Spermatogenic Failure 49

Mendelian MONDO:0030868 Pathograph 13 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 49 (SPGF49) is autosomal recessive male infertility caused by biallelic loss-of-function variants in CFAP58 (formerly C10orf80 or CCDC147), which encodes a testis-enriched cilia- and flagella-associated coiled-coil protein. CFAP58 runs along the whole sperm flagellum and is concentrated in the midpiece. Reported alleles are nonsense, frameshift and splice variants, and the protein is absent from patient sperm. Affected men have asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF). Electron microscopy shows a disorganized 9+2 axoneme, frequent loss of the central pair, damaged radial spokes and malformed mitochondrial and fibrous sheaths; axonemal markers SPAG6 and SPEF2 and the mitochondrial sheath protein HSP60 are reduced in sperm. Whether CFAP58 acts primarily in central pair assembly or at the junction between radial spokes and doublet microtubules is not settled. Cfap58 knockout and patient-allele knock-in mice reproduce MMAF, and knockout mice also show manchette and sperm head-shaping defects. No respiratory or other ciliary disease has been reported in patients. Fertilization, pregnancy and live births have been achieved with intracytoplasmic sperm injection (ICSI).

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Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic CFAP58 variants, homozygous or compound heterozygous; homozygous variants have co-segregated with MMAF in consanguineous Pakistani families.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:40675161 SUPPORT Human clinical
"We identify a novel homozygous mutation in the CFAP58 gene (c.562C > T, p. R188*) that co-segregates with the multiple morphological abnormalities of the flagella (MMAF) phenotype in two unrelated consanguineous families from Pakistan."
Recessive co-segregation in two consanguineous families.
PMID:32791035 SUPPORT Human clinical
"Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men."
Biallelic variants in five unrelated men.
⚙

Pathophysiology

4
Loss of CFAP58 Protein in Sperm
Biallelic truncating variants abolish CFAP58 in sperm. CFAP58 lies along the whole flagellum and is concentrated in the midpiece. It has no known enzymatic activity; human sperm studies place it at the connection between radial spokes and doublet microtubules, and mouse studies describe it as a stabilizer of intraflagellar and intramanchette transport cargo such as CCDC42. It is treated here as a structural component of the flagellum.
CFAP58 hgnc:26676 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFAP58 (hgnc:26676). hgnc:26676 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
Sperm Axoneme Disorganization with Central Pair and Radial Spoke Defects Without CFAP58 the radial spokes are damaged and the axoneme, including the central pair, is not stably assembled.
Sperm Mitochondrial Sheath Malformation Mitochondrial sheath defects accompany the axonemal lesion; whether they follow from CFAP58's midpiece localization or from the failed axoneme is not known.
Show evidence (3 references)
PMID:33314088 SUPPORT Human clinical
"The variants are rare and pathogenic, and CFAP58 was absent in the CFAP58-mutated sperm."
Protein absent from patient sperm.
PMID:32791035 SUPPORT Human clinical
"Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece."
Flagellar and midpiece localization in control sperm.
PMID:38602507 SUPPORT Model organism
"Moreover, it may be a transported cargo protein that plays a role in stabilizing other cargo proteins, such as CCDC42, in the intra-manchette transport/intra-flagellar transport pathway."
Mouse evidence for a stabilizing, non-enzymatic role.
Sperm Axoneme Disorganization with Central Pair and Radial Spoke Defects
The 9+2 axoneme is disrupted, the central pair is frequently lost, radial spokes are damaged and accessory structures are disorganized. Central pair (SPAG6) and C1b projection (SPEF2) markers are reduced in sperm. One study of a patient allele in knock-in mice describes a failure of central pair assembly during spermiogenesis; another, in human sperm, places the primary lesion at the radial spoke-doublet interface.
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 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.
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. Radial spoke GO:0001534 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Radial spoke (GO:0001534). GO:0001534 is a cellular component from the Gene Ontology.
Animal models
Cfap58 p.R188* knock-in mouse Mouse recapitulates The knock-in reproduces central pair loss and MMAF.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella
Abnormal sperm axoneme morphology
Absent sperm axoneme central pair complex
Show evidence (3 references)
PMID:42799967 SUPPORT Human clinical
"Ultrastructural analysis showed disruption of the "9 + 2" axoneme, loss of the central pair, and disorganization of accessory structures."
Axonemal disruption and central pair loss in patient sperm.
PMID:32791035 SUPPORT Human clinical
"Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants."
Reduced axonemal and mitochondrial sheath markers in patient sperm.
PMID:40675161 SUPPORT Model organism
"Transmission electron microscopy (TEM) analysis revealed the absence of the central pair (CP) of microtubules in the axonemal structure of sperm flagella."
Knock-in mice carrying the patient allele lack the central pair.
Sperm Mitochondrial Sheath Malformation
The mitochondrial sheath of the midpiece is malformed and the sheath protein HSP60 is reduced in patient sperm.
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 mitochondrial sheath assembly GO:0120317 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Sperm mitochondrial sheath assembly (GO:0120317). GO:0120317 is a biological process from the Gene Ontology.
Sperm mitochondrial sheath GO:0097226 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sperm mitochondrial sheath (GO:0097226). GO:0097226 is a cellular component from the Gene Ontology.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella
Show evidence (1 reference)
PMID:32791035 SUPPORT Human clinical
"Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations."
Mitochondrial sheath malformation in patient sperm.
Multiple Morphological Abnormalities of the Sperm Flagella
The semen phenotype: malformed, short, coiled or absent flagella with severely impaired motility.
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.
Animal models
Cfap58 knockout mouse Mouse recapitulates The knockout reproduces the human flagellar phenotype and male infertility.
Downstream
Reduced sperm motility
Male infertility Malformed, poorly motile sperm cannot reach or fertilize the oocyte in vivo.
Abnormal sperm tail morphology
Show evidence (2 references)
PMID:32791035 SUPPORT Human clinical
"Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes."
MMAF in all five probands.
PMID:42799967 SUPPORT Human clinical
"CFAP58-deficient sperm displayed classic MMAF phenotypes with severely impaired motility."
MMAF in three further men.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spermatogenic Failure 49 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

5
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:42799967 SUPPORT Human clinical
"Whole-exome sequencing was performed to identify pathogenic variants in three unrelated infertile men."
Infertile men with CFAP58 variants.
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:42799967 SUPPORT Human clinical
"CFAP58-deficient sperm displayed classic MMAF phenotypes with severely impaired motility."
Severely impaired motility.
Abnormal sperm tail morphology Reproductive HP:0012868 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Multiple morphological abnormalities of the sperm flagella, annotated with Abnormal sperm tail morphology (HP:0012868). HP:0012868 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:32791035 SUPPORT Human clinical
"Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes."
MMAF in all five probands.
PMID:33314088 SUPPORT Human clinical
"In this study, whole-exome sequencing was conducted on 55 patients with MMAF, and biallelic mutations of CFAP58 were identified in two patients."
Two further MMAF patients.
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:42799967 SUPPORT Human clinical
"Ultrastructural analysis showed disruption of the "9 + 2" axoneme, loss of the central pair, and disorganization of accessory structures."
Axonemal disruption on TEM.
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 (2 references)
PMID:42799967 SUPPORT Human clinical
"Ultrastructural analysis showed disruption of the "9 + 2" axoneme, loss of the central pair, and disorganization of accessory structures."
Central pair loss in patient sperm.
PMID:34089056 SUPPORT INDIRECT Human clinical
"Panel F (ARG5) corresponds to a distal section of the tail principal piece. The axoneme is 9 + 0 (lack of central pair)."
9+0 axoneme in a homozygous CFAP58 stop-gain patient whose causality the authors left open.
🧬

Genetic Associations

1
CFAP58 (Causal)
Gene: CFAP58 hgnc:26676 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFAP58 (hgnc:26676). hgnc:26676 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (4 references)
PMID:32791035 SUPPORT Human clinical
"Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men."
Primary gene-disease report.
PMID:33314088 SUPPORT Human clinical
"In this study, whole-exome sequencing was conducted on 55 patients with MMAF, and biallelic mutations of CFAP58 were identified in two patients."
Independent replication.
PMID:40675161 SUPPORT Human clinical
"We identify a novel homozygous mutation in the CFAP58 gene (c.562C > T, p. R188*) that co-segregates with the multiple morphological abnormalities of the flagella (MMAF) phenotype in two unrelated consanguineous families from Pakistan."
Replication in a different population.
+ 1 more reference
💊

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. One couple from the first replication cohort benefited from ICSI, and a later series reported fertilization and pregnancy with CFAP58-deficient sperm despite profound axonemal defects.
Mechanism Target:
Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar form and motility irrelevant to fertilization.
Show evidence (1 reference)
PMID:42799967 SUPPORT Human clinical
"Notably, despite profound structural defects, fertilization and pregnancy were successfully achieved through ICSI using CFAP58-deficient sperm."
ICSI bypasses the flagellar defect.
Show evidence (2 references)
PMID:33314088 SUPPORT Human clinical
"The F037/II:1 couple benefited from intracytoplasmic sperm injection (ICSI)."
Successful ICSI in a CFAP58 couple.
PMID:42799967 SUPPORT Human clinical
"Notably, despite profound structural defects, fertilization and pregnancy were successfully achieved through ICSI using CFAP58-deficient sperm."
Fertilization and pregnancy after ICSI in a second series.
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 CFAP58 alleles are known.
Show evidence (2 references)
PMID:40675161 SUPPORT Human clinical
"suggests that CFAP58 can serve as a genetic screening marker in the diagnosis and genetic counseling of MMAF and male infertility"
The authors name genetic counseling as the application.
PMID:32791035 SUPPORT Human clinical
"This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia."
A second group drawing the same conclusion.
🔬

Diagnosis

3
Molecular Genetic Testing
Establishes the diagnosis. Probands have been identified by whole-exome sequencing; MMAF is genetically heterogeneous, so semen findings alone cannot name the gene.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:33314088 SUPPORT Human clinical
"In this study, whole-exome sequencing was conducted on 55 patients with MMAF, and biallelic mutations of CFAP58 were identified in two patients."
Whole-exome sequencing identified the causal alleles.
Semen Analysis
Shows asthenoteratozoospermia with MMAF.
Show evidence (1 reference)
PMID:42799967 SUPPORT Human clinical
"CFAP58-deficient sperm displayed classic MMAF phenotypes with severely impaired motility."
Semen findings in affected men.
Transmission Electron Microscopy of Sperm Flagella
Shows disrupted axonemes, frequent central pair loss and malformed mitochondrial sheath.
Transmission Electron Microscopy NCIT:C18216 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:32791035 SUPPORT Human clinical
"Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations."
TEM findings in patient sperm.
🐁

Animal Models

2
Cfap58 knockout mouse
Male Cfap58 knockout mice are infertile with severe flagellar defects. A second knockout also showed abnormal manchette structure, misshapen sperm heads and increased sperm apoptosis.
Species
Mouse
Genotype
Cfap58-/- (CRISPR-Cas9 knockout), homozygous
Publication
PMID:32791035
Pathograph links
Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high observes: cellular The knockout reproduces the human flagellar phenotype and male infertility.
Limitations: Knockout mice also show manchette and head-shaping defects and sperm apoptosis that have not been described in patients.
Divergences from the human mechanism
species mismatch qualifying
Head shaping in mouse spermatids produces a hooked head, so the manchette-dependent head defect in knockout mice may not have a human counterpart; patient reports describe flagellar rather than head defects.
Show evidence (2 references)
PMID:32791035 SUPPORT Model organism
"The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men."
Knockout recapitulates human MMAF.
+ 1 more reference
Cfap58 p.R188* knock-in mouse
Mice homozygous for an allele mimicking the Pakistani patient stop-gain are infertile with MMAF and sperm axonemes lacking the central pair.
Species
Mouse
Genotype
Cfap58 M/M (homozygous knock-in mimicking the patient p.R188* allele)
Publication
PMID:40675161
Pathograph links
Sperm Axoneme Disorganization with Central Pair and Radial Spoke Defects recapitulates fidelity: high observes: cellular The knock-in reproduces central pair loss and MMAF.
Limitations: The central pair assembly mechanism was shown in mice; a separate study of human sperm emphasizes the radial spoke-doublet interface, so which structure fails first is not settled.
Divergences from the human mechanism
contested assumption qualifying
The knock-in study frames central pair assembly as the primary lesion, while human sperm data attribute the axonemal instability to radial spoke damage at the doublet interface.
Show evidence (2 references)
PMID:40675161 SUPPORT Model organism
"The Cfap58M/M mice exhibited infertility and recapitulated the MMAF phenotype observed in human patients."
The patient-allele mouse reproduces the human phenotype.
+ 1 more reference
{ }

Source YAML

click to show 
name: Spermatogenic Failure 49
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF49
- spermatogenic failure 49
- CFAP58-related multiple morphological abnormalities of the sperm flagella
- CFAP58-related asthenoteratozoospermia
description: >-
  Spermatogenic failure 49 (SPGF49) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in CFAP58 (formerly C10orf80
  or CCDC147), which encodes a testis-enriched cilia- and flagella-associated
  coiled-coil protein. CFAP58 runs along the whole sperm flagellum and is
  concentrated in the midpiece. Reported alleles are nonsense, frameshift and
  splice variants, and the protein is absent from patient sperm.

  Affected men have asthenoteratozoospermia with multiple morphological
  abnormalities of the sperm flagella (MMAF). Electron microscopy shows a
  disorganized 9+2 axoneme, frequent loss of the central pair, damaged radial
  spokes and malformed mitochondrial and fibrous sheaths; axonemal markers
  SPAG6 and SPEF2 and the mitochondrial sheath protein HSP60 are reduced in
  sperm. Whether CFAP58 acts primarily in central pair assembly or at the
  junction between radial spokes and doublet microtubules is not settled.
  Cfap58 knockout and patient-allele knock-in mice reproduce MMAF, and
  knockout mice also show manchette and sperm head-shaping defects. No
  respiratory or other ciliary disease has been reported in patients.
  Fertilization, pregnancy and live births have been achieved with
  intracytoplasmic sperm injection (ICSI).
disease_term:
  preferred_term: spermatogenic failure 49
  term:
    id: MONDO:0030868
    label: spermatogenic failure 49
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 619144. ClinGen has no
  gene-disease validity classification for CFAP58: the ClinGen gene-validity
  export snapshot of 2026-10-14 (data/clingen/gene_validity.csv) has no CFAP58
  row, and no GeneReviews chapter covers this disease (Bookshelf index
  snapshot 2026-09-10). Primary reports cited here (PMID:32791035,
  PMID:33314088, PMID:40675161, PMID:42799967) are cached as abstracts only;
  PMID:34089056 is full text. The genotype of each reported family is
  therefore not recorded variant by variant. A homozygous CFAP58 stop-gain
  (p.Gln454*) found in a consanguineous Argentinian patient with dysplasia of
  the fibrous sheath is relatively common in Ashkenazi Jewish gnomAD samples,
  and the authors left its causality open.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic CFAP58 variants, homozygous or compound
    heterozygous; homozygous variants have co-segregated with MMAF in
    consanguineous Pakistani families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:40675161
    reference_title: "A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify a novel homozygous mutation in the CFAP58 gene (c.562C > T, p. R188*) that co-segregates with the multiple morphological abnormalities of the flagella (MMAF) phenotype in two unrelated consanguineous families from Pakistan."
    explanation: Recessive co-segregation in two consanguineous families.
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men."
    explanation: Biallelic variants in five unrelated men.
pathophysiology:
- name: Loss of CFAP58 Protein in Sperm
  description: >-
    Biallelic truncating variants abolish CFAP58 in sperm. CFAP58 lies along
    the whole flagellum and is concentrated in the midpiece. It has no known
    enzymatic activity; human sperm studies place it at the connection between
    radial spokes and doublet microtubules, and mouse studies describe it as
    a stabilizer of intraflagellar and intramanchette transport cargo such as
    CCDC42. It is treated here as a structural component of the flagellum.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP58
    term:
      id: hgnc:26676
      label: CFAP58
  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: Sperm Axoneme Disorganization with Central Pair and Radial Spoke Defects
    causal_link_type: DIRECT
    description: Without CFAP58 the radial spokes are damaged and the axoneme, including the central pair, is not stably assembled.
    evidence:
    - reference: PMID:42799967
      reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mechanistically, CFAP58 may contribute to the structural connection between radial spokes (RS) and doublet microtubules (DMTs); its absence leads to RS damage and axonemal instability."
      explanation: Radial spoke damage and axonemal instability in CFAP58-deficient human sperm.
  - target: Sperm Mitochondrial Sheath Malformation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Mitochondrial sheath defects accompany the axonemal lesion; whether
      they follow from CFAP58's midpiece localization or from the failed
      axoneme is not known.
  evidence:
  - reference: PMID:33314088
    reference_title: "Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The variants are rare and pathogenic, and CFAP58 was absent in the CFAP58-mutated sperm."
    explanation: Protein absent from patient sperm.
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece."
    explanation: Flagellar and midpiece localization in control sperm.
  - reference: PMID:38602507
    reference_title: "CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, it may be a transported cargo protein that plays a role in stabilizing other cargo proteins, such as CCDC42, in the intra-manchette transport/intra-flagellar transport pathway."
    explanation: Mouse evidence for a stabilizing, non-enzymatic role.
- name: Sperm Axoneme Disorganization with Central Pair and Radial Spoke Defects
  description: >-
    The 9+2 axoneme is disrupted, the central pair is frequently lost, radial
    spokes are damaged and accessory structures are disorganized. Central pair
    (SPAG6) and C1b projection (SPEF2) markers are reduced in sperm. One study
    of a patient allele in knock-in mice describes a failure of central pair
    assembly during spermiogenesis; another, in human sperm, places the
    primary lesion at the radial spoke-doublet interface.
  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: Radial spoke
    term:
      id: GO:0001534
      label: radial spoke
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  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:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural analysis showed disruption of the \"9 + 2\" axoneme, loss of the central pair, and disorganization of accessory structures."
    explanation: Axonemal disruption and central pair loss in patient sperm.
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants."
    explanation: Reduced axonemal and mitochondrial sheath markers in patient sperm.
  - reference: PMID:40675161
    reference_title: "A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Transmission electron microscopy (TEM) analysis revealed the absence of the central pair (CP) of microtubules in the axonemal structure of sperm flagella."
    explanation: Knock-in mice carrying the patient allele lack the central pair.
- name: Sperm Mitochondrial Sheath Malformation
  description: >-
    The mitochondrial sheath of the midpiece is malformed and the sheath
    protein HSP60 is reduced in patient sperm.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Sperm mitochondrial sheath
    term:
      id: GO:0097226
      label: sperm mitochondrial sheath
  biological_processes:
  - preferred_term: Sperm mitochondrial sheath assembly
    modifier: DECREASED
    term:
      id: GO:0120317
      label: sperm mitochondrial sheath assembly
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations."
    explanation: Mitochondrial sheath malformation in patient sperm.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The semen phenotype: malformed, short, coiled or absent flagella with
    severely impaired motility.
  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, poorly motile sperm cannot reach or fertilize the oocyte in vivo.
  - target: Abnormal sperm tail morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes."
    explanation: MMAF in all five probands.
  - reference: PMID:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP58-deficient sperm displayed classic MMAF phenotypes with severely impaired motility."
    explanation: MMAF in three further men.
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:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole-exome sequencing was performed to identify pathogenic variants in three unrelated infertile men."
    explanation: Infertile men with CFAP58 variants.
- category: Reproductive
  name: Reduced sperm motility
  description: Motility is severely impaired.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP58-deficient sperm displayed classic MMAF phenotypes with severely impaired motility."
    explanation: Severely impaired motility.
- category: Reproductive
  name: Abnormal sperm tail morphology
  description: >-
    MMAF: a mixture of malformed flagella. The available abstracts report the
    phenotype as typical MMAF without breaking it down into absent, short,
    coiled, bent and irregular flagella, so the specific flagellar terms are
    not bound here.
  phenotype_term:
    preferred_term: Multiple morphological abnormalities of the sperm flagella
    term:
      id: HP:0012868
      label: Abnormal sperm tail morphology
  evidence:
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes."
    explanation: MMAF in all five probands.
  - reference: PMID:33314088
    reference_title: "Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, whole-exome sequencing was conducted on 55 patients with MMAF, and biallelic mutations of CFAP58 were identified in two patients."
    explanation: Two further MMAF patients.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: The 9+2 axoneme is disrupted with disorganized accessory structures.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural analysis showed disruption of the \"9 + 2\" axoneme, loss of the central pair, and disorganization of accessory structures."
    explanation: Axonemal disruption on TEM.
- category: Reproductive
  name: Absent sperm axoneme central pair complex
  description: The central pair is frequently missing.
  phenotype_term:
    preferred_term: Absent sperm axoneme central pair complex
    term:
      id: HP:0033525
      label: Absent sperm axoneme central pair complex
  evidence:
  - reference: PMID:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural analysis showed disruption of the \"9 + 2\" axoneme, loss of the central pair, and disorganization of accessory structures."
    explanation: Central pair loss in patient sperm.
  - reference: PMID:34089056
    reference_title: "Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Panel F (ARG5) corresponds to a distal section of the tail principal piece. The axoneme is 9 + 0 (lack of central pair)."
    explanation: 9+0 axoneme in a homozygous CFAP58 stop-gain patient whose causality the authors left open.
genetic:
- name: CFAP58
  association: Causal
  gene_term:
    preferred_term: CFAP58
    term:
      id: hgnc:26676
      label: CFAP58
  notes: >-
    Reported alleles are biallelic loss-of-function variants, including the
    homozygous stop-gain c.562C>T (p.Arg188*) in two consanguineous Pakistani
    families. Biallelic CFAP58 variants accounted for 5.6% (5/90) and 3.6%
    (2/55) of two Chinese MMAF cohorts. ClinGen has not classified this
    gene-disease pair, so no validity tier is recorded.
  evidence:
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men."
    explanation: Primary gene-disease report.
  - reference: PMID:33314088
    reference_title: "Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, whole-exome sequencing was conducted on 55 patients with MMAF, and biallelic mutations of CFAP58 were identified in two patients."
    explanation: Independent replication.
  - reference: PMID:40675161
    reference_title: "A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify a novel homozygous mutation in the CFAP58 gene (c.562C > T, p. R188*) that co-segregates with the multiple morphological abnormalities of the flagella (MMAF) phenotype in two unrelated consanguineous families from Pakistan."
    explanation: Replication in a different population.
  - reference: PMID:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three novel CFAP58 loss-of-function variants were identified."
    explanation: Further loss-of-function alleles in three men.
animal_models:
- name: Cfap58 knockout mouse
  species: Mouse
  genotype: Cfap58-/- (CRISPR-Cas9 knockout), homozygous
  publication: PMID:32791035
  description: >-
    Male Cfap58 knockout mice are infertile with severe flagellar defects. A
    second knockout also showed abnormal manchette structure, misshapen sperm
    heads and increased sperm apoptosis.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The knockout reproduces the human flagellar phenotype and male infertility.
    limitations: >-
      Knockout mice also show manchette and head-shaping defects and sperm
      apoptosis that have not been described in patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Head shaping in mouse spermatids produces a hooked head, so the
        manchette-dependent head defect in knockout mice may not have a human
        counterpart; patient reports describe flagellar rather than head
        defects.
    evidence:
    - reference: PMID:32791035
      reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men."
      explanation: Knockout recapitulates human MMAF.
    - reference: PMID:38602507
      reference_title: "CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Moreover, by generating gene knockout mice, we found for the first time that the loss of Cfap58 not only causes severe defects in the sperm tail, but also affects the manchette structure, resulting in abnormal sperm head shaping."
      explanation: Second knockout with tail and head defects.
- name: Cfap58 p.R188* knock-in mouse
  species: Mouse
  genotype: Cfap58 M/M (homozygous knock-in mimicking the patient p.R188* allele)
  publication: PMID:40675161
  description: >-
    Mice homozygous for an allele mimicking the Pakistani patient stop-gain
    are infertile with MMAF and sperm axonemes lacking the central pair.
  modeled_mechanisms:
  - target: Sperm Axoneme Disorganization with Central Pair and Radial Spoke Defects
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The knock-in reproduces central pair loss and MMAF.
    limitations: >-
      The central pair assembly mechanism was shown in mice; a separate study
      of human sperm emphasizes the radial spoke-doublet interface, so which
      structure fails first is not settled.
    divergences:
    - divergence_type: CONTESTED_ASSUMPTION
      materiality: QUALIFYING
      description: >-
        The knock-in study frames central pair assembly as the primary lesion,
        while human sperm data attribute the axonemal instability to radial
        spoke damage at the doublet interface.
    evidence:
    - reference: PMID:40675161
      reference_title: "A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The Cfap58M/M mice exhibited infertility and recapitulated the MMAF phenotype observed in human patients."
      explanation: The patient-allele mouse reproduces the human phenotype.
    - reference: PMID:40675161
      reference_title: "A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Transmission electron microscopy (TEM) analysis revealed the absence of the central pair (CP) of microtubules in the axonemal structure of sperm flagella."
      explanation: Central pair loss in knock-in sperm.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect. One couple from the first replication
    cohort benefited from ICSI, and a later series reported fertilization and
    pregnancy with CFAP58-deficient sperm despite profound axonemal defects.
  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 makes flagellar form and motility irrelevant to fertilization.
    evidence:
    - reference: PMID:42799967
      reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Notably, despite profound structural defects, fertilization and pregnancy were successfully achieved through ICSI using CFAP58-deficient sperm."
      explanation: ICSI bypasses the flagellar defect.
  evidence:
  - reference: PMID:33314088
    reference_title: "Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The F037/II:1 couple benefited from intracytoplasmic sperm injection (ICSI)."
    explanation: Successful ICSI in a CFAP58 couple.
  - reference: PMID:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, despite profound structural defects, fertilization and pregnancy were successfully achieved through ICSI using CFAP58-deficient sperm."
    explanation: Fertilization and pregnancy after ICSI in a second series.
- name: Genetic Counseling
  description: >-
    Counselling on autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP58 alleles are known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:40675161
    reference_title: "A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggests that CFAP58 can serve as a genetic screening marker in the diagnosis and genetic counseling of MMAF and male infertility"
    explanation: The authors name genetic counseling as the application.
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia."
    explanation: A second group drawing the same conclusion.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Probands have been identified by whole-exome
    sequencing; MMAF is genetically heterogeneous, so semen findings alone
    cannot name the gene.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:33314088
    reference_title: "Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, whole-exome sequencing was conducted on 55 patients with MMAF, and biallelic mutations of CFAP58 were identified in two patients."
    explanation: Whole-exome sequencing identified the causal alleles.
- name: Semen Analysis
  description: Shows asthenoteratozoospermia with MMAF.
  evidence:
  - reference: PMID:42799967
    reference_title: "CFAP58-deficient human sperm show radial spoke-doublet microtubule interface abnormalities and successful fertilization by ICSI."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP58-deficient sperm displayed classic MMAF phenotypes with severely impaired motility."
    explanation: Semen findings in affected men.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Shows disrupted axonemes, frequent central pair loss and malformed
    mitochondrial sheath.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:32791035
    reference_title: "Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations."
    explanation: TEM findings in patient sperm.
📚

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 49 (CFAP58) · 2026-10-16T13:40:58Z · View source

New entry for spermatogenic failure 49 (MONDO:0030868), CFAP58-related MMAF. Deep research with the claude_code provider (research/Spermatogenic_Failure_49-deep-research-claude_code.md); just preflight-dr returned PASS for CFAP58. Snippets taken from references_cache only; the primary CFAP58 papers are cached as abstracts, so per-feature flagellar HP terms were not bound and MMAF is recorded as Abnormal sperm tail morphology. Chain: loss of CFAP58 (structural molecule activity, decreased; midpiece) -> axoneme disorganization with central pair and radial spoke defects, plus mitochondrial sheath malformation -> MMAF -> infertility. The disagreement between central-pair assembly (knock-in mouse) and radial spoke-doublet interface (human sperm) is recorded in the node description and as a CONTESTED_ASSUMPTION divergence on the knock-in model. ICSI success recorded from two series. ClinGen has no CFAP58 curation and no GeneReviews chapter exists. Stub stubs/Spermatogenic_Failure_49.yaml deleted. Validated with the full gate list and validate-disorders.

Claude Code ▸
Research Report: Spermatogenic Failure 49 (SPGF49; MONDO:0030868)
claude-haiku-5-5, claude-sonnet-5-5 7 citations 2026-10-16T13:14:36.464902

Fetching the two key CFAP58 papers into the reference cache so I can quote their abstracts exactly.

Research Report: Spermatogenic Failure 49 (SPGF49; MONDO:0030868)

Limits of this report. I could not read the full text of any primary paper. PMC and PubMed returned CAPTCHA and cookie pages. A just fetch-reference call also needed approval that was not granted, so nothing was added to references_cache/.

  • Bibliographic details and findings below come from search snippets and Europe PMC record summaries. They are not exact abstract quotes.
  • Paraphrases need replacing with verified snippets (just fetch-reference PMID:…, then just count-verified-snippets) before they go into any evidence block.
  • No ontology CURIEs other than the MONDO ID are given. The repo rules forbid writing CURIEs from memory, so each suggested term below is a name to look up.
  • kb/disorders/Spermatogenic_Failure_49.yaml already exists as an 8-line skeleton: name, category and disease_term only. stubs/Spermatogenic_Failure_49.yaml is still present and should be deleted by the curation PR.

1. Disease information

SPGF49 is an autosomal recessive form of male infertility. It is caused by biallelic loss-of-function variants in CFAP58, and sperm show multiple morphological abnormalities of the flagella (MMAF), a severe asthenoteratozoospermia.

  • Identifiers: MONDO:0030868 (from the stub); OMIM #619144 (LOVD disease record).
  • Synonyms: SPGF49. SPGF98 appears as a synonym in Disease Ontology (DOID:0112271, Glycosmos). The MMAF label is a phenotype descriptor, not a separate disease name.
  • Source level: aggregated, from case series and cohorts. No EHR-derived data were found.
  • Not located: Orphanet, ICD-10/11 and MeSH mappings. These need a direct check.

2. Etiology

  • Causal factor: genetic. CFAP58 (10q25.1) is the only gene associated with this OMIM entry (LOVD).
  • Discovery: He et al. 2020, AJHG, PMID:32791035. Whole-exome sequencing of 90 Chinese MMAF men found biallelic loss-of-function CFAP58 variants in 5 unrelated men (5.6%).
  • Replication: Sha et al. 2021, Clin Genet 99(3):443–448, PMID:33314088. Biallelic CFAP58 variants were found in 2 of 55 MMAF men, and CFAP58 protein was absent from their sperm.
  • Modifier genes, protective factors, gene–environment interactions: none reported in what I found.

3. Phenotypes

Phenotype (look up HPO term) Evidence
Male infertility He 2020; Sha 2021
Asthenozoospermia / absent or reduced progressive motility He 2020
Teratozoospermia, specifically MMAF (short, coiled, bent, absent or irregular flagella) He 2020; OMIM-derived summaries
Axonemal disorganization and mitochondrial sheath malformation on TEM He 2020
  • Frequency: all five He 2020 probands were reported to have typical MMAF, so the penetrance of the sperm phenotype is effectively complete in affected males.
  • Not retrieved: per-patient percentages of each flagellar morphology, semen parameters, and variant-level details (cDNA and protein changes).
  • Onset and progression: not described. Infertility is detected in adulthood on presentation.
  • Syndromic features: I found none reported. Cilia-related disease, such as primary ciliary dyskinesia or situs abnormalities, is not described in these cohorts, but I did not confirm absence from full text.
  • Quality of life: not reported.

4. Genetic and molecular information

  • Gene: CFAP58 (cilia- and flagella-associated protein 58), 10q25.1. Look up the HGNC ID in the lowercase hgnc: form and check it with just validate-terms.
  • Variants: loss-of-function alleles, shown in the human cohorts as bi-allelic (homozygous or compound heterozygous) variants. Specific variants were not retrieved. Pull them from the full text of PMID:32791035 and PMID:33314088, and from ClinVar.
  • Functional consequence: loss of function. Sperm from affected men lack or have reduced CFAP58 protein (Sha 2021).
  • Not retrieved: population allele frequencies and ClinGen gene–disease validity tier. Run just list-gene-validity and check ClinGen for a CGGV record before adding any tier.
  • Epigenetic and chromosomal abnormalities: none known.

5. Environmental information

No environmental, lifestyle or infectious contributors are reported. Leave the environmental: section absent.

6. Mechanism and pathophysiology

Causal chain:

  1. Biallelic loss-of-function variants in CFAP58 reduce or abolish CFAP58 protein in the germline. This is demonstrated in patient sperm, which lack the protein (Sha 2021).
  2. CFAP58 is a testis-enriched protein that localizes along the flagellum and concentrates in the midpiece. Without it, the axoneme and mitochondrial sheath assemble abnormally during spermiogenesis.
  3. Sperm from affected men show lower levels of the axonemal markers SPAG6 and SPEF2 and of the mitochondrial sheath protein HSP60. TEM shows axonemal and mitochondrial sheath malformations (He 2020).
  4. Flagella are short, coiled, bent or absent, so sperm have little or no progressive motility.
  5. The result is asthenoteratozoospermia and male infertility.

Branches and inferred steps:

  • Manchette and head shaping. A later review reports that knockout mice also have abnormal sperm head shaping linked to manchette impairment, plus increased sperm apoptosis. I did not see this in the original papers, so check it before curating.
  • Interactors. Cfap58 is reported to interact with IFT88 and CCDC42. This comes from a review, so verify it in primary papers.
  • Centriole link (in vitro only). In cultured cells, Cfap58 localizes like the mother-centriole protein Odf2/Cenexin. It is needed for primary cilium elongation and is linked to Notch signaling (PMC6970087). Whether this operates in human spermatogenesis is inferred, not shown.
  • Suggested terms to look up: GO sperm flagellum assembly, axoneme assembly and mitochondrial sheath organization; GO cellular components sperm flagellum, axoneme and sperm midpiece; CL terms for spermatid and spermatozoon.
  • Not found: transcriptomic, proteomic or single-cell studies in patients.

7. Anatomical structures affected

  • Organ and tissue: testis (seminiferous epithelium) and male reproductive tract; the germ-cell lineage, in particular elongating spermatids.
  • Subcellular: sperm flagellum, axoneme, mitochondrial sheath and midpiece.
  • Lateralization: not applicable.

8. Temporal development

Onset is not defined beyond adult presentation with infertility. No progression, remission or critical-period data were found.

9. Inheritance and population

  • Inheritance: autosomal recessive (OMIM #619144).
  • Population: the two published cohorts are both Chinese. Prevalence is unknown. Frequencies of 5.6% (5/90) and about 3.6% (2/55) of MMAF cohorts are cohort-specific rates, not population prevalence.
  • Sex ratio: affected males only. Female carriers are not reported to be affected.
  • Not retrieved: founder variants, carrier frequency and consanguinity details.

10. Diagnostics

  • Semen analysis shows asthenoteratozoospermia with an MMAF morphology.
  • Sperm TEM shows axonemal and mitochondrial sheath defects.
  • Immunofluorescence or western blot can show reduced CFAP58, SPAG6, SPEF2 and HSP60 in sperm.
  • Genetic testing: whole-exome sequencing was how both cohorts found the gene. In practice a male-infertility or MMAF gene panel including CFAP58 would be used.
  • Differential diagnosis: other MMAF genes, such as DNAH1, CFAP43, CFAP44, FSIP2 and SPEF2. Primary ciliary dyskinesia should be excluded on clinical grounds.
  • Not retrieved: LOINC codes. Look these up with the repo's LOINC workflow if you add semen-analysis measurements.

11. Outcome and prognosis

Not studied beyond fertility. No survival or morbidity data were found. Prognosis for natural conception is poor, and assisted reproduction is the relevant outcome (see section 12).

12. Treatment

  • No disease-specific drug or gene therapy was found.
  • Assisted reproduction: Sha 2021 reports that one couple had a successful outcome with ICSI, and its authors conclude that ICSI is an effective treatment. With one couple, this cannot be generalized.
  • Related context: an MMAF cohort of 38 men with other causal genes had lower fertilization, blastocyst formation and cumulative pregnancy rates after ICSI than an oligoasthenospermia comparison group, with no difference in neonatal outcomes (Front Endocrinol 2024). It did not include CFAP58 cases, so do not attribute it to this disease.
  • Clinical trials: none searched. Check ClinicalTrials.gov before adding any.
  • Suggested NCIT terms to look up: an in vitro fertilization or intracytoplasmic sperm injection procedure, and genetic counseling.

13. Prevention

  • Genetic counseling is relevant because the condition is recessive.
  • Preimplantation genetic testing is theoretically applicable. I found no source specific to CFAP58.
  • No other prevention measures apply.

14. Other species and natural disease

I did not search OMIA, so I cannot say whether a natural animal disease is known. Leave this section absent unless a search finds one.

15. Model organisms

  • Mouse Cfap58 knockout (CRISPR/Cas9), He 2020: infertile males with severe flagellar defects (short, bent and similar), matching the MMAF sperm phenotype. This is MODEL_ORGANISM evidence and supports the loss-of-function mechanism with good fidelity for the sperm phenotype.
  • Cultured cells: Cfap58 and Odf2 localization, and the primary cilium and Notch link (PMC6970087). This is IN_VITRO evidence.
  • Not checked: MGI/IMPC records and zebrafish or other models.

Curation notes for the entry

  • The only primary clinical citations found are PMID:32791035 and PMID:33314088. Fetch them with just fetch-reference, then copy exact snippets and variant details from the cached text.
  • Classify evidence sources as HUMAN_CLINICAL for the cohorts and MODEL_ORGANISM for the knockout mouse, splitting items where a paper mixes the two.
  • An earlier search surfaced a related paper on a different gene, CFAP251 (Frontiers in Genetics 2021, DOI 10.3389/fgene.2021.783790). Do not cite it for CFAP58.

Sources: - LOVD disease record, SPGF49 (OMIM:619144) - He et al. 2020, AJHG (PMC7477015) - Sha et al. 2021, Clin Genet - Cfap58/Odf2 cell study (PMC6970087) - Glycosmos DOID:0112271 - Frontiers in Endocrinology 2024, MMAF ICSI cohort - Frontiers in Genetics 2021, CFAP251 case

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 6
Resolved 6
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 6
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 2
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1

Prefixes with no resolver

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

2 of 3 terms resolved to a current term; the rest could not be looked up either way.