4, lehti2016microtubulemediatedproteintransport pages 31-34, aprea2023pathogenicgenevariants pages 2-3)

Proteomics of sperm from three SPEF2-mutant patients found 1,262 differentially expressed proteins: 486 increased and 776 decreased. Reduced proteins included central-pair/radial-spoke and dynein-associated components such as SPAG6, RSPH1, RSPH4A, DNALI1, DNAH5, DNAI2, DYNLT1, and MNS1. IFT20, IFT27, IFT54, and IFT144/WDR19 were increased, potentially representing failed cargo assembly or compensatory feedback. SPEF2–IFT20 and SPEF2–RSPH9 interactions were experimentally supported. (li2022spermflagellar2 pages 4-6, li2022spermflagellar2 pages 3-4)

TOM20, AKAP3/AKAP4, oxidative-phosphorylation, glycolytic, and carbon-metabolism proteins were altered. These findings support secondary energetic dysfunction but do not establish a primary metabolic disease. Retained cytoplasm and altered IQUB, UBTD2, ZNRF4, and USP14 suggest disturbed protein degradation; its causal importance is unresolved. (li2022spermflagellar2 pages 4-6, li2022spermflagellar2 pages 6-7)

There is no demonstrated canonical Wnt, MAPK, mTOR, or PI3K–AKT driver, no evidence that inflammation or autoimmunity initiates the disorder, and no disease-specific human metabolomic, lipidomic, epigenomic, single-cell, spatial-transcriptomic, or integrated multi-omic signature beyond sperm proteomics.

Suggested annotations: GO biological processes—spermatid development, spermiogenesis, sperm flagellum assembly, cilium movement, microtubule-based movement, intraflagellar transport, protein localization to cilium; GO cellular components—sperm flagellum, axoneme, central-pair apparatus, manchette, basal body, radial spoke, mitochondrial sheath; CL—spermatid, spermatozoon, Sertoli cell, and respiratory ciliated epithelial cell. Exact ontology accessions should be resolved against current GO/CL releases.

7. Anatomical structures affected

The primary organ is the testis, specifically seminiferous epithelium and differentiating haploid spermatids; the clinically assayed cells are ejaculated spermatozoa from the epididymis/seminal tract. External genitalia and testes may appear normal on routine examination despite profound cellular disease. (liu2019lossoffunctionmutationsin pages 1-2)

Primary subcellular sites are the sperm-tail axoneme, central pair/C1b projection, radial spokes, dynein-associated structures, outer dense fibres, fibrous sheath, mitochondrial sheath, basal body, and the transient spermatid manchette. No lateralization applies. Suggested UBERON concepts are testis, seminiferous tubule, epididymis, spermatic part of flagellum, and respiratory epithelium. If PCD-like disease occurs, nasal/sinus and airway ciliated epithelia are secondary sites.

8. Temporal development

The molecular lesion is congenital and lifelong, but the reproductive phenotype develops during post-pubertal spermiogenesis and is usually diagnosed in adulthood during infertility evaluation. Onset is insidious rather than acute. There are no validated clinical stages, spontaneous remissions, relapsing pattern, or evidence that malformed sperm improve with age. Each new spermatogenic cycle reproduces the assembly defect.

The critical biological window is elongating-spermatid differentiation, when manchette-dependent trafficking and flagellar assembly occur. For family planning, the actionable window is before ART: establish a molecular diagnosis, assess respiratory features, provide recurrence counseling, and discuss reproductive options.

9. Inheritance and population

Inheritance is autosomal recessive. Affected males generally have biallelic variants; parents are expected to be heterozygous carriers. For two carrier parents, Mendelian risks per pregnancy are 25% biallelic, 50% carrier, and 25% inheriting neither familial allele. A biallelic female may not manifest “spermatogenic failure,” but could theoretically have motile-cilia manifestations; female reproductive consequences are insufficiently characterized.

Consanguinity is prominent in several reports, but compound heterozygous cases demonstrate that disease also occurs in outbred families. Reported subjects include Han Chinese and Iranian individuals and European PCD/infertility cohorts; these observations do not establish ethnic enrichment or a founder effect. (liu2020homozygousmutationsin pages 2-2, lu2024novelspef2variants pages 1-2, aprea2023pathogenicgenevariants pages 2-3)

No prevalence, incidence, carrier-frequency, or sex-ratio estimate exists for SPGF43. Clinically recognized reproductive disease is male-limited by definition. Penetrance for severe sperm dysfunction appears high among published biallelic males, but publication/ascertainment bias precludes a numerical estimate. Respiratory expressivity is variable. Genetic anticipation and confirmed germline mosaicism have not been reported.

10. Diagnostics

Recommended workflow

  1. Clinical infertility assessment: reproductive/family history, consanguinity, medication/exposure history, physical examination, and at least two semen analyses under current WHO methods.
  2. Sperm phenotyping: quantify concentration, total/progressive motility, vitality, and detailed tail morphology. MMAF should prompt a genetic cause even when genital anatomy and routine hormones are normal.
  3. Exclude common causes: karyotype and Y-chromosome microdeletion testing when indicated by severe oligo-/azoospermia; evaluate obstruction, hypogonadism, varicocele, infection, and gonadotoxic exposure.
  4. Molecular testing: a validated male-infertility/MMAF/PCD panel including SPEF2, or WES/WGS with copy-number and splice-aware analysis. Confirm variants and parental phase by Sanger or equivalent testing. WES successfully discovered most reported variants. WGS is useful when WES is negative, particularly for deep-intronic, structural, regulatory, or poorly captured exons.
  5. Functional/pathology support: sperm immunofluorescence for SPEF2 and interacting structures, and TEM where available. A 2023 study emphasized that sperm immunofluorescence can help classify uncertain missense defects affecting the axonemal ruler, radial-spoke head, and central-pair apparatus. (aprea2023pathogenicgenevariants pages 2-3)
  6. PCD evaluation when symptomatic: nasal nitric oxide where age/standards permit, high-speed video microscopy, respiratory-cilium IF/TEM, and a comprehensive PCD gene panel. Normal TEM does not exclude PCD or SPEF2-related functional disease.

RNA sequencing of patient cells may demonstrate splice consequences, but is not yet a standardized diagnostic. Proteomics is mechanistically informative rather than routine. CMA, FISH, mitochondrial sequencing, and repeat-expansion testing are not targeted tests for SPGF43 unless another diagnosis is suspected.

Differential diagnosis. Other MMAF genes include DNAH1, CFAP43, CFAP44, CFAP65, CFAP69, FSIP2, ARMC2, CFAP61, TTC29, DNHD1, HYDIN, RSPH1, RSPH9, CCDC39, and CCDC40. Broader differentials include primary mitochondrial sperm-motility disorders, globozoospermia, macrozoospermia, acephalic spermatozoa syndrome, Kartagener/other PCD, endocrine infertility, obstruction, varicocele, infection, and acquired toxic/thermal damage. Central-pair loss and absent/reduced SPEF2 staining support—but alone do not absolutely prove—SPEF2 causation.

There are no universally accepted SPGF43-specific clinical criteria, newborn screening, or population screening programs. Cascade testing is appropriate after a familial genotype is established.

11. Outcome and prognosis

SPGF43 is not known to shorten human life expectancy. Disease-specific mortality and survival statistics are not applicable/available. The major morbidity is persistent infertility; respiratory morbidity may occur in PCD-like cases. Natural conception is expected to be markedly impaired when progressive motility is 0%, but absolute natural-conception probabilities have not been estimated.

ICSI can bypass the requirement for sperm propulsion. In 2019, one couple produced two blastocysts but did not achieve pregnancy after one transfer; maternal age was considered a possible contributor. (liu2019lossoffunctionmutationsin pages 6-6) In the 2024 three-family series, reported ICSI fertilization rates were 100%, 90%, and 82%, and all three couples had healthy live births. These results are encouraging but are only three cycles and must not be interpreted as a general response rate. (lu2024novelspef2variants pages 12-13, lu2024novelspef2variants pages 1-2)

A broader 2024 MMAF cohort—not SPEF2-specific—found reduced embryo-development measures and lower cumulative pregnancy rates relative to controls, while neonatal outcomes did not differ. This reinforces the need for gene- and couple-specific counseling rather than assuming uniformly normal ART outcomes.

12. Treatment and current applications

There is no therapy that restores SPEF2 protein or repairs sperm-tail assembly. Antioxidants, hormones, antibiotics, or motility stimulants have no demonstrated SPEF2-specific efficacy unless treating an independent condition.

Current reproductive strategy:

  • Genetic counseling and confirmatory testing.
  • ICSI using viable ejaculated sperm when available; suggested NCIt intervention concepts: Intracytoplasmic Sperm Injection, Assisted Reproductive Technology, and Genetic Counseling.
  • Surgical sperm retrieval may be considered if adequate ejaculated sperm are unavailable, but SPGF43-specific outcome evidence is lacking.
  • Standard embryo culture/transfer and obstetric follow-up.
  • Discussion of donor sperm, adoption, or remaining child-free.
  • Preimplantation genetic testing for monogenic disease (PGT-M) or prenatal diagnosis when the familial variants are known, based on informed preferences and local regulation.

If PCD is diagnosed, use established PCD supportive care—airway-clearance techniques, prompt culture-guided treatment of respiratory exacerbations, vaccination, and specialist surveillance—not a SPEF2-targeted drug.

Gene replacement/editing, mRNA, ASO, and germ-cell therapies remain preclinical concepts. The 2021 proteomics paper stated that its findings “could provide a theoretical basis for gene therapy … in the future,” not that such therapy currently exists. (li2022spermflagellar2 pages 4-6, li2022spermflagellar2 pages 3-4) No relevant SPEF2/SPGF43 interventional clinical trial or NCT identifier was identified.

13. Prevention

The genotype cannot be prevented by behavioral modification or immunization. Primary genetic prevention options are voluntary carrier/cascade testing, reproductive counseling, PGT-M, donor gametes, and prenatal diagnosis. There is no newborn screening indication. Secondary prevention consists of early recognition of severe MMAF and timely molecular/PCD assessment, reducing diagnostic delay and avoiding ineffective empiric treatment. Tertiary prevention includes ART for infertility and PCD respiratory care where applicable. Population-wide carrier screening is not currently justified because prevalence and carrier frequency are unknown.

14. Other species and natural disease

Mouse—Mus musculus (NCBI Taxon 10090): spontaneous/global Spef2 mutants develop male infertility, defective sperm-tail formation, sinusitis, reduced ciliary beat, severe hydrocephalus, and early mortality. Tracheal cilia can look structurally normal while beating about 17% more slowly. Germ-cell conditional knockout avoids some systemic confounding and produces abnormal manchettes and basal bodies, club-shaped heads, truncated/stump tails, impaired spermiation, and very few epididymal sperm; acrosome formation remains comparatively normal. (virtanen2016theroleofa pages 44-47, lehti2016microtubulemediatedproteintransport pages 31-34, virtanen2016theroleof pages 44-47)

Pig—Sus scrofa (NCBI Taxon 9823): the naturally occurring immotile short-tail sperm defect is caused by a LINE-1/intronic SPEF2/KPL2 insertion producing aberrant splicing, premature termination, loss of protein, reduced sperm count, and short immotile tails. EM shows missing central microtubules or reduced outer doublets. (liu2020homozygousmutationsin pages 4-4, lehti2016microtubulemediatedproteintransport pages 31-34)

Cattle—Bos taurus (NCBI Taxon 9913): a natural SPEF2 splice-disrupting variant in Holstein cattle has been associated with malformed sperm and reduced post-cryopreservation motility. (liu2020homozygousmutationsin pages 4-4)

These are hereditary, noninfectious traits with no zoonotic or cross-species transmission. Their value is comparative: conserved central-pair and transport functions strongly support human variant causality, although severe murine hydrocephalus does not reliably predict the human phenotype.

15. Model organisms and experimental systems

  • Global and spontaneous Spef2-mutant mice: useful for motile-cilium/PCD biology, hydrocephalus, airway clearance, and infertility; limited by early lethality and a systemic phenotype more severe than most reported humans.
  • Male-germ-cell conditional Spef2 knockout mice: best suited to spermiogenesis, manchette, basal-body, spermiation, and sperm-tail assembly without lethal hydrocephalus; they reproduce infertility and severe flagellar defects but not human allelic heterogeneity. (virtanen2016theroleofa pages 44-47, virtanen2016theroleof pages 44-47)
  • Pig and bull natural mutants: valuable large-animal models of sperm-tail defects and agricultural fertility, including semen cryopreservation; breed structure and species-specific transcripts limit direct penetrance estimates for humans. (liu2020homozygousmutationsin pages 4-4, lehti2016microtubulemediatedproteintransport pages 31-34)
  • Human sperm and HEK293T interaction assays: patient sperm supports disease-relevant IF/TEM/proteomics; heterologous co-immunoprecipitation demonstrated SPEF2–RSPH9 interaction but cannot reproduce spermatid architecture. (li2022spermflagellar2 pages 3-4, li2022spermflagellar2 pages 6-7)
  • Chlamydomonas reinhardtii: a 2024 preprint used a SPEF2-homolog motility mutant to model SPGF43 and explore rescue. This is a tractable conserved-axoneme platform, not evidence of a human treatment.

Recent developments and expert interpretation

The 2023 Aprea study moved sperm immunofluorescence toward a clinically useful functional assay for uncertain variants and localized SPEF2 within central-pair disease biology. (aprea2023pathogenicgenevariants pages 2-3) The 2024 Lu study expanded the allelic spectrum by four variants, strengthened evidence that SPEF2 disease can bridge MMAF and PCD, and provided three successful ICSI live births. (lu2024novelspef2variants pages 1-2, lu2024novelspef2variants pages 12-13) Current expert interpretation should therefore avoid classifying SPEF2 solely as an isolated-infertility gene: respiratory history and PCD testing are warranted when symptoms are present. Conversely, murine hydrocephalus should not be assigned as a routine human phenotype without human evidence.

The most important limitations are tiny cohorts, infertility/PCD ascertainment bias, inconsistent transcript nomenclature, incomplete ClinVar-level classification, and sparse longitudinal follow-up. Consequently, statements such as complete penetrance, population prevalence, variant-specific respiratory risk, and an ICSI success percentage are presently unsupported.

Key primary sources and dates

  1. Liu W et al. “Loss-of-function mutations in SPEF2 cause multiple morphological abnormalities of the sperm flagella (MMAF).” Journal of Medical Genetics 56:678–684; published May 2019. DOI/URL: https://doi.org/10.1136/jmedgenet-2018-105952. (liu2019lossoffunctionmutationsin pages 1-2)
  2. Liu C et al. “Homozygous mutations in SPEF2 induce multiple morphological abnormalities of the sperm flagella and male infertility.” Journal of Medical Genetics 57:31–37; 2020. DOI/URL: https://doi.org/10.1136/jmedgenet-2019-106011. Abstract conclusion: “We identified SPEF2 as a novel gene for human MMAF across the populations.” (liu2020homozygousmutationsin pages 2-2, liu2020homozygousmutationsin pages 3-4)
  3. Li D-Y et al. “Sperm flagellar 2 (SPEF2) is essential for sperm flagellar assembly in humans.” Asian Journal of Andrology 24:359–366; online November 2021. DOI/URL: https://doi.org/10.4103/aja202154. Abstract: “A total of 1262 differentially expressed proteins were detected, including 486 upregulated and 776 downregulated.” (li2022spermflagellar2 pages 4-6, li2022spermflagellar2 pages 3-4)
  4. Aprea I et al. “Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility.” Frontiers in Genetics 14; published 3 February 2023. DOI/URL: https://doi.org/10.3389/fgene.2023.1117821. (aprea2023pathogenicgenevariants pages 2-3)
  5. Lu W et al. “Novel SPEF2 variants cause male infertility and likely primary ciliary dyskinesia.” Journal of Assisted Reproduction and Genetics 41:1485–1498; online 3 April 2024. DOI/URL: https://doi.org/10.1007/s10815-024-03106-9. (lu2024novelspef2variants pages 1-2)

PMIDs were not exposed in the retrieved full-text metadata and therefore are not guessed here; they should be programmatically resolved from the DOIs through PubMed/Crossref before knowledge-base loading.

References

  1. (liu2019lossoffunctionmutationsin pages 1-2): Wensheng Liu, Yanwei Sha, Yang Li, Libin Mei, Shaobin Lin, Xianjing Huang, Jinhua Lu, Lu Ding, Shuangbo Kong, and Zhongxian Lu. Loss-of-function mutations in spef2 cause multiple morphological abnormalities of the sperm flagella (mmaf). Journal of Medical Genetics, 56:678-684, May 2019. URL: https://doi.org/10.1136/jmedgenet-2018-105952, doi:10.1136/jmedgenet-2018-105952. This article has 83 citations and is from a domain leading peer-reviewed journal.

  2. (liu2020homozygousmutationsin pages 2-2): Chunyu Liu, Mingrong Lv, Xiaojin He, Yong Zhu, Amir Amiri-Yekta, Weiyu Li, Huan Wu, Zine-Eddine Kherraf, Wangjie Liu, Jingjing Zhang, Qing Tan, Shuyan Tang, Yong-Jun Zhu, Yading Zhong, Caihua Li, Shixiong Tian, Zhiguo Zhang, Li Jin, Pierre Ray, Feng Zhang, and Yunxia Cao. Homozygous mutations in spef2 induce multiple morphological abnormalities of the sperm flagella and male infertility. Journal of Medical Genetics, 57:31-37, May 2020. URL: https://doi.org/10.1136/jmedgenet-2019-106011, doi:10.1136/jmedgenet-2019-106011. This article has 95 citations and is from a domain leading peer-reviewed journal.

  3. (liu2020homozygousmutationsin pages 3-4): Chunyu Liu, Mingrong Lv, Xiaojin He, Yong Zhu, Amir Amiri-Yekta, Weiyu Li, Huan Wu, Zine-Eddine Kherraf, Wangjie Liu, Jingjing Zhang, Qing Tan, Shuyan Tang, Yong-Jun Zhu, Yading Zhong, Caihua Li, Shixiong Tian, Zhiguo Zhang, Li Jin, Pierre Ray, Feng Zhang, and Yunxia Cao. Homozygous mutations in spef2 induce multiple morphological abnormalities of the sperm flagella and male infertility. Journal of Medical Genetics, 57:31-37, May 2020. URL: https://doi.org/10.1136/jmedgenet-2019-106011, doi:10.1136/jmedgenet-2019-106011. This article has 95 citations and is from a domain leading peer-reviewed journal.

  4. (liu2020homozygousmutationsin pages 4-5): Chunyu Liu, Mingrong Lv, Xiaojin He, Yong Zhu, Amir Amiri-Yekta, Weiyu Li, Huan Wu, Zine-Eddine Kherraf, Wangjie Liu, Jingjing Zhang, Qing Tan, Shuyan Tang, Yong-Jun Zhu, Yading Zhong, Caihua Li, Shixiong Tian, Zhiguo Zhang, Li Jin, Pierre Ray, Feng Zhang, and Yunxia Cao. Homozygous mutations in spef2 induce multiple morphological abnormalities of the sperm flagella and male infertility. Journal of Medical Genetics, 57:31-37, May 2020. URL: https://doi.org/10.1136/jmedgenet-2019-106011, doi:10.1136/jmedgenet-2019-106011. This article has 95 citations and is from a domain leading peer-reviewed journal.

  5. (li2022spermflagellar2 pages 4-6): Dong-Yan Li, Xiao-Xuan Yang, Chao-Feng Tu, Wei-Li Wang, Lan-Lan Meng, Guang-Xiu Lu, Yue-Qiu Tan, Qian-Jun Zhang, and Juan Du. Sperm flagellar 2 (spef2) is essential for sperm flagellar assembly in humans. Asian Journal of Andrology, 24:359-366, Nov 2021. URL: https://doi.org/10.4103/aja202154, doi:10.4103/aja202154. This article has 34 citations and is from a peer-reviewed journal.

  6. (liu2020homozygousmutationsin pages 5-6): Chunyu Liu, Mingrong Lv, Xiaojin He, Yong Zhu, Amir Amiri-Yekta, Weiyu Li, Huan Wu, Zine-Eddine Kherraf, Wangjie Liu, Jingjing Zhang, Qing Tan, Shuyan Tang, Yong-Jun Zhu, Yading Zhong, Caihua Li, Shixiong Tian, Zhiguo Zhang, Li Jin, Pierre Ray, Feng Zhang, and Yunxia Cao. Homozygous mutations in spef2 induce multiple morphological abnormalities of the sperm flagella and male infertility. Journal of Medical Genetics, 57:31-37, May 2020. URL: https://doi.org/10.1136/jmedgenet-2019-106011, doi:10.1136/jmedgenet-2019-106011. This article has 95 citations and is from a domain leading peer-reviewed journal.

  7. (lu2024novelspef2variants pages 1-2): Wenqing Lu, Yong Li, Lanlan Meng, Chen Tan, Hongchuan Nie, Qianjun Zhang, Yuying Song, Huan Zhang, Yue-Qiu Tan, Chaofeng Tu, Haichun Guo, Longxiang Wu, and Juan Du. Novel spef2 variants cause male infertility and likely primary ciliary dyskinesia. Journal of assisted reproduction and genetics, 41:1485-1498, Apr 2024. URL: https://doi.org/10.1007/s10815-024-03106-9, doi:10.1007/s10815-024-03106-9. This article has 5 citations and is from a peer-reviewed journal.

  8. (liu2019lossoffunctionmutationsin pages 6-6): Wensheng Liu, Yanwei Sha, Yang Li, Libin Mei, Shaobin Lin, Xianjing Huang, Jinhua Lu, Lu Ding, Shuangbo Kong, and Zhongxian Lu. Loss-of-function mutations in spef2 cause multiple morphological abnormalities of the sperm flagella (mmaf). Journal of Medical Genetics, 56:678-684, May 2019. URL: https://doi.org/10.1136/jmedgenet-2018-105952, doi:10.1136/jmedgenet-2018-105952. This article has 83 citations and is from a domain leading peer-reviewed journal.

  9. (li2022spermflagellar2 pages 3-4): Dong-Yan Li, Xiao-Xuan Yang, Chao-Feng Tu, Wei-Li Wang, Lan-Lan Meng, Guang-Xiu Lu, Yue-Qiu Tan, Qian-Jun Zhang, and Juan Du. Sperm flagellar 2 (spef2) is essential for sperm flagellar assembly in humans. Asian Journal of Andrology, 24:359-366, Nov 2021. URL: https://doi.org/10.4103/aja202154, doi:10.4103/aja202154. This article has 34 citations and is from a peer-reviewed journal.

  10. (li2022spermflagellar2 pages 6-7): Dong-Yan Li, Xiao-Xuan Yang, Chao-Feng Tu, Wei-Li Wang, Lan-Lan Meng, Guang-Xiu Lu, Yue-Qiu Tan, Qian-Jun Zhang, and Juan Du. Sperm flagellar 2 (spef2) is essential for sperm flagellar assembly in humans. Asian Journal of Andrology, 24:359-366, Nov 2021. URL: https://doi.org/10.4103/aja202154, doi:10.4103/aja202154. This article has 34 citations and is from a peer-reviewed journal.

  11. (aprea2023pathogenicgenevariants pages 2-3): I. Aprea, A. Wilken, C. Krallmann, T. Nöthe-Menchen, H. Olbrich, N. T. Loges, G. W. Dougherty, D. Bracht, C. Brenker, S. Kliesch, T. Strünker, F. Tüttelmann, J. Raidt, and H. Omran. Pathogenic gene variants in ccdc39, ccdc40, rsph1, rsph9, hydin, and spef2 cause defects of sperm flagella composition and male infertility. Frontiers in Genetics, Feb 2023. URL: https://doi.org/10.3389/fgene.2023.1117821, doi:10.3389/fgene.2023.1117821. This article has 38 citations and is from a peer-reviewed journal.

  12. (lu2024novelspef2variants pages 12-13): Wenqing Lu, Yong Li, Lanlan Meng, Chen Tan, Hongchuan Nie, Qianjun Zhang, Yuying Song, Huan Zhang, Yue-Qiu Tan, Chaofeng Tu, Haichun Guo, Longxiang Wu, and Juan Du. Novel spef2 variants cause male infertility and likely primary ciliary dyskinesia. Journal of assisted reproduction and genetics, 41:1485-1498, Apr 2024. URL: https://doi.org/10.1007/s10815-024-03106-9, doi:10.1007/s10815-024-03106-9. This article has 5 citations and is from a peer-reviewed journal.

  13. (virtanen2016theroleofa pages 44-47): S Virtanen. The role of spef2 in spermatogenesis. Unknown journal, 2016.

  14. (lehti2016microtubulemediatedproteintransport pages 31-34): M Lehti. Microtubule-mediated protein transport mechanisms during spermiogenesis. Unknown journal, 2016.

  15. (liu2020homozygousmutationsin pages 4-4): Chunyu Liu, Mingrong Lv, Xiaojin He, Yong Zhu, Amir Amiri-Yekta, Weiyu Li, Huan Wu, Zine-Eddine Kherraf, Wangjie Liu, Jingjing Zhang, Qing Tan, Shuyan Tang, Yong-Jun Zhu, Yading Zhong, Caihua Li, Shixiong Tian, Zhiguo Zhang, Li Jin, Pierre Ray, Feng Zhang, and Yunxia Cao. Homozygous mutations in spef2 induce multiple morphological abnormalities of the sperm flagella and male infertility. Journal of Medical Genetics, 57:31-37, May 2020. URL: https://doi.org/10.1136/jmedgenet-2019-106011, doi:10.1136/jmedgenet-2019-106011. This article has 95 citations and is from a domain leading peer-reviewed journal.

  16. (virtanen2016theroleof pages 44-47): S Virtanen. The role of spef2 in spermatogenesis. Unknown journal, 2016.

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

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References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 4
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All extracted references resolved successfully.

Term Validation

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

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Terms checked 8
Resolved 8
Unresolved (possible confabulation) 0
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Terms whose name was checked 1
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Terms the report names something else

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

  • MONDO:0032898 (2 mentions) - the report calls it "if available"; MONDO calls it spermatogenic failure 43