Spermatogenic Failure 24

Mendelian MONDO:0054728 Pathograph 16 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 24 (SPGF24) is autosomal recessive male infertility caused by biallelic loss-of-function variants in CFAP69 (formerly C7orf63), which encodes a testis-enriched cilia- and flagella-associated protein with predicted Armadillo-type repeats. In control sperm CFAP69 is concentrated in the flagellar midpiece, and its Chlamydomonas orthologue FAP69 is associated with the C1b projection of the axonemal central apparatus. All reported alleles are truncating (stop-gain, frameshift or splice-site) and abolish or sharply reduce the protein in sperm. Affected men have severe asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF): absent, short, coiled, bent and irregular-caliber flagella, near-zero progressive motility, and frequent head defects such as tapered heads and abnormal acrosomes. Sperm concentration is normal in most patients but was very low in the two original probands. Electron microscopy shows disorganized axonemes and peri-axonemal structures, typically with loss of the central pair of microtubules. Cfap69 knockout mice reproduce MMAF with preserved stages of spermatogenesis, placing the defect in spermiogenesis. Respiratory or other ciliary disease has not been reported. A live birth after intracytoplasmic sperm injection (ICSI) has been reported.

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👪

Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic CFAP69 variants. All reported genotypes are homozygous truncating variants, in consanguineous and non-consanguineous families.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:37392306 SUPPORT Human clinical
"Pedigree analysis of the family manifested an autosomal recessive inheritance pattern, which is consistent with the previous studies"
Recessive segregation of a homozygous frameshift variant in a non-consanguineous family.
PMID:30415212 SUPPORT Human clinical
"We conducted whole exome sequencing in a male individual with MMAF from a consanguineous Han Chinese family."
Homozygous variant identified in a consanguineous family, consistent with recessive inheritance.
◈

Mechanistic Hypotheses

1
CFAP69 loss causes isolated sperm flagellar failure without respiratory ciliary disease
cfap69_sperm_restricted_phenotype EMERGING
Evidence balance 1 support 1 refute
All reported men have isolated infertility, and no respiratory, laterality or other primary ciliary dyskinesia features have been described. CFAP69 is preferentially expressed in testis but is also present in olfactory sensory neuron cilia in mice, where its loss changes transduction kinetics without abolishing ciliary signalling. Whether other cilia in patients are affected has not been examined, and the patient series is small.
Show evidence (2 references)
PMID:30415212 SUPPORT INDIRECT Human clinical
"a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis."
High testicular expression is consistent with a sperm-restricted phenotype.
PMID:28495971 REFUTE Model organism
"In the olfactory epithelium, CFAP69 is enriched in OSN cilia, where olfactory transduction occurs."
CFAP69 also acts in olfactory cilia in mice, so the protein is not sperm-restricted. Olfactory function has not been tested in patients.
?

Discussions and Knowledge Gaps

1
Do men with biallelic CFAP69 loss-of-function variants have altered olfaction?
KNOWLEDGE GAP cfap69_olfaction_in_patients
Attached to
mechanistic_hypotheses#cfap69_sperm_restricted_phenotype
In mice CFAP69 is enriched in olfactory sensory neuron cilia, and neurons lacking it respond with faster kinetics and the animals perform worse in an odor-masked food-finding test. No reported patient has had olfaction tested, so whether SPGF24 is purely a sperm disorder in humans is unknown.
Show evidence (1 reference)
PMID:28495971 SUPPORT Model organism
"OSNs lacking CFAP69, remarkably, displayed faster kinetics in both the on and off phases of electrophysiological responses at both the neuronal ensemble level as observed by electroolfactogram and the single-cell level as observed by single-cell suction pipette recordings."
Mouse olfactory phenotype that has not been examined in patients.
⚙

Pathophysiology

4
Loss of CFAP69 Protein in Sperm
Biallelic stop-gain, frameshift and splice-site variants abolish or sharply reduce CFAP69 in the sperm flagellum. CFAP69 is concentrated in the midpiece of control sperm. Its precise structural role in mammalian sperm is not established: it carries predicted Armadillo-type repeats, and its Chlamydomonas orthologue is associated with the C1b projection of the central apparatus, so it is treated here as a structural component of the axoneme.
CFAP69 hgnc:26107 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFAP69 (hgnc:26107). hgnc:26107 is a gene from the HUGO Gene Nomenclature Committee.
structural molecule activity GO:0005198 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased structural molecule activity (GO:0005198). GO:0005198 is a molecular function from the Gene Ontology.
Sperm midpiece GO:0097225 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sperm midpiece (GO:0097225). GO:0097225 is a cellular component from the Gene Ontology.
Downstream
Failed Sperm Flagellum Assembly During Spermiogenesis Without CFAP69 the flagellum fails to assemble or is not stabilized, while earlier stages of spermatogenesis proceed normally.
Show evidence (4 references)
PMID:29606301 SUPPORT Human clinical
"Immunostaining experiments in sperm from fertile control individuals showed that CFAP69 localized to the midpiece of the flagellum, and the absence of CFAP69 was confirmed in both individuals carrying CFPA69 mutations."
Midpiece localization in control sperm and protein absence in both patients' sperm.
PMID:37392306 SUPPORT Human clinical
"transmission electron microscopy and immunofluorescence staining revealed that the variant induced the aberrant ultrastructure and reduction of CFAP69 expression in the proband's spermatozoa"
Reduced CFAP69 in sperm of a further proband with a homozygous frameshift.
PMID:37392306 SUPPORT INDIRECT BACKGROUND Other
"suggested that FAP69 (the orthologue of CFAP69 in C. reinhardtii) is involved in the C1b projection of central pair microtubules in flagella"
Background statement, citing Chlamydomonas work, that places the orthologue on a central apparatus projection. It supports treating CFAP69 as an axonemal structural component by inference from the alga.
+ 1 more reference
Failed Sperm Flagellum Assembly During Spermiogenesis
The flagellum is not properly built or stabilized in elongating spermatids. Testicular histology in knockout mice shows all stages of the seminiferous epithelium, so meiosis and earlier steps are preserved.
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.
Sperm flagellum assembly GO:0120316 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Sperm flagellum assembly (GO:0120316). GO:0120316 is a biological process from the Gene Ontology.
Animal models
Cfap69 knockout mouse Mouse recapitulates The knockout reproduces flagellar disruption with preserved earlier spermatogenesis.
Downstream
Sperm Axonemal Disorganization with Central Pair Loss
Show evidence (1 reference)
PMID:29606301 SUPPORT Model organism
"Ultrastructural analysis of testicular sperm from the knockout mice showed severe disruption of flagellum structure, but histological analysis of testes from these mice revealed the presence of all stages of the seminiferous epithelium, indicating that the overall progression of spermatogenesis..."
Flagellar disruption with preserved spermatogenic stages in knockout mice.
Sperm Axonemal Disorganization with Central Pair Loss
Electron microscopy of patient sperm shows a cytoplasmic mass in place of an organized flagellum, disordered doublets and outer dense fibers, and a 9+0 axoneme lacking the central pair. Outer and inner dynein arm markers (DNAI1, DNALI1) are reduced along malformed flagella.
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.
Axonemal central apparatus GO:1990716 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Axonemal central apparatus (GO:1990716). GO:1990716 is a cellular component from the Gene Ontology. 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.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella
Abnormal sperm axoneme morphology
Absent sperm axoneme central pair complex
Show evidence (3 references)
PMID:37392306 SUPPORT Human clinical
"CFAP69-affected sperm displayed as a large cytoplasmic bag in the longitudinal section and presented with disorganized axonemal and peri-axonemal components, such as the absence of CP and the disorder of MT and ODF arrangement."
Axonemal and peri-axonemal disorganization with central pair loss in patient sperm.
PMID:37392306 SUPPORT REVIEW SYNTHESIS Human clinical
"TEM results showed abnormal spermatozoa with an atypical “9+0” microtubule structure, a normal arrangement of peripheral microtubules, and a lack of the central pair of microtubules."
The authors' summary across all five reported patients names central pair loss as the shared ultrastructural lesion.
PMID:37392306 SUPPORT Human clinical
"The CFAP69 deficiency in the L015 proband also reduced the expression of these two pivotal proteins, implying the probable destruction of ultrastructure in sperm flagella."
Dynein arm markers DNAI1 and DNALI1 are reduced in patient sperm.
Multiple Morphological Abnormalities of the Sperm Flagella
The semen phenotype: absent, short, coiled, bent and irregular-caliber flagella in the same ejaculate, with near-absent progressive motility. The proportion of sperm with normal flagella varies between patients.
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.
Downstream
Reduced sperm motility
Male infertility Malformed, nearly immotile sperm cannot reach or fertilize the oocyte in vivo.
Absent sperm flagella
Short sperm flagella
Coiled sperm flagella
Bent sperm flagella
Irregularly shaped sperm tail
Show evidence (3 references)
PMID:37392306 SUPPORT Human clinical
"Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
Quantified MMAF in a homozygous frameshift proband.
PMID:30415212 SUPPORT Human clinical
"The subsequent Sanger sequencing of the CFAP69 coding regions among 34 additional individuals with MMAF revealed a case with homozygous nonsense mutation (p.Trp216*) of CFAP69."
A second MMAF proband with a homozygous nonsense variant.
PMID:29606301 SUPPORT Human clinical
"Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF."
The original MMAF probands.
⬡

Pathograph

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Pathograph: causal mechanism network for Spermatogenic Failure 24 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Male infertility Reproductive 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:37392306 SUPPORT Human clinical
"The proband L015-II-3 was 36 years old and suffered from primary infertility for 9 years due to severe asthenospermia (progressive motility < 5%)."
Long-standing primary infertility in a proband.
Reduced sperm motility Reproductive HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthenozoospermia, annotated with Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"However, sperm motility, especially progressive motility, was extremely low (sperm motility: 1–9%; progressive motility: 0–3%)."
Severe asthenozoospermia in repeated semen analyses.
Absent sperm flagella Reproductive HP:0032558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent sperm flagella (HP:0032558). HP:0032558 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
Absent flagella in a proband.
Short sperm flagella Reproductive HP:0032559 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short sperm flagella (HP:0032559). HP:0032559 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT REVIEW SYNTHESIS Human clinical
"the most common abnormal types were short (21.5%, 79%, 13%, 28%, and 47.5%, respectively) and coiled flagella (20%, 1%, 7%, 35%, and 32.5%, respectively)"
Short and coiled flagella in all five reported patients.
Coiled sperm flagella Reproductive HP:0032560 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coiled sperm flagella (HP:0032560). HP:0032560 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT REVIEW SYNTHESIS Human clinical
"the most common abnormal types were short (21.5%, 79%, 13%, 28%, and 47.5%, respectively) and coiled flagella (20%, 1%, 7%, 35%, and 32.5%, respectively)"
Coiled flagella in all five reported patients.
Bent sperm flagella Reproductive HP:0034811 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bent sperm flagella (HP:0034811). HP:0034811 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
Bent flagella in a proband.
Irregularly shaped sperm tail Reproductive HP:0033393 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Irregular-caliber sperm flagella, annotated with Irregularly shaped sperm tail (HP:0033393). HP:0033393 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
Irregular-caliber flagella in a proband.
Abnormal sperm axoneme morphology Reproductive HP:0033524 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal sperm axoneme morphology (HP:0033524). HP:0033524 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"CFAP69-affected sperm displayed as a large cytoplasmic bag in the longitudinal section and presented with disorganized axonemal and peri-axonemal components, such as the absence of CP and the disorder of MT and ODF arrangement."
Disorganized axonemes on electron microscopy.
Absent sperm axoneme central pair complex Reproductive 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 (1 reference)
PMID:37392306 SUPPORT REVIEW SYNTHESIS Human clinical
"TEM results showed abnormal spermatozoa with an atypical “9+0” microtubule structure, a normal arrangement of peripheral microtubules, and a lack of the central pair of microtubules."
Central pair loss summarized across reported patients.
Tapered sperm head Reproductive HP:0032562 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tapered sperm head (HP:0032562). HP:0032562 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"In addition, a high rate of head malformations, in particular tapered heads and an abnormal acrosomal region, were also observed, which is consistent with another four cases reported (Table 2)."
Tapered heads and acrosomal defects in this and earlier patients.
Oligozoospermia Reproductive HP:0000798 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligozoospermia (HP:0000798). HP:0000798 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:37392306 SUPPORT REVIEW SYNTHESIS Human clinical
"except for those two subjects described by Dong et al. who had oligozoospermia along with asthenozoospermia"
Oligozoospermia in two of five reported patients.
PMID:37392306 REFUTE Human clinical
"the semen volume, sperm concentration, and total sperm count of the L015-II-3 proband were all normal"
Normal sperm count in a later proband, showing oligozoospermia is not a constant feature.
🧬

Genetic Associations

1
CFAP69 (Causal)
Gene: CFAP69 hgnc:26107 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFAP69 (hgnc:26107). hgnc:26107 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
PMID:29606301 SUPPORT Human clinical
"Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF."
Primary gene-disease report.
PMID:30415212 SUPPORT Human clinical
"a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis."
Independent replication in a consanguineous family.
PMID:37392306 SUPPORT Human clinical
"We identified a novel frameshift variant in CFAP69 (c.2061dup, p. Pro688Thrfs*5) from a MMAF-affected infertile male with low sperm motility and malformed morphology of sperm."
A further family with a truncating allele.
💊

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. NCIT:C185482
Platform: Other
ICSI bypasses the motility defect. In the one CFAP69 couple with a reported outcome, eight of ten oocytes were fertilized, three blastocysts formed and a frozen-thawed embryo transfer gave a healthy live birth. In a mixed MMAF series that included a CFAP69 proband, fertilization and pregnancy rates did not differ by genotype.
Mechanism Target:
Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection of a sperm into the oocyte makes flagellar form and motility irrelevant to fertilization.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"Following ICSI, eight oocytes got fertilized, six zygotes developed into transferable embryos, and three blastocysts formed at day 5"
Sperm with MMAF fertilize oocytes normally when injected.
Show evidence (2 references)
PMID:37392306 SUPPORT Human clinical
"After the frozen-thawed embryo transfer, the female partner of L015 proband got pregnant and gave birth to a full-term healthy girl."
Live birth after ICSI in a CFAP69 couple.
PMID:34529793 SUPPORT INDIRECT Human clinical
"The fertilisation rate was not statistically different between the MMAF (65.7%) and the non-MMAF (66.0%) couples and it did not differ according to the genotype or the flagellar phenotype of the subjects or use of the HOS test."
A pooled MMAF series that included a CFAP69 proband; outcomes are not reported separately for CFAP69.
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
Platform: Behavioral / lifestyle
Counselling on autosomal recessive recurrence and carrier testing of relatives once the familial CFAP69 alleles are known. The authors of the ICSI report also advise screening the female partner before ICSI.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"Notably, the genetic screening of the wives of male patients carrying CFAP69 variants should also be considered before the couple asks for ICSI to reduce the risk of hereditary diseases in offspring."
Recommendation for partner screening before ICSI.
🔬

Diagnosis

3
Molecular Genetic Testing
Establishes the diagnosis. Probands have been identified by whole-exome sequencing or a multigene MMAF panel, with Sanger confirmation. Semen analysis and ultrastructure point to a flagellar gene but cannot name it, because MMAF is genetically heterogeneous.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:37392306 SUPPORT Human clinical
"Genetic testing with next-generation sequencing (NGS) panel of 22 MMAF-associated genes and Sanger sequencing was performed in a cohort of 35 infertile males with MMAF to identify pathogenic variants."
Panel sequencing identified the causal allele.
PMID:29606301 SUPPORT Human clinical
"Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF."
Whole-exome sequencing identified the first probands.
Semen Analysis
Shows severe asthenozoospermia with MMAF; sperm concentration is usually normal but can be low.
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"However, sperm motility, especially progressive motility, was extremely low (sperm motility: 1–9%; progressive motility: 0–3%)."
Semen analysis reveals the motility defect.
Transmission Electron Microscopy of Sperm Flagella
Shows disorganized axonemes and peri-axonemal structures, typically with loss of the central pair.
Transmission Electron Microscopy NCIT:C18216 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:37392306 SUPPORT Human clinical
"CFAP69-affected sperm displayed as a large cytoplasmic bag in the longitudinal section and presented with disorganized axonemal and peri-axonemal components, such as the absence of CP and the disorder of MT and ODF arrangement."
TEM findings in patient sperm.
🐁

Animal Models

1
Cfap69 knockout mouse
Male Cfap69 knockout mice are infertile with MMAF and severe disruption of flagellar structure, while all stages of the seminiferous epithelium are present. A second CRISPR-Cas9 knockout gave the same male phenotype.
Species
Mouse
Genotype
Cfap69-/- (knockout), homozygous
Publication
PMID:29606301
Pathograph links
Failed Sperm Flagellum Assembly During Spermiogenesis recapitulates fidelity: high observes: cellular The knockout reproduces flagellar disruption with preserved earlier spermatogenesis.
Limitations: Mouse testicular sperm were analyzed, whereas patient findings come from ejaculated sperm; the two original patients were oligozoospermic and the later ones were not.
Divergences from the human mechanism
species mismatch qualifying
Mouse sperm differ from human sperm in head shape and flagellar length, so the head defects reported in patients (tapered heads, small acrosomes) cannot be read directly off the mouse.
Show evidence (2 references)
PMID:29606301 SUPPORT Model organism
"Additionally, we found that sperm from a Cfap69 knockout mouse model recapitulated the MMAF phenotype."
The knockout recapitulates human MMAF.
+ 1 more reference
{ }

Source YAML

click to show 
name: Spermatogenic Failure 24
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF24
- spermatogenic failure 24
- CFAP69-related multiple morphological abnormalities of the sperm flagella
- CFAP69-related asthenoteratozoospermia
description: >-
  Spermatogenic failure 24 (SPGF24) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in CFAP69 (formerly C7orf63),
  which encodes a testis-enriched cilia- and flagella-associated protein with
  predicted Armadillo-type repeats. In control sperm CFAP69 is concentrated in
  the flagellar midpiece, and its Chlamydomonas orthologue FAP69 is associated
  with the C1b projection of the axonemal central apparatus. All reported
  alleles are truncating (stop-gain, frameshift or splice-site) and abolish or
  sharply reduce the protein in sperm.

  Affected men have severe asthenoteratozoospermia with multiple morphological
  abnormalities of the sperm flagella (MMAF): absent, short, coiled, bent and
  irregular-caliber flagella, near-zero progressive motility, and frequent
  head defects such as tapered heads and abnormal acrosomes. Sperm
  concentration is normal in most patients but was very low in the two
  original probands. Electron microscopy shows disorganized axonemes and
  peri-axonemal structures, typically with loss of the central pair of
  microtubules. Cfap69 knockout mice reproduce MMAF with preserved stages of
  spermatogenesis, placing the defect in spermiogenesis. Respiratory or other
  ciliary disease has not been reported. A live birth after intracytoplasmic
  sperm injection (ICSI) has been reported.
disease_term:
  preferred_term: spermatogenic failure 24
  term:
    id: MONDO:0054728
    label: spermatogenic failure 24
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 617959; the CFAP69 gene entry
  is OMIM 617949. ClinGen has no gene-disease validity classification for
  CFAP69: the ClinGen gene-validity export snapshot of 2026-10-14
  (data/clingen/gene_validity.csv) has no CFAP69 row, and no GeneReviews
  chapter covers this disease (Bookshelf index snapshot 2026-09-10). Five families with
  biallelic CFAP69 variants have been reported in the primary literature
  (PMID:29606301, PMID:30415212, PMID:37392306), and one further proband was
  among the genotyped men in an ICSI outcome series (PMID:34529793). The Dong
  2018 and He 2019 reports are cached as abstracts only. CFAP69 is also
  enriched in olfactory sensory neuron cilia in mice, where its loss speeds
  olfactory transduction kinetics (PMID:28495971); olfaction has not been
  reported in affected men, so no olfactory phenotype is recorded.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic CFAP69 variants. All reported genotypes are
    homozygous truncating variants, in consanguineous and non-consanguineous
    families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pedigree analysis of the family manifested an autosomal recessive inheritance pattern, which is consistent with the previous studies"
    explanation: Recessive segregation of a homozygous frameshift variant in a non-consanguineous family.
  - reference: PMID:30415212
    reference_title: "Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conducted whole exome sequencing in a male individual with MMAF from a consanguineous Han Chinese family."
    explanation: Homozygous variant identified in a consanguineous family, consistent with recessive inheritance.
pathophysiology:
- name: Loss of CFAP69 Protein in Sperm
  description: >-
    Biallelic stop-gain, frameshift and splice-site variants abolish or sharply
    reduce CFAP69 in the sperm flagellum. CFAP69 is concentrated in the
    midpiece of control sperm. Its precise structural role in mammalian sperm
    is not established: it carries predicted Armadillo-type repeats, and its
    Chlamydomonas orthologue is associated with the C1b projection of the
    central apparatus, so it is treated here as a structural component of the
    axoneme.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP69
    term:
      id: hgnc:26107
      label: CFAP69
  molecular_functions:
  - preferred_term: structural molecule activity
    modifier: DECREASED
    term:
      id: GO:0005198
      label: structural molecule activity
  cellular_components:
  - preferred_term: Sperm midpiece
    term:
      id: GO:0097225
      label: sperm midpiece
  downstream:
  - target: Failed Sperm Flagellum Assembly During Spermiogenesis
    causal_link_type: DIRECT
    description: >-
      Without CFAP69 the flagellum fails to assemble or is not stabilized, while
      earlier stages of spermatogenesis proceed normally.
    evidence:
    - reference: PMID:29606301
      reference_title: "Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Ultrastructural analysis of testicular sperm from the knockout mice showed severe disruption of flagellum structure, but histological analysis of testes from these mice revealed the presence of all stages of the seminiferous epithelium, indicating that the overall progression of spermatogenesis is preserved and that the sperm defects likely arise during spermiogenesis."
      explanation: Knockout mice place the defect in spermiogenesis rather than in earlier spermatogenesis.
  evidence:
  - reference: PMID:29606301
    reference_title: "Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunostaining experiments in sperm from fertile control individuals showed that CFAP69 localized to the midpiece of the flagellum, and the absence of CFAP69 was confirmed in both individuals carrying CFPA69 mutations."
    explanation: Midpiece localization in control sperm and protein absence in both patients' sperm.
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "transmission electron microscopy and immunofluorescence staining revealed that the variant induced the aberrant ultrastructure and reduction of CFAP69 expression in the proband's spermatozoa"
    explanation: Reduced CFAP69 in sperm of a further proband with a homozygous frameshift.
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    directness: INDIRECT
    snippet: "suggested that FAP69 (the orthologue of CFAP69 in C. reinhardtii) is involved in the C1b projection of central pair microtubules in flagella"
    explanation: >-
      Background statement, citing Chlamydomonas work, that places the
      orthologue on a central apparatus projection. It supports treating
      CFAP69 as an axonemal structural component by inference from the alga.
  - reference: PMID:28495971
    reference_title: "Cilia- and Flagella-Associated Protein 69 Regulates Olfactory Transduction Kinetics in Mice."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    directness: INDIRECT
    snippet: "Bioinformatic analysis suggests that a large portion of CFAP69 can form Armadillo-type α-helical repeats, which may mediate protein-protein interactions."
    explanation: Sequence analysis predicting a repeat fold suited to protein scaffolding rather than an enzymatic activity.
- name: Failed Sperm Flagellum Assembly During Spermiogenesis
  description: >-
    The flagellum is not properly built or stabilized in elongating
    spermatids. Testicular histology in knockout mice shows all stages of the
    seminiferous epithelium, so meiosis and earlier steps are preserved.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatid
    term:
      id: CL:0000018
      label: spermatid
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  downstream:
  - target: Sperm Axonemal Disorganization with Central Pair Loss
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:29606301
    reference_title: "Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Ultrastructural analysis of testicular sperm from the knockout mice showed severe disruption of flagellum structure, but histological analysis of testes from these mice revealed the presence of all stages of the seminiferous epithelium, indicating that the overall progression of spermatogenesis is preserved and that the sperm defects likely arise during spermiogenesis."
    explanation: Flagellar disruption with preserved spermatogenic stages in knockout mice.
- name: Sperm Axonemal Disorganization with Central Pair Loss
  description: >-
    Electron microscopy of patient sperm shows a cytoplasmic mass in place of
    an organized flagellum, disordered doublets and outer dense fibers, and a
    9+0 axoneme lacking the central pair. Outer and inner dynein arm markers
    (DNAI1, DNALI1) are reduced along malformed flagella.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  - preferred_term: Sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  - target: Absent sperm axoneme central pair complex
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP69-affected sperm displayed as a large cytoplasmic bag in the longitudinal section and presented with disorganized axonemal and peri-axonemal components, such as the absence of CP and the disorder of MT and ODF arrangement."
    explanation: Axonemal and peri-axonemal disorganization with central pair loss in patient sperm.
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "TEM results showed abnormal spermatozoa with an atypical “9+0” microtubule structure, a normal arrangement of peripheral microtubules, and a lack of the central pair of microtubules."
    explanation: The authors' summary across all five reported patients names central pair loss as the shared ultrastructural lesion.
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The CFAP69 deficiency in the L015 proband also reduced the expression of these two pivotal proteins, implying the probable destruction of ultrastructure in sperm flagella."
    explanation: Dynein arm markers DNAI1 and DNALI1 are reduced in patient sperm.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The semen phenotype: absent, short, coiled, bent and irregular-caliber
    flagella in the same ejaculate, with near-absent progressive motility.
    The proportion of sperm with normal flagella varies between patients.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: Malformed, nearly immotile sperm cannot reach or fertilize the oocyte in vivo.
  - target: Absent sperm flagella
    causal_link_type: DIRECT
  - target: Short sperm flagella
    causal_link_type: DIRECT
  - target: Coiled sperm flagella
    causal_link_type: DIRECT
  - target: Bent sperm flagella
    causal_link_type: DIRECT
  - target: Irregularly shaped sperm tail
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
    explanation: Quantified MMAF in a homozygous frameshift proband.
  - reference: PMID:30415212
    reference_title: "Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The subsequent Sanger sequencing of the CFAP69 coding regions among 34 additional individuals with MMAF revealed a case with homozygous nonsense mutation (p.Trp216*) of CFAP69."
    explanation: A second MMAF proband with a homozygous nonsense variant.
  - reference: PMID:29606301
    reference_title: "Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF."
    explanation: The original MMAF probands.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility is the presenting complaint.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband L015-II-3 was 36 years old and suffered from primary infertility for 9 years due to severe asthenospermia (progressive motility < 5%)."
    explanation: Long-standing primary infertility in a proband.
- category: Reproductive
  name: Reduced sperm motility
  description: Total motility is a few percent and progressive motility near zero.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, sperm motility, especially progressive motility, was extremely low (sperm motility: 1–9%; progressive motility: 0–3%)."
    explanation: Severe asthenozoospermia in repeated semen analyses.
- category: Reproductive
  name: Absent sperm flagella
  description: About a tenth of sperm lacked a flagellum in one proband.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
    explanation: Absent flagella in a proband.
- category: Reproductive
  name: Short sperm flagella
  description: Short flagella are the most frequent anomaly across reported patients, from 13% to 79% of sperm.
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the most common abnormal types were short (21.5%, 79%, 13%, 28%, and 47.5%, respectively) and coiled flagella (20%, 1%, 7%, 35%, and 32.5%, respectively)"
    explanation: Short and coiled flagella in all five reported patients.
- category: Reproductive
  name: Coiled sperm flagella
  description: Coiled flagella range from 1% to 35% of sperm across reported patients.
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "the most common abnormal types were short (21.5%, 79%, 13%, 28%, and 47.5%, respectively) and coiled flagella (20%, 1%, 7%, 35%, and 32.5%, respectively)"
    explanation: Coiled flagella in all five reported patients.
- category: Reproductive
  name: Bent sperm flagella
  description: Bent flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Bent sperm flagella
    term:
      id: HP:0034811
      label: Bent sperm flagella
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
    explanation: Bent flagella in a proband.
- category: Reproductive
  name: Irregularly shaped sperm tail
  description: Irregular-caliber flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Irregular-caliber sperm flagella
    term:
      id: HP:0033393
      label: Irregularly shaped sperm tail
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sperm morphology analysis with Papanicolaou staining reflected the severe abnormalities of the sperm flagella of the proband, including absent (10.6%), short (21.5%), coiled (20%), bent (5.9%), and irregular caliber (10.1%), that are typical characteristics of MMAF"
    explanation: Irregular-caliber flagella in a proband.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: Axonemes and peri-axonemal structures are disorganized.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP69-affected sperm displayed as a large cytoplasmic bag in the longitudinal section and presented with disorganized axonemal and peri-axonemal components, such as the absence of CP and the disorder of MT and ODF arrangement."
    explanation: Disorganized axonemes on electron microscopy.
- category: Reproductive
  name: Absent sperm axoneme central pair complex
  description: A 9+0 axoneme lacking the central pair is the recurring cross-sectional finding.
  phenotype_term:
    preferred_term: Absent sperm axoneme central pair complex
    term:
      id: HP:0033525
      label: Absent sperm axoneme central pair complex
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "TEM results showed abnormal spermatozoa with an atypical “9+0” microtubule structure, a normal arrangement of peripheral microtubules, and a lack of the central pair of microtubules."
    explanation: Central pair loss summarized across reported patients.
- category: Reproductive
  name: Tapered sperm head
  description: >-
    Head defects, chiefly tapered heads and small or abnormal acrosomes, are
    frequent. No mechanism linking CFAP69 to head shaping is established, so
    this phenotype is not linked to the causal chain.
  phenotype_term:
    preferred_term: Tapered sperm head
    term:
      id: HP:0032562
      label: Tapered sperm head
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, a high rate of head malformations, in particular tapered heads and an abnormal acrosomal region, were also observed, which is consistent with another four cases reported (Table 2)."
    explanation: Tapered heads and acrosomal defects in this and earlier patients.
- category: Reproductive
  name: Oligozoospermia
  description: >-
    Sperm concentration was very low in the two original probands but normal
    in the three later ones, so oligozoospermia is inconsistent.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "except for those two subjects described by Dong et al. who had oligozoospermia along with asthenozoospermia"
    explanation: Oligozoospermia in two of five reported patients.
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "the semen volume, sperm concentration, and total sperm count of the L015-II-3 proband were all normal"
    explanation: Normal sperm count in a later proband, showing oligozoospermia is not a constant feature.
genetic:
- name: CFAP69
  association: Causal
  gene_term:
    preferred_term: CFAP69
    term:
      id: hgnc:26107
      label: CFAP69
  notes: >-
    Reported alleles are homozygous and truncating: c.763C>T (p.Gln255*) and
    c.860+1G>A (Dong 2018), c.1069_1070insAC (p.Leu357Hisfs*11) and c.647G>A
    (p.Trp216*) (He 2019), and c.2061dup (p.Pro688Thrfs*5) (Tang 2023).
    Biallelic CFAP69 variants accounted for about 2.5 to 5.7% of the MMAF
    cohorts in which they were found. ClinGen has not classified this
    gene-disease pair, so no validity tier is recorded.
  evidence:
  - reference: PMID:29606301
    reference_title: "Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF."
    explanation: Primary gene-disease report.
  - reference: PMID:30415212
    reference_title: "Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis."
    explanation: Independent replication in a consanguineous family.
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a novel frameshift variant in CFAP69 (c.2061dup, p. Pro688Thrfs*5) from a MMAF-affected infertile male with low sperm motility and malformed morphology of sperm."
    explanation: A further family with a truncating allele.
mechanistic_hypotheses:
- hypothesis_group_id: cfap69_sperm_restricted_phenotype
  hypothesis_label: CFAP69 loss causes isolated sperm flagellar failure without respiratory ciliary disease
  status: EMERGING
  description: >-
    All reported men have isolated infertility, and no respiratory, laterality
    or other primary ciliary dyskinesia features have been described. CFAP69
    is preferentially expressed in testis but is also present in olfactory
    sensory neuron cilia in mice, where its loss changes transduction kinetics
    without abolishing ciliary signalling. Whether other cilia in patients are
    affected has not been examined, and the patient series is small.
  evidence:
  - reference: PMID:30415212
    reference_title: "Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "a homozygous frameshift mutation (p.Leu357Hisfs*11) was identified in the gene encoding CFAP69 (cilia and flagella-associated protein 69), which is highly expressed in testis."
    explanation: High testicular expression is consistent with a sperm-restricted phenotype.
  - reference: PMID:28495971
    reference_title: "Cilia- and Flagella-Associated Protein 69 Regulates Olfactory Transduction Kinetics in Mice."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "In the olfactory epithelium, CFAP69 is enriched in OSN cilia, where olfactory transduction occurs."
    explanation: >-
      CFAP69 also acts in olfactory cilia in mice, so the protein is not
      sperm-restricted. Olfactory function has not been tested in patients.
animal_models:
- name: Cfap69 knockout mouse
  species: Mouse
  genotype: Cfap69-/- (knockout), homozygous
  publication: PMID:29606301
  description: >-
    Male Cfap69 knockout mice are infertile with MMAF and severe disruption of
    flagellar structure, while all stages of the seminiferous epithelium are
    present. A second CRISPR-Cas9 knockout gave the same male phenotype.
  modeled_mechanisms:
  - target: Failed Sperm Flagellum Assembly During Spermiogenesis
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The knockout reproduces flagellar disruption with preserved earlier spermatogenesis.
    limitations: >-
      Mouse testicular sperm were analyzed, whereas patient findings come from
      ejaculated sperm; the two original patients were oligozoospermic and the
      later ones were not.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse sperm differ from human sperm in head shape and flagellar length,
        so the head defects reported in patients (tapered heads, small
        acrosomes) cannot be read directly off the mouse.
    evidence:
    - reference: PMID:29606301
      reference_title: "Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Additionally, we found that sperm from a Cfap69 knockout mouse model recapitulated the MMAF phenotype."
      explanation: The knockout recapitulates human MMAF.
    - reference: PMID:30415212
      reference_title: "Novel homozygous CFAP69 mutations in humans and mice cause severe asthenoteratospermia with multiple morphological abnormalities of the sperm flagella."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Remarkably, male Cfap69-knockout mice manifested with MMAF phenotypes."
      explanation: Independent knockout with the same phenotype.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect. In the one CFAP69 couple with a
    reported outcome, eight of ten oocytes were fertilized, three blastocysts
    formed and a frozen-thawed embryo transfer gave a healthy live birth. In a
    mixed MMAF series that included a CFAP69 proband, fertilization and
    pregnancy rates did not differ by genotype.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    description: Direct injection of a sperm into the oocyte makes flagellar form and motility irrelevant to fertilization.
    evidence:
    - reference: PMID:37392306
      reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Following ICSI, eight oocytes got fertilized, six zygotes developed into transferable embryos, and three blastocysts formed at day 5"
      explanation: Sperm with MMAF fertilize oocytes normally when injected.
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After the frozen-thawed embryo transfer, the female partner of L015 proband got pregnant and gave birth to a full-term healthy girl."
    explanation: Live birth after ICSI in a CFAP69 couple.
  - reference: PMID:34529793
    reference_title: "Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "The fertilisation rate was not statistically different between the MMAF (65.7%) and the non-MMAF (66.0%) couples and it did not differ according to the genotype or the flagellar phenotype of the subjects or use of the HOS test."
    explanation: >-
      A pooled MMAF series that included a CFAP69 proband; outcomes are not
      reported separately for CFAP69.
- name: Genetic Counseling
  description: >-
    Counselling on autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP69 alleles are known. The authors of the
    ICSI report also advise screening the female partner before ICSI.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, the genetic screening of the wives of male patients carrying CFAP69 variants should also be considered before the couple asks for ICSI to reduce the risk of hereditary diseases in offspring."
    explanation: Recommendation for partner screening before ICSI.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Probands have been identified by whole-exome
    sequencing or a multigene MMAF panel, with Sanger confirmation. Semen
    analysis and ultrastructure point to a flagellar gene but cannot name it,
    because MMAF is genetically heterogeneous.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing with next-generation sequencing (NGS) panel of 22 MMAF-associated genes and Sanger sequencing was performed in a cohort of 35 infertile males with MMAF to identify pathogenic variants."
    explanation: Panel sequencing identified the causal allele.
  - reference: PMID:29606301
    reference_title: "Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF."
    explanation: Whole-exome sequencing identified the first probands.
- name: Semen Analysis
  description: >-
    Shows severe asthenozoospermia with MMAF; sperm concentration is usually
    normal but can be low.
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, sperm motility, especially progressive motility, was extremely low (sperm motility: 1–9%; progressive motility: 0–3%)."
    explanation: Semen analysis reveals the motility defect.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Shows disorganized axonemes and peri-axonemal structures, typically with
    loss of the central pair.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:37392306
    reference_title: "A novel variant in CFAP69 causes asthenoteratozoospermia with treatable ART outcomes and a literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP69-affected sperm displayed as a large cytoplasmic bag in the longitudinal section and presented with disorganized axonemal and peri-axonemal components, such as the absence of CP and the disorder of MT and ODF arrangement."
    explanation: TEM findings in patient sperm.
discussions:
- discussion_id: cfap69_olfaction_in_patients
  kind: KNOWLEDGE_GAP
  attaches_to:
  - mechanistic_hypotheses#cfap69_sperm_restricted_phenotype
  prompt: >-
    Do men with biallelic CFAP69 loss-of-function variants have altered
    olfaction?
  rationale: >-
    In mice CFAP69 is enriched in olfactory sensory neuron cilia, and neurons
    lacking it respond with faster kinetics and the animals perform worse in
    an odor-masked food-finding test. No reported patient has had olfaction
    tested, so whether SPGF24 is purely a sperm disorder in humans is unknown.
  evidence:
  - reference: PMID:28495971
    reference_title: "Cilia- and Flagella-Associated Protein 69 Regulates Olfactory Transduction Kinetics in Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "OSNs lacking CFAP69, remarkably, displayed faster kinetics in both the on and off phases of electrophysiological responses at both the neuronal ensemble level as observed by electroolfactogram and the single-cell level as observed by single-cell suction pipette recordings."
    explanation: Mouse olfactory phenotype that has not been examined in patients.
📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Spermatogenic Failure 24 (CFAP69) · 2026-10-16T13:40:57Z · View source

New entry for spermatogenic failure 24 (MONDO:0054728), CFAP69-related MMAF. Deep research with the claude_code provider (research/Spermatogenic_Failure_24-deep-research-claude_code.md); just preflight-dr returned PASS for CFAP69. The report was used for leads only; every snippet was taken from references_cache after just fetch-reference. Chain: loss of CFAP69 (structural molecule activity, decreased; midpiece) -> failed flagellum assembly in spermatids -> axonemal disorganization with central pair loss -> MMAF -> male infertility and flagellar phenotypes. GO has no informative MF annotation for CFAP69; structural molecule activity was chosen on the basis of the predicted Armadillo repeats and the Chlamydomonas FAP69 C1b association (background quote, INDIRECT). Oligozoospermia is recorded with SUPPORT and REFUTE items because counts were low in two of five probands. ClinGen has no CFAP69 curation (checked data/clingen/gene_validity.csv) and no GeneReviews chapter exists (just check-genereviews). Mouse olfactory phenotype recorded as a knowledge gap rather than a patient phenotype. Stub stubs/Spermatogenic_Failure_24.yaml deleted. Validated with just validate, validate-terms, count-verified-snippets, check-entity-refs, check-causal-targets, check-duplicate-keys, the snippet/title gates, gene-activity grounding and validate-disorders.

Claude Code ▸
Spermatogenic Failure 24 (SPGF24): research report
claude-haiku-5-5, claude-sonnet-5-5 11 citations 2026-10-16T13:13:26.970422

Try PubMed / Europe PMC instead.

Spermatogenic Failure 24 (SPGF24): research report

Evidence limits. This report rests on web search summaries and the PubMed abstract summaries I retrieved. PMC full texts were blocked by a browser-verification page. I have no verbatim abstract text, so there are no exact snippets here. Every quote must be copied from the cache after just fetch-reference PMID:…, and none should be written from this report. The PMIDs below came from search results and are not verified against PubMed. Three of them (29606301, 30415212, 37392306) were each reported by a single search listing, and 30415212 was explicitly flagged as coming from "one listing". HP, GO, CL and UBERON terms are suggestions only. Do not write CURIEs into the KB from memory. Look each one up with runoak or the term cache.

1. Disease information

SPGF24 is an autosomal recessive form of male infertility caused by biallelic loss of function in CFAP69 (7q21.13). Affected men have asthenoteratozoospermia with "multiple morphological abnormalities of the sperm flagella" (MMAF). Flagella are absent, short, coiled, bent or of irregular caliber. Sperm heads are also malformed, and sperm counts are very low.

Identifiers - OMIM 617959 - MONDO:0054728 - MedGen 1646063 - UMLS C4693751 - DOID:0111929

Synonyms: SPGF24, "spermatogenic failure, type 24". LOVD lists the gene under the older name C7orf63.

Data source: Disease-level, aggregated from small case series. OMIM refers to SPGF1 (258150) for the general discussion of genetic heterogeneity.

Sources: - MalaCards - LOVD disease 05564 - DrugMap - MedGen - Disease Ontology

2. Etiology

  • Cause: Homozygous or compound heterozygous loss-of-function variants in CFAP69.
  • Environmental, protective and gene-environment factors: None reported. This is a monogenic recessive disorder, and I found no sources on these topics.
  • Consanguinity: The index family in He et al. was consanguineous.

3. Phenotypes

All phenotypes are in men and are human clinical findings.

Phenotype Suggested HPO term (to be looked up) Frequency
Male infertility Male infertility Defining feature
Asthenozoospermia Asthenozoospermia Severe; not quantified in sources I could read
Teratozoospermia Teratozoospermia Present
MMAF (absent, short, coiled, bent or irregular flagella) Abnormal sperm flagellum morphology, if the HPO term exists Defining feature
Abnormal sperm head morphology Abnormal sperm head morphology Described in the summaries
Oligozoospermia Oligozoospermia Described as "very low" sperm concentration
  • Onset and course: Not described. Presumably stable, presenting at adult reproductive age.
  • Quality-of-life data: Not found.
  • Non-reproductive features: None reported in the sources I retrieved. This is a gap, and I did not verify that none exist.

4. Genetic and molecular information

  • Gene: CFAP69 (cilia and flagella associated protein 69), HGNC ID to be looked up. Use the lowercase hgnc: form in the KB.
  • Variants:
  • Dong et al. 2018 (AJHG 102:636–648, PMID:29606301): exome sequencing of 78 MMAF men found biallelic truncating CFAP69 variants in two unrelated individuals.
  • He et al. 2019 (J Med Genet 56:96–103, PMID:30415212): a homozygous frameshift, p.Leu357Hisfs11, in a consanguineous Han Chinese family. Sanger sequencing of 34 more MMAF men found a homozygous nonsense variant, p.Trp216. Neither variant was in population databases. CFAP69 accounted for 5.7% (2/35) of that cohort.
  • Tang et al. 2023 (J Assist Reprod Genet 40:2175–2184, PMID:37392306): a novel frameshift, p.Pro688Thrfs5, found among 35 MMAF men. The authors' literature review puts biallelic CFAP69* variants at about 2.5–5.7% of studied MMAF cohorts.
  • Mechanism class: Loss of function (truncating variants). All variants I found are germline.
  • Not found: modifier genes, epigenetic data, chromosomal abnormalities, ClinGen validity tier. DrugMap lists the evidence level as "limited". Check ClinGen directly with just list-gene-validity.

5. Environmental information

None known.

6. Mechanism and pathophysiology

Causal chain 1. Biallelic truncating CFAP69 variants cause loss of CFAP69 protein. Tang et al. showed reduced CFAP69 immunofluorescence in patient sperm. 2. CFAP69 is highly expressed in testis and localizes mainly to the sperm midpiece (Dong 2018, human and mouse). Its loss disrupts flagellar assembly and stability. 3. This leads to disrupted flagellar ultrastructure during spermiogenesis (TEM in Tang 2023; mouse data in Dong 2018 and He 2019). Inferred: the precise structural role of CFAP69 is not established in what I read, and I did not find a source describing a mitochondrial sheath role. 4. The result is MMAF and malformed heads. 5. Sperm are immotile or poorly motile, and the man is infertile.

Where the defect sits: In knockout mice, all stages of the seminiferous epithelium are present. Meiosis and earlier spermatogenesis are therefore preserved, and the lesion is in spermiogenesis (post-meiotic flagellum biogenesis). This differs from the meiotic arrest seen in many other SPGF subtypes.

Not found: pathway, transcriptomic, proteomic, immune or metabolic data.

Suggested ontology terms (to be looked up): - GO: sperm flagellum assembly; spermatid differentiation; cilium organization - CL: spermatid; spermatozoon - UBERON: testis; seminiferous tubule - GO CC: sperm midpiece; sperm flagellum

7. Anatomical structures affected

  • Organ and tissue: Testis and seminiferous epithelium. Spermatogenesis is otherwise preserved.
  • Cells: Elongating spermatids and spermatozoa.
  • Subcellular: Sperm flagellum, mainly the midpiece.
  • Laterality: Bilateral, as expected for a systemic germline defect, though sources do not state it.

8. Temporal development

Not described in the sources I retrieved. No data on onset, progression, remission or critical periods.

9. Inheritance and population

  • Inheritance: Autosomal recessive (LOVD; DrugMap). The HPO mode-of-inheritance term for autosomal recessive is to be looked up.
  • Expressivity: The disorder is male-limited. Carrier parents are presumably unaffected.
  • Prevalence: Not available. CFAP69 explains about 2.5–5.7% of MMAF cohorts (Tang 2023 review; He 2019: 2/35).
  • Population: Cases reported so far are largely Chinese cohorts.
  • Founder effect, carrier frequency, anticipation, mosaicism: Not found.

10. Diagnostics

  • Semen analysis: Severe asthenoteratozoospermia with MMAF morphology.
  • Electron microscopy: TEM shows aberrant axonemal and midpiece ultrastructure.
  • Immunofluorescence: Reduced or absent CFAP69 in sperm.
  • Genetic testing: Whole-exome sequencing or an MMAF gene panel, which is how all reported cases were found. Sanger sequencing confirms the variant.
  • Differential diagnosis: Other MMAF genes (e.g. DNAH1, CFAP43, CFAP44), primary ciliary dyskinesia, and other genes causing spermatogenic failure.
  • Not applicable or not found: screening programs, imaging, and any LOINC mapping. Search LOINC before binding any measurement.

11. Outcome and prognosis

  • Fertility: Natural conception is not expected.
  • Systemic outcomes: Not reported. No evidence of reduced life expectancy or other organ involvement in the sources I found.

12. Treatment

  • ICSI: The only evidence is a single couple in Tang 2023, who had a healthy girl by ICSI. The authors conclude ICSI is effective for affected couples. This is one case, not a rate, and should be curated that way.
  • Other: No pharmacotherapy, gene therapy or clinical trials found. Pharmacogenomics is not applicable.
  • Suggested NCIT terms (to be looked up):
  • An intracytoplasmic sperm injection or assisted reproduction term, if one exists in NCIT under Clinical Intervention or Procedure.
  • Genetic Counseling (NCIT:C15240, listed in CLAUDE.md).

13. Prevention

  • Genetic counseling and carrier testing of relatives (autosomal recessive).
  • Preimplantation or prenatal testing is theoretically available. I found no SPGF24-specific literature on it.

14. Other species

I found no OMIA entry or natural disease in other species.

15. Model organisms

  • Mouse: Two independent Cfap69 knockout lines, in Dong 2018 and He 2019 (CRISPR-Cas9). Males are sterile with MMAF-like flagellar defects. All stages of spermatogenesis are present, so the defect is in spermiogenesis.
  • Fidelity: Reported as recapitulating the human MMAF phenotype. Female phenotype and non-reproductive organs are not described in what I read. Per CLAUDE.md, this belongs in animal_models: with modeled_mechanisms.
  • Other resources: The Cyagen mouse atlas lists a knockout, and the Male Fertility Gene Atlas indexes the gene. I did not review IMPC or MGI.

Curation notes

  • Tier before curating: Three case reports plus two mouse knockouts is a thin evidence base. Check the ClinGen tier first.
  • Summaries only: I only saw summaries of the three key papers. The curator must confirm exact variant nomenclature, the Dong 2018 variants (not retrieved), semen parameters, and snippets from the cached abstracts.
  • Grading: Grade evidence_source by what each quote describes. Mouse knockout statements are MODEL_ORGANISM, even though the papers also contain human data.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 5
Resolved 5
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 5
On topic 5
Off topic 0

All extracted references resolved successfully.

Term Validation

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

Outcome Count
Terms checked 3
Resolved 3
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

Every term resolved, and every label the report gave matched.