Spermatogenic Failure 84

Mendelian MONDO:0957301 Pathograph 16 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 84 (SPGF84) is autosomal recessive male infertility caused by biallelic variants in CFAP61. CFAP61 is a subunit of the calmodulin- and spoke-associated complex (CSC), which with CFAP91 and CFAP251 builds the base of radial spoke 3 (RS3); CFAP61 forms part of the RS3 stem and also binds the radial spoke stalk and head. Without it, radial spoke components fail to assemble in spermatids, CFAP251 is lost from the flagellum, and the axoneme becomes unstable and scatters as spermiogenesis proceeds. Affected men have asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF): absent, short, coiled, bent and irregular-caliber flagella. Electron microscopy shows disorganized axonemes with loss of the central pair, radial spokes and inner dynein arms. Sperm concentration is usually normal, but compound heterozygous missense carriers have presented with oligoasthenoteratozoospermia, and one patient had defective sperm chromatin condensation. Respiratory and other ciliary symptoms are absent. ICSI with ejaculated sperm has produced a live birth, but one couple had poor embryo development.

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Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic CFAP61 variants: homozygous truncating and splice variants in consanguineous families, and compound heterozygous missense and splice variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:35174165 SUPPORT Human clinical
"Subsequent Sanger sequencing of all the available family members confirmed that the CFAP61 variants were recessively inherited from their heterozygous parents except P11 whose sperm morphology was not yet assessed (Figures 1C–E)."
Recessive segregation in three consanguineous families.
◈

Mechanistic Hypotheses

1
CFAP61 loss causes isolated male infertility without primary ciliary dyskinesia
cfap61_sperm_restricted CANONICAL
Evidence balance 2 support 1 refute
Patients in three Pakistani families were questioned for PCD features and had none, and Cfap61 knockout mice are infertile without PCD-like symptoms. The organ-specific axoneme stabilization role proposed for CFAP61 would explain why sperm, but not respiratory cilia, are affected. In Tetrahymena, loss of the orthologue does alter ciliary waveform, so a subtle ciliary defect in humans has not been excluded; no ciliary ultrastructure or nasal nitric oxide data from patients are available.
Show evidence (3 references)
PMID:35174165 SUPPORT Human clinical
"In this study, we recruited three unrelated Pakistani families, having 11 primary infertile individuals diagnosed with MMAF without manifesting any primary ciliary dyskinesia (PCD) symptoms."
No PCD symptoms in eleven affected men.
PMID:34792097 SUPPORT Model organism
"We generated Cfap61 knockout mice that recapitulate the infertility phenotype of the human CFAP61 mutation, but without other symptoms usually observed in PCD."
Knockout mice have no PCD-like phenotype.
PMID:25694453 REFUTE Model organism
"We show that in Tetrahymena, loss of either FAP61 or FAP251 reduces cell swimming and affects the ciliary waveform and that RS3 is either missing or incomplete, whereas RS1 and RS2 are unaffected."
In a ciliate, the orthologue is needed for normal ciliary beating.
⚙

Pathophysiology

4
Loss of CFAP61
Frameshift, nonsense and splice alleles remove or truncate CFAP61, and compound heterozygous missense alleles reduce it in sperm. CFAP61 is a structural CSC subunit at the base of radial spoke 3 that also interacts with the radial spoke stalk and head.
CFAP61 hgnc:15872 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFAP61 (hgnc:15872). hgnc:15872 is a gene from the HUGO Gene Nomenclature Committee.
structural constituent of the axonemal cytoskeleton GO:0005200 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased structural constituent of the axonemal cytoskeleton, annotated with structural constituent of cytoskeleton (GO:0005200). GO:0005200 is a molecular function from the Gene Ontology.
Radial spoke base 3 GO:0120342 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Radial spoke base 3 (GO:0120342). GO:0120342 is a cellular component from the Gene Ontology.
Downstream
Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme Without CFAP61 its CSC partner CFAP251 is absent from the sperm tail, and radial spoke components fail to assemble in developing spermatids.
Show evidence (3 references)
PMID:34792097 SUPPORT Model organism
"We find that CFAP61 interacts with the CSC, radial spoke stalk and head."
CFAP61 binds the CSC and radial spoke components.
PMID:35387802 SUPPORT Human clinical
"Further immunofluorescence assays revealed markedly reduced CFAP61 staining in the sperm flagella."
Compound heterozygous missense and splice alleles reduce CFAP61 in sperm.
PMID:38775994 SUPPORT Human clinical
"Using exome sequencing, we identified this variant, which led to exon 12 skipping and the production of a truncated CFAP61 protein."
A splice allele truncates the protein.
Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
The CSC (CFAP61, CFAP91 and CFAP251 with calmodulin) sits at the base of radial spoke 3 and links it to the doublet microtubules. Loss of any one subunit destabilizes the others: CFAP251 is absent from sperm of men with CFAP61 variants, and in Cfap61 knockout spermatids radial spoke assembly is impaired. In Tetrahymena, FAP61-null cilia lack part of the RS3 stem.
Radial spoke assembly GO:0062177 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Radial spoke assembly (GO:0062177). GO:0062177 is a biological process from the Gene Ontology.
Radial spoke 3 GO:0120335 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Radial spoke 3 (GO:0120335). GO:0120335 is a cellular component from the Gene Ontology.
Animal models
Cfap61 knockout mouse Mouse recapitulates Radial spoke assembly is impaired in knockout spermatids.
Downstream
Sperm Axonemal Disorganization Radial spokes anchor the central pair; without them the central pair rotates and is lost, and later in spermiogenesis the whole axoneme becomes unstable. How loss of one spoke base destabilizes the entire sperm axoneme is not established.
Show evidence (3 references)
PMID:34792097 SUPPORT Model organism
"During early stages of Cfap61-/- spermatid development, the assembly of radial spoke components is impaired."
Radial spoke assembly fails in knockout spermatids.
PMID:25694453 SUPPORT Model organism
"Specifically, FAP251-null cilia lack an arch-like density at the RS3 base, whereas FAP61-null cilia lack an adjacent portion of the RS3 stem region."
Cryo-electron tomography of Tetrahymena cilia places the orthologue in the RS3 stem.
PMID:35174165 SUPPORT Human clinical
"CFAP61 and CFAP251 signals were absent from sperm tails of the patients, which suggested the loss of functional CSC in sperm flagella."
Both CSC subunits are missing from patient sperm.
Sperm Axonemal Disorganization
Most flagellar cross-sections show severely disorganized axonemes with missing doublets, dynein arms, radial spokes and central pair; where a 9+2 arrangement remains, the central pair is often rotated. The central pair proteins SPAG6 and TSGA2 and the inner-arm heavy chain DNAH1 are lost. Mitochondrial sheath malformation and mitochondria trapped in residual cytoplasm are also reported.
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.
Axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology. 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. Inner dynein arm GO:0036156 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Inner dynein arm (GO:0036156). GO:0036156 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:35174165 SUPPORT Human clinical
"In our study, the patients carrying CFAP61 variants showed severe disorganizations of the axonemal structures with loss of CP, RSs, and IDAs, which was confirmed by IF staining of SPAG6, TSGA2, and DNAH1."
Central pair, radial spoke and inner-arm loss in patient sperm.
PMID:35387802 SUPPORT Human clinical
"Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants."
Central pair loss and mitochondrial sheath malformation with compound heterozygous alleles.
PMID:38775994 SUPPORT Human clinical
"Transmission electron microscopy analysis of the patient's spermatozoa revealed various flagellar abnormalities, including defective nuclear chromatin condensation, axoneme disorganization, and mitochondria embedded in residual cytoplasmic droplets."
Axoneme disorganization with a homozygous splice allele.
Multiple Morphological Abnormalities of the Sperm Flagella
Absent, short, coiled, bent and irregular-caliber flagella in the same ejaculate. Motility is reduced in nearly all patients; one man in the Pakistani families had normal motility on routine analysis despite the morphological defects.
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.
Animal models
Cfap61 knockout mouse Mouse recapitulates Knockout sperm have short, coiled and irregular flagella and impaired motility.
Downstream
Reduced sperm motility
Male infertility Malformed, poorly motile 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 (2 references)
PMID:35174165 SUPPORT Human clinical
"Here, we recruited three unrelated Pakistani families comprising of 11 infertile male patients diagnosed with MMAF."
MMAF in all affected men of three families.
PMID:34792097 SUPPORT Human clinical
"We find that a CFAP61 splice variant, c.143+5G>A, causes exon skipping/intron retention in human, inducing a multiple morphological abnormalities of the flagella (MMAF) phenotype."
MMAF with a homozygous splice allele.
⬡

Pathograph

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Pathograph: causal mechanism network for Spermatogenic Failure 84 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:35174165 SUPPORT Human clinical
"Altogether, our findings report that homozygous variants in CFAP61 are associated with MMAF and male infertility, demonstrating the essential role of this gene in normal sperm flagellum structure in humans."
Male infertility in homozygous carriers.
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:35174165 SUPPORT Human clinical
"However, all the patients had asthenozoospermia, with <40% sperm motility or <32% progressive motility, except for P8, whose sperm motility and progressive motility were found normal in the routine semen analysis (Table 1)."
Reduced motility in all but one patient.
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:35387802 SUPPORT Human clinical
"Our findings indicate that CFAP61 is essential for spermatogenesis and that biallelic CFAP61 variants lead to male infertility in humans and mice with OAT."
Oligoasthenoteratozoospermia in compound heterozygous carriers.
PMID:35174165 REFUTE Human clinical
"P3 had a low sperm concentration (6 million/ml) and sperm concentrations were all in the normal range for the rest of patients."
Low concentration is the exception in the largest family series.
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:35174165 SUPPORT Human clinical
"Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
Scanning electron microscopy of patient sperm.
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:35174165 SUPPORT Human clinical
"Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
Scanning electron microscopy of patient sperm.
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:35174165 SUPPORT Human clinical
"Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
Scanning electron microscopy of patient sperm.
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:35174165 SUPPORT Human clinical
"Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
Scanning electron microscopy of patient sperm.
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:35174165 SUPPORT Human clinical
"Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
Scanning electron microscopy of patient sperm.
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:35174165 SUPPORT Human clinical
"In contrast to the typical “9 + 2” axoneme arrangement in the spermatozoa from a fertile control, most of the flagellar cross-sections from spermatozoa of patients exhibited severely disorganized axoneme structure, along with the missings of MTDs, dynein arms, RSs, and/or CP (Figure 2A)."
Axonemal disorganization in patient sperm.
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:35387802 SUPPORT Human clinical
"Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants."
Central pair absence in patient sperm.
Abnormal sperm head morphology Reproductive HP:0012865 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal sperm head morphology (HP:0012865). HP:0012865 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38775994 SUPPORT Human clinical
"Furthermore, nearly half of the observed sperm heads displayed chromatin condensation defects, possibly contributing to the low blastulation rate."
Chromatin condensation defects in sperm heads.
🧬

Genetic Associations

1
CFAP61 (Causal)
Gene: CFAP61 hgnc:15872 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFAP61 (hgnc:15872). hgnc:15872 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (4 references)
PMID:35174165 SUPPORT Human clinical
"CFAP61 variants, c.451_452del (p.I151Nfs*4) in family 1 and c.847C > T (p.R283*) in family 2 and 3, were identified recessively co-segregating with the MMAF phenotype."
Homozygous truncating variants in three families.
PMID:34792097 SUPPORT Human clinical
"We find that a CFAP61 splice variant, c.143+5G>A, causes exon skipping/intron retention in human, inducing a multiple morphological abnormalities of the flagella (MMAF) phenotype."
Splice allele with knockout mouse support.
PMID:35387802 SUPPORT Human clinical
"We identified biallelic CFAP61 variants (NM_015585.4: c.1654C>T (p.R552C) and c.2911G>A (p.D971N), c.144-2A>G and c.1666G>A (p.G556R)) in two (0.62%) of the 325 OAT-affected men."
Compound heterozygous carriers in an OAT cohort.
+ 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 with ejaculated sperm bypasses the flagellar defect. One of two compound heterozygous men fathered a healthy child. In another couple the fertilization rate was high but embryos developed poorly and no pregnancy followed, possibly because of the sperm chromatin condensation defect.
Mechanism Target:
Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar propulsion and form irrelevant to fertilization.
Show evidence (1 reference)
PMID:35387802 SUPPORT Human clinical
"Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby."
Live birth after ICSI with ejaculated sperm.
Show evidence (2 references)
PMID:35387802 SUPPORT Human clinical
"Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby."
One live birth in two treated couples.
PMID:38775994 REFUTE Human clinical
"Here, despite a ICSI procedure, pregnancy did not occur due to poor embryo quality at cleavage stage."
Fertilization succeeded but no pregnancy resulted in a homozygous splice carrier.
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 for autosomal recessive recurrence and carrier testing of relatives once the familial CFAP61 variants are known; sons conceived by ICSI inherit one variant.
Show evidence (2 references)
PMID:38775994 SUPPORT Human clinical
"This case underscores the significance of genetic counseling and testing, particularly for couples dealing with infertility and MMAF."
The authors recommend counselling and testing for MMAF couples.
PMID:35174165 SUPPORT Human clinical
"These findings will expand the current understanding in the disease-causing mutations and the associated flagellar phenotypes of MMAF and provide guidance for genetic counseling and diagnosis of the disease."
Genetic counselling named as an application of the molecular diagnosis.
🔬

Diagnosis

4
Molecular Genetic Testing
Establishes the diagnosis. Patients were identified by whole-exome sequencing with Sanger confirmation; splice variants need RNA or minigene studies to confirm exon skipping.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:38775994 SUPPORT Human clinical
"Using exome sequencing, we identified this variant, which led to exon 12 skipping and the production of a truncated CFAP61 protein."
Exome sequencing plus splicing analysis established the diagnosis.
Semen Analysis
Shows asthenozoospermia with MMAF, usually with normal sperm concentration and occasionally with oligozoospermia.
Show evidence (1 reference)
PMID:35174165 SUPPORT Human clinical
"However, all the patients had asthenozoospermia, with <40% sperm motility or <32% progressive motility, except for P8, whose sperm motility and progressive motility were found normal in the routine semen analysis (Table 1)."
Semen analysis findings in the family series.
Transmission Electron Microscopy of Sperm Flagella
Shows disorganized axonemes with loss of the central pair, radial spokes and inner dynein arms.
Transmission Electron Microscopy NCIT:C18216 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:35174165 SUPPORT Human clinical
"Transmission electron microscopy analyses revealed severe disorganized axonemal ultrastructures, and missings of central pair, RSs, and inner dynein arms were also observed and confirmed by immunofluorescence staining in spermatozoa from patients."
TEM findings in patient sperm.
Immunofluorescence of CFAP61 and CFAP251 in Sperm
Absent CFAP61 and CFAP251 staining of sperm tails supports pathogenicity of the variants.
Show evidence (1 reference)
PMID:35174165 SUPPORT Human clinical
"CFAP61 and CFAP251 signals were absent from sperm tails of the patients, which suggested the loss of functional CSC in sperm flagella."
Immunostaining confirmed loss of both CSC subunits.
🐁

Animal Models

1
Cfap61 knockout mouse
Independent knockout lines give infertile males with MMAF, impaired radial spoke assembly in spermatids, axonemal scattering and reduced sperm counts, without PCD-like features.
Species
Mouse
Genotype
Cfap61-/- (knockout), homozygous
Publication
PMID:34792097
Pathograph links
Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme recapitulates fidelity: high observes: cellular Radial spoke assembly is impaired in knockout spermatids.
Show evidence (1 reference)
PMID:34792097 SUPPORT Model organism
"During early stages of Cfap61-/- spermatid development, the assembly of radial spoke components is impaired."
Spoke assembly defect in the knockout.
Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high observes: cellular Knockout sperm have short, coiled and irregular flagella and impaired motility.
Divergences from the human mechanism
species mismatch qualifying
Knockout mice have reduced total sperm counts, whereas most men with truncating CFAP61 variants have normal sperm concentration; low counts in patients are limited to one man and the missense carriers.
Show evidence (2 references)
PMID:36659204 SUPPORT Model organism
"Here, we found that cilia-and flagella-associated protein 61 (Cfap61) is highly expressed specifically in murine testes and show that the Cfap61-knockout male mice demonstrate MMAF phenotype, including sperm with short, coiled, and irregular flagella."
An independent knockout line reproduces MMAF.
+ 1 more reference
{ }

Source YAML

click to show 
name: Spermatogenic Failure 84
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF84
- spermatogenic failure 84
- CFAP61-related multiple morphological abnormalities of the sperm flagella
- CFAP61-related oligoasthenoteratozoospermia
description: >-
  Spermatogenic failure 84 (SPGF84) is autosomal recessive male infertility
  caused by biallelic variants in CFAP61. CFAP61 is a subunit of the
  calmodulin- and spoke-associated complex (CSC), which with CFAP91 and CFAP251
  builds the base of radial spoke 3 (RS3); CFAP61 forms part of the RS3 stem
  and also binds the radial spoke stalk and head. Without it, radial spoke
  components fail to assemble in spermatids, CFAP251 is lost from the
  flagellum, and the axoneme becomes unstable and scatters as spermiogenesis
  proceeds.

  Affected men have asthenoteratozoospermia with multiple morphological
  abnormalities of the sperm flagella (MMAF): absent, short, coiled, bent and
  irregular-caliber flagella. Electron microscopy shows disorganized axonemes
  with loss of the central pair, radial spokes and inner dynein arms. Sperm
  concentration is usually normal, but compound heterozygous missense
  carriers have presented with oligoasthenoteratozoospermia, and one patient
  had defective sperm chromatin condensation. Respiratory and other ciliary
  symptoms are absent. ICSI with ejaculated sperm has produced a live birth,
  but one couple had poor embryo development.
disease_term:
  preferred_term: spermatogenic failure 84
  term:
    id: MONDO:0957301
    label: spermatogenic failure 84
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 620409. ClinGen has not
  classified CFAP61 for spermatogenic failure 84: no CFAP61 row is present in
  the ClinGen gene-disease validity export dated 2026-10-14
  (data/clingen/gene_validity.csv), so gene_disease_validity is left absent.
  No GeneReviews chapter covers this disease (Bookshelf index snapshot
  2026-09-10). A study reporting low CFAP61 expression in testes of infertile
  men and reduced testosterone secretion after CFAP61 knockdown in a Leydig
  cell line (PMID:37982895) is not used here: it involves no CFAP61 variants
  and no patients with this disease.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic CFAP61 variants: homozygous truncating and
    splice variants in consanguineous families, and compound heterozygous
    missense and splice variants.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Subsequent Sanger sequencing of all the available family members confirmed that the CFAP61 variants were recessively inherited from their heterozygous parents except P11 whose sperm morphology was not yet assessed (Figures 1C–E)."
    explanation: Recessive segregation in three consanguineous families.
pathophysiology:
- name: Loss of CFAP61
  description: >-
    Frameshift, nonsense and splice alleles remove or truncate CFAP61, and
    compound heterozygous missense alleles reduce it in sperm. CFAP61 is a
    structural CSC subunit at the base of radial spoke 3 that also interacts
    with the radial spoke stalk and head.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP61
    term:
      id: hgnc:15872
      label: CFAP61
  molecular_functions:
  - preferred_term: structural constituent of the axonemal cytoskeleton
    modifier: DECREASED
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  cellular_components:
  - preferred_term: Radial spoke base 3
    term:
      id: GO:0120342
      label: radial spoke base 3
  downstream:
  - target: Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
    causal_link_type: DIRECT
    description: >-
      Without CFAP61 its CSC partner CFAP251 is absent from the sperm tail,
      and radial spoke components fail to assemble in developing spermatids.
    evidence:
    - reference: PMID:35174165
      reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Furthermore, we observed a complete absence of CFAP251 proteins in the sperm tails of the patients with CFAP61 variants, indicating that CFAP61 is essential for the localization of CFAP251 in sperm flagella."
      explanation: Loss of CFAP61 removes CFAP251 from patient sperm.
  evidence:
  - reference: PMID:34792097
    reference_title: "CFAP61 is required for sperm flagellum formation and male fertility in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We find that CFAP61 interacts with the CSC, radial spoke stalk and head."
    explanation: CFAP61 binds the CSC and radial spoke components.
  - reference: PMID:35387802
    reference_title: "Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Further immunofluorescence assays revealed markedly reduced CFAP61 staining in the sperm flagella."
    explanation: Compound heterozygous missense and splice alleles reduce CFAP61 in sperm.
  - reference: PMID:38775994
    reference_title: "Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we identified this variant, which led to exon 12 skipping and the production of a truncated CFAP61 protein."
    explanation: A splice allele truncates the protein.
- name: Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
  description: >-
    The CSC (CFAP61, CFAP91 and CFAP251 with calmodulin) sits at the base of
    radial spoke 3 and links it to the doublet microtubules. Loss of any one
    subunit destabilizes the others: CFAP251 is absent from sperm of men with
    CFAP61 variants, and in Cfap61 knockout spermatids radial spoke assembly is
    impaired. In Tetrahymena, FAP61-null cilia lack part of the RS3 stem.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Radial spoke 3
    term:
      id: GO:0120335
      label: radial spoke 3
  biological_processes:
  - preferred_term: Radial spoke assembly
    modifier: DECREASED
    term:
      id: GO:0062177
      label: radial spoke assembly
  downstream:
  - target: Sperm Axonemal Disorganization
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Radial spokes anchor the central pair; without them the central pair
      rotates and is lost, and later in spermiogenesis the whole axoneme
      becomes unstable. How loss of one spoke base destabilizes the entire
      sperm axoneme is not established.
    evidence:
    - reference: PMID:34792097
      reference_title: "CFAP61 is required for sperm flagellum formation and male fertility in human and mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "As spermiogenesis progresses, the axoneme in Cfap61-/- cells becomes unstable and scatters, and the distribution of intraflagellar transport proteins is disrupted."
      explanation: The axoneme destabilizes after the initial spoke assembly defect.
  evidence:
  - reference: PMID:34792097
    reference_title: "CFAP61 is required for sperm flagellum formation and male fertility in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "During early stages of Cfap61-/- spermatid development, the assembly of radial spoke components is impaired."
    explanation: Radial spoke assembly fails in knockout spermatids.
  - reference: PMID:25694453
    reference_title: "The CSC proteins FAP61 and FAP251 build the basal substructures of radial spoke 3 in cilia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Specifically, FAP251-null cilia lack an arch-like density at the RS3 base, whereas FAP61-null cilia lack an adjacent portion of the RS3 stem region."
    explanation: Cryo-electron tomography of Tetrahymena cilia places the orthologue in the RS3 stem.
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP61 and CFAP251 signals were absent from sperm tails of the patients, which suggested the loss of functional CSC in sperm flagella."
    explanation: Both CSC subunits are missing from patient sperm.
- name: Sperm Axonemal Disorganization
  description: >-
    Most flagellar cross-sections show severely disorganized axonemes with
    missing doublets, dynein arms, radial spokes and central pair; where a 9+2
    arrangement remains, the central pair is often rotated. The central pair
    proteins SPAG6 and TSGA2 and the inner-arm heavy chain DNAH1 are lost.
    Mitochondrial sheath malformation and mitochondria trapped in residual
    cytoplasm are also reported.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Axoneme
    term:
      id: GO:0005930
      label: axoneme
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  - preferred_term: Inner dynein arm
    term:
      id: GO:0036156
      label: inner dynein arm
  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:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In our study, the patients carrying CFAP61 variants showed severe disorganizations of the axonemal structures with loss of CP, RSs, and IDAs, which was confirmed by IF staining of SPAG6, TSGA2, and DNAH1."
    explanation: Central pair, radial spoke and inner-arm loss in patient sperm.
  - reference: PMID:35387802
    reference_title: "Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants."
    explanation: Central pair loss and mitochondrial sheath malformation with compound heterozygous alleles.
  - reference: PMID:38775994
    reference_title: "Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopy analysis of the patient's spermatozoa revealed various flagellar abnormalities, including defective nuclear chromatin condensation, axoneme disorganization, and mitochondria embedded in residual cytoplasmic droplets."
    explanation: Axoneme disorganization with a homozygous splice allele.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    Absent, short, coiled, bent and irregular-caliber flagella in the same
    ejaculate. Motility is reduced in nearly all patients; one man in the
    Pakistani families had normal motility on routine analysis despite the
    morphological defects.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  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: 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:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we recruited three unrelated Pakistani families comprising of 11 infertile male patients diagnosed with MMAF."
    explanation: MMAF in all affected men of three families.
  - reference: PMID:34792097
    reference_title: "CFAP61 is required for sperm flagellum formation and male fertility in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We find that a CFAP61 splice variant, c.143+5G>A, causes exon skipping/intron retention in human, inducing a multiple morphological abnormalities of the flagella (MMAF) phenotype."
    explanation: MMAF with a homozygous splice allele.
mechanistic_hypotheses:
- hypothesis_group_id: cfap61_sperm_restricted
  hypothesis_label: CFAP61 loss causes isolated male infertility without primary ciliary dyskinesia
  status: CANONICAL
  description: >-
    Patients in three Pakistani families were questioned for PCD features and
    had none, and Cfap61 knockout mice are infertile without PCD-like
    symptoms. The organ-specific axoneme stabilization role proposed for
    CFAP61 would explain why sperm, but not respiratory cilia, are affected. In
    Tetrahymena, loss of the orthologue does alter ciliary waveform, so a
    subtle ciliary defect in humans has not been excluded; no ciliary
    ultrastructure or nasal nitric oxide data from patients are available.
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we recruited three unrelated Pakistani families, having 11 primary infertile individuals diagnosed with MMAF without manifesting any primary ciliary dyskinesia (PCD) symptoms."
    explanation: No PCD symptoms in eleven affected men.
  - reference: PMID:34792097
    reference_title: "CFAP61 is required for sperm flagellum formation and male fertility in human and mouse."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We generated Cfap61 knockout mice that recapitulate the infertility phenotype of the human CFAP61 mutation, but without other symptoms usually observed in PCD."
    explanation: Knockout mice have no PCD-like phenotype.
  - reference: PMID:25694453
    reference_title: "The CSC proteins FAP61 and FAP251 build the basal substructures of radial spoke 3 in cilia."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "We show that in Tetrahymena, loss of either FAP61 or FAP251 reduces cell swimming and affects the ciliary waveform and that RS3 is either missing or incomplete, whereas RS1 and RS2 are unaffected."
    explanation: In a ciliate, the orthologue is needed for normal ciliary beating.
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:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, our findings report that homozygous variants in CFAP61 are associated with MMAF and male infertility, demonstrating the essential role of this gene in normal sperm flagellum structure in humans."
    explanation: Male infertility in homozygous carriers.
- category: Reproductive
  name: Reduced sperm motility
  description: >-
    Asthenozoospermia in nearly all patients; one man had normal motility on
    routine semen analysis.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, all the patients had asthenozoospermia, with <40% sperm motility or <32% progressive motility, except for P8, whose sperm motility and progressive motility were found normal in the routine semen analysis (Table 1)."
    explanation: Reduced motility in all but one patient.
- category: Reproductive
  name: Oligozoospermia
  description: >-
    Sperm concentration is normal in most patients. Low concentration was
    found in one man in the Pakistani families and in the compound
    heterozygous carriers identified from an oligoasthenoteratozoospermia
    cohort.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:35387802
    reference_title: "Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings indicate that CFAP61 is essential for spermatogenesis and that biallelic CFAP61 variants lead to male infertility in humans and mice with OAT."
    explanation: Oligoasthenoteratozoospermia in compound heterozygous carriers.
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "P3 had a low sperm concentration (6 million/ml) and sperm concentrations were all in the normal range for the rest of patients."
    explanation: Low concentration is the exception in the largest family series.
- category: Reproductive
  name: Absent sperm flagella
  description: Some sperm lack a flagellum, as part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
    explanation: Scanning electron microscopy of patient sperm.
- category: Reproductive
  name: Short sperm flagella
  description: Shortened flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
    explanation: Scanning electron microscopy of patient sperm.
- category: Reproductive
  name: Coiled sperm flagella
  description: Coiled flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
    explanation: Scanning electron microscopy of patient sperm.
- 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:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
    explanation: Scanning electron microscopy of patient sperm.
- 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:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Representative SEM micrographs showing sperm morphological abnormalities observed in patients, including absent (ii), short (iii), coiled (iv), bent (v) flagella, and flagella of irregular caliber (vi)."
    explanation: Scanning electron microscopy of patient sperm.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: >-
    Disorganized axonemes with missing doublets, dynein arms, radial spokes
    and central pair.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to the typical “9 + 2” axoneme arrangement in the spermatozoa from a fertile control, most of the flagellar cross-sections from spermatozoa of patients exhibited severely disorganized axoneme structure, along with the missings of MTDs, dynein arms, RSs, and/or CP (Figure 2A)."
    explanation: Axonemal disorganization in patient sperm.
- category: Reproductive
  name: Absent sperm axoneme central pair complex
  description: The central pair is missing from many flagellar cross-sections.
  phenotype_term:
    preferred_term: Absent sperm axoneme central pair complex
    term:
      id: HP:0033525
      label: Absent sperm axoneme central pair complex
  evidence:
  - reference: PMID:35387802
    reference_title: "Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, H&E staining and electron microscopy analyses of the spermatozoa revealed multiple morphological abnormalities of sperm flagella, the absence of central pair microtubules and mitochondrial sheath malformation in sperm flagella from man with CFAP61 variants."
    explanation: Central pair absence in patient sperm.
- category: Reproductive
  name: Abnormal sperm head morphology
  description: >-
    In one patient with a homozygous splice variant, about half of sperm heads
    had defective chromatin condensation. How CFAP61 loss affects the head is
    not established, so this phenotype is not linked to the causal chain.
  phenotype_term:
    preferred_term: Abnormal sperm head morphology
    term:
      id: HP:0012865
      label: Abnormal sperm head morphology
  evidence:
  - reference: PMID:38775994
    reference_title: "Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Furthermore, nearly half of the observed sperm heads displayed chromatin condensation defects, possibly contributing to the low blastulation rate."
    explanation: Chromatin condensation defects in sperm heads.
genetic:
- name: CFAP61
  association: Causal
  gene_term:
    preferred_term: CFAP61
    term:
      id: hgnc:15872
      label: CFAP61
  notes: >-
    Reported alleles include frameshift c.451_452del (p.I151Nfs*4) and
    nonsense c.847C>T (p.R283*) in Pakistani families, splice variants
    c.143+5G>A and c.1245+6T>C, and compound heterozygous c.1654C>T
    (p.R552C)/c.2911G>A (p.D971N) and c.144-2A>G/c.1666G>A (p.G556R). ClinGen
    has not classified this gene-disease pair.
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP61 variants, c.451_452del (p.I151Nfs*4) in family 1 and c.847C > T (p.R283*) in family 2 and 3, were identified recessively co-segregating with the MMAF phenotype."
    explanation: Homozygous truncating variants in three families.
  - reference: PMID:34792097
    reference_title: "CFAP61 is required for sperm flagellum formation and male fertility in human and mouse."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We find that a CFAP61 splice variant, c.143+5G>A, causes exon skipping/intron retention in human, inducing a multiple morphological abnormalities of the flagella (MMAF) phenotype."
    explanation: Splice allele with knockout mouse support.
  - reference: PMID:35387802
    reference_title: "Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified biallelic CFAP61 variants (NM_015585.4: c.1654C>T (p.R552C) and c.2911G>A (p.D971N), c.144-2A>G and c.1666G>A (p.G556R)) in two (0.62%) of the 325 OAT-affected men."
    explanation: Compound heterozygous carriers in an OAT cohort.
  - reference: PMID:38775994
    reference_title: "Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we investigated the role of a newly identified homozygous variant (c.1245 + 6T > C) in the CFAP61 gene in the development of multiple morphologically abnormal flagella (MMAF) in an infertile patient."
    explanation: A further homozygous splice allele.
animal_models:
- name: Cfap61 knockout mouse
  species: Mouse
  genotype: Cfap61-/- (knockout), homozygous
  publication: PMID:34792097
  description: >-
    Independent knockout lines give infertile males with MMAF, impaired radial
    spoke assembly in spermatids, axonemal scattering and reduced sperm
    counts, without PCD-like features.
  modeled_mechanisms:
  - target: Loss of the Calmodulin- and Spoke-Associated Complex from the Sperm Axoneme
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Radial spoke assembly is impaired in knockout spermatids.
    evidence:
    - reference: PMID:34792097
      reference_title: "CFAP61 is required for sperm flagellum formation and male fertility in human and mouse."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "During early stages of Cfap61-/- spermatid development, the assembly of radial spoke components is impaired."
      explanation: Spoke assembly defect in the knockout.
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Knockout sperm have short, coiled and irregular flagella and impaired motility.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Knockout mice have reduced total sperm counts, whereas most men with
        truncating CFAP61 variants have normal sperm concentration; low counts
        in patients are limited to one man and the missense carriers.
    evidence:
    - reference: PMID:36659204
      reference_title: "Absence of murine CFAP61 causes male infertility due to multiple morphological abnormalities of the flagella."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we found that cilia-and flagella-associated protein 61 (Cfap61) is highly expressed specifically in murine testes and show that the Cfap61-knockout male mice demonstrate MMAF phenotype, including sperm with short, coiled, and irregular flagella."
      explanation: An independent knockout line reproduces MMAF.
    - reference: PMID:36659204
      reference_title: "Absence of murine CFAP61 causes male infertility due to multiple morphological abnormalities of the flagella."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Deletion of Cfap61 resulted in severe morphological and behavior abnormalities in sperm, reduced total sperm counts, impaired sperm motility, and led to male infertility."
      explanation: Records the reduced counts behind the species divergence.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI with ejaculated sperm bypasses the flagellar defect. One of two
    compound heterozygous men fathered a healthy child. In another couple the
    fertilization rate was high but embryos developed poorly and no pregnancy
    followed, possibly because of the sperm chromatin condensation defect.
  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 propulsion and form irrelevant to fertilization.
    evidence:
    - reference: PMID:35387802
      reference_title: "Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby."
      explanation: Live birth after ICSI with ejaculated sperm.
  evidence:
  - reference: PMID:35387802
    reference_title: "Biallelic CFAP61 variants cause male infertility in humans and mice with severe oligoasthenoteratozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two individuals accepted ICSI therapy using their own ejaculated sperm, and one of them succeeded in fathering a healthy baby."
    explanation: One live birth in two treated couples.
  - reference: PMID:38775994
    reference_title: "Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, despite a ICSI procedure, pregnancy did not occur due to poor embryo quality at cleavage stage."
    explanation: Fertilization succeeded but no pregnancy resulted in a homozygous splice carrier.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP61 variants are known; sons conceived by
    ICSI inherit one variant.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:38775994
    reference_title: "Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case underscores the significance of genetic counseling and testing, particularly for couples dealing with infertility and MMAF."
    explanation: The authors recommend counselling and testing for MMAF couples.
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These findings will expand the current understanding in the disease-causing mutations and the associated flagellar phenotypes of MMAF and provide guidance for genetic counseling and diagnosis of the disease."
    explanation: Genetic counselling named as an application of the molecular diagnosis.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Patients were identified by whole-exome
    sequencing with Sanger confirmation; splice variants need RNA or minigene
    studies to confirm exon skipping.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:38775994
    reference_title: "Identification of a novel CFAP61 homozygous splicing variant associated with multiple morphological abnormalities of the flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Using exome sequencing, we identified this variant, which led to exon 12 skipping and the production of a truncated CFAP61 protein."
    explanation: Exome sequencing plus splicing analysis established the diagnosis.
- name: Semen Analysis
  description: >-
    Shows asthenozoospermia with MMAF, usually with normal sperm concentration
    and occasionally with oligozoospermia.
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, all the patients had asthenozoospermia, with <40% sperm motility or <32% progressive motility, except for P8, whose sperm motility and progressive motility were found normal in the routine semen analysis (Table 1)."
    explanation: Semen analysis findings in the family series.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Shows disorganized axonemes with loss of the central pair, radial spokes
    and inner dynein arms.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transmission electron microscopy analyses revealed severe disorganized axonemal ultrastructures, and missings of central pair, RSs, and inner dynein arms were also observed and confirmed by immunofluorescence staining in spermatozoa from patients."
    explanation: TEM findings in patient sperm.
- name: Immunofluorescence of CFAP61 and CFAP251 in Sperm
  description: >-
    Absent CFAP61 and CFAP251 staining of sperm tails supports pathogenicity
    of the variants.
  evidence:
  - reference: PMID:35174165
    reference_title: "Biallelic Variants in CFAP61 Cause Multiple Morphological Abnormalities of the Flagella and Male Infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP61 and CFAP251 signals were absent from sperm tails of the patients, which suggested the loss of functional CSC in sperm flagella."
    explanation: Immunostaining confirmed loss of both CSC subunits.
📚

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_84 · 2026-10-16T13:41:26Z · View source

Created the SPGF84 entry for CFAP61-related male infertility (MONDO:0957301). Sources: a claude_code deep-research report (research/Spermatogenic_Failure_84-deep-research-claude_code.md, preflight WARN only because 'OAT' was read as a gene symbol; it is the abbreviation oligoasthenoteratozoospermia) used as leads only, plus PubMed searches. Evidence: Ma 2021 (three Pakistani families, 11 men, refetched as full text), Liu 2021 (splice allele plus knockout mouse), Hu 2023 (compound heterozygous carriers with OAT, ICSI live birth), Barbotin 2024 (splice allele, chromatin condensation defect, ICSI without pregnancy), Huang 2020 (independent knockout) and Tetrahymena CSC structure. Pathograph mirrors SPGF33/SPGF51 with the same CSC node names; the axonemal node adds central apparatus and inner dynein arm components and links to HP:0033525. Oligozoospermia is recorded with SUPPORT (OAT cohort) and REFUTE (normal counts in most of the family series) items; a CANONICAL hypothesis records the absence of PCD features with a Tetrahymena REFUTE item. A Leydig-cell knockdown study (PMID:37982895) was deliberately not used. ClinGen has not classified the pair and there is no GeneReviews chapter. All validation recipes passed, including validate-disorders. Stub deleted.

Claude Code ▸
Spermatogenic Failure 84 (SPGF84): research report
claude-haiku-5-5, claude-sonnet-5-5 12 citations 2026-10-16T13:13:28.451833

I'm still gathering primary-literature details on CFAP61 (the gene behind SPGF84). The PubMed and PMC pages are blocked, so I'm looking for PMIDs and abstracts elsewhere.

Spermatogenic Failure 84 (SPGF84): research report

Reliability note. This report comes from web searches only. PubMed, PMC and the Development PDF were blocked or rate-limited, so I read no abstract or full text directly. The facts below come from search-result summaries and aggregator pages.

  • No quotes: I give no exact abstract quotes. Any snippet written for the KB must be taken from just fetch-reference output.
  • PMIDs: only PMID 35387802 was seen in a search result. The other papers are cited by DOI or title, and their PMIDs still need to be fetched.
  • Ontology IDs: I give only labels for HPO, GO, CL, UBERON and NCIT terms. Look up every CURIE with runoak or the cache before binding it.

1. Disease information

SPGF84 is an autosomal recessive form of male infertility caused by biallelic loss-of-function variants in CFAP61. The main feature is multiple morphological abnormalities of the sperm flagella (MMAF), which severely reduce motility. Some men also have reduced sperm counts.

  • Identifiers (NCBI MedGen C5830562):
  • OMIM #620409
  • MONDO:0957301
  • gene locus 20p11.23
  • Ontology placement: MONDO places it under spermatogenic failure, as a reproductive system disorder (SAIL Concept Library).
  • Other resources: KEGG spermatogenic failure H01282 and MalaCards list the entry.
  • Synonyms and series: SPGF84; CFAP61-related MMAF; asthenoteratozoospermia due to CFAP61. It belongs to the numbered SPGF series, which is heterogeneous, and many of its members are flagellar or MMAF genes.
  • Source type: disease-level and aggregated, built from small family and cohort studies.
  • Not found: Orphanet and ICD identifiers. Check these directly.

2. Etiology

  • Cause: homozygous or compound heterozygous CFAP61 variants (MalaCards via Disease Ontology).
  • Environmental risk factors: none established. Other causes of male infertility must be excluded in the differential.
  • Protective factors and gene-environment interactions: none reported.
  • Possible modifiers: other axonemal genes, such as CFAP251, appear to be involved downstream. That is a mechanistic link, not a demonstrated modifier effect.

3. Phenotypes

Male-limited phenotypes (candidate HPO labels, all to be verified):

Phenotype Notes
Male infertility Universal. Onset becomes apparent in adulthood. Stable.
Asthenozoospermia Severely reduced progressive motility.
Teratozoospermia, with short, absent, coiled, bent or irregular flagella (MMAF) Core feature (MedGen).
Oligozoospermia Seen in some men, so the sperm count varies.
  • Cohort observation: in the J Med Genet cohort, two of 325 men with oligoasthenoteratozoospermia (OAT), 0.62%, carried biallelic CFAP61 variants.
  • Other organs: no primary ciliary dyskinesia (PCD) features are described. The mouse knockout lacks the usual PCD symptoms.
  • Frequencies and quality of life: no per-phenotype frequencies or quality-of-life data are available. Infertility is expected to have psychosocial impact, but I found no study.

4. Genetic and molecular information

  • Gene: CFAP61 (cilia and flagella associated protein 61, also C20orf26), 20p11.23. A homolog of the radial spoke protein Rsp19. HGNC ID not retrieved. Look it up and write it in lowercase hgnc: form.
  • Reported variants:
  • Pakistani families (Ma et al., Frontiers in Cell and Developmental Biology, DOI 10.3389/fcell.2021.803818):
    • 11 infertile men in three unrelated families.
    • c.451_452del (p.I151Nfs*4) in family 1.
    • c.847C>T (p.R283*) in families 2 and 3.
    • Both variants truncate the protein.
  • Splice variant: c.143+5G>A causes exon skipping (Liu et al., Development 2021, DOI 10.1242/dev.199805).
  • Later reports: a novel homozygous splicing variant (J Assist Reprod Genet 2024) and two of 325 OAT men in the J Med Genet cohort.
  • Consequence: loss of function (truncation or exon skipping). No dominant-negative or gain-of-function mechanism is known.
  • Origin: germline.
  • Not retrieved: ClinVar and ClinGen classifications, gnomAD frequencies, ClinGen gene-disease validity, and epigenetic or chromosomal findings. Check just check-gene-validity and ClinGen before recording any tier.

5. Environmental information

None known. No infectious agents and no lifestyle factors are linked.

6. Mechanism and pathophysiology

  1. Biallelic CFAP61 loss-of-function variants (truncating or splicing) reduce or abolish CFAP61 protein in the testis.
  2. CFAP61 is a component of the calmodulin- and radial-spoke-associated complex (CSC) in the axoneme. This is a conserved role, described in a bioRxiv preprint of the Development paper.
  3. Early in spermiogenesis, radial spoke assembly is impaired in Cfap61-/- mice (preprint, mouse data).
  4. The axoneme becomes unstable and scatters. The distribution of intraflagellar transport (IFT) proteins is disrupted (preprint, mouse data).
  5. In patient sperm, the central pair and radial spokes are missing and the axonemes are disorganized. CFAP61 and CFAP251 signals are absent from the tail (Frontiers 2021). The J Med Genet cohort also found missing central pair microtubules and mitochondrial sheath malformation.

  6. The result is short, coiled or absent flagella with no progressive motility, which leads to male infertility. The step from structural defect to loss of motility is inferred, not separately demonstrated.

  7. Cells: spermatid and spermatozoon, in the seminiferous epithelium of the testis.

  8. Cell component: the sperm flagellar axoneme, radial spoke and central pair (GO labels to verify).
  9. Not available: omics, single-cell, metabolomic and CRISPR screen data.
  10. Possible Leydig cell link: one paper reports that CFAP61 knockdown reduced Leydig cell testosterone via the MAPK/COX-2 pathway (Funct Integr Genomics 2023). This is a cell-line finding that needs corroboration.

7. Anatomical structures affected

Testis and seminiferous tubules, with spermatids as the target cells. The sperm flagellum (axoneme, mitochondrial sheath) is the affected structure. The condition is male-limited and systemic involvement is not described.

8. Temporal development

Congenital genotype. Infertility presents in adulthood, during attempts to conceive. It does not progress and is lifelong. No remission is reported.

9. Inheritance and population

  • Inheritance: autosomal recessive.
  • Consanguinity: the Pakistani families suggest a role for consanguinity (homozygous variants), but I did not verify this in the paper.
  • Population: Pakistani families, Chinese cohorts and others.
  • Prevalence: not established. About 0.6% of OAT men in one cohort.
  • Sex ratio: affects males only.
  • Not retrieved: carrier frequency, founder effects, penetrance and expressivity.

10. Diagnostics

  • Semen analysis: severe asthenoteratozoospermia, with a high proportion of MMAF flagella. Counts vary.
  • Electron microscopy: disorganized axonemes. Findings in the cohorts include missing central pair, radial spokes and inner dynein arms.
  • Immunofluorescence: absent CFAP61 and CFAP251 signals in sperm tails.
  • Genetic testing: exome or MMAF/asthenoteratozoospermia gene panel with CFAP61 included. Confirm biallelic variants. A sample report from Arcensus Diagnostics notes ICSI is likely to be effective. It is a commercial sample, not primary evidence.
  • Differential:
  • Other MMAF genes (DNAH1, CFAP43, CFAP44, CFAP69, CFAP251 and others).
  • PCD (check for respiratory symptoms).
  • Acquired causes of OAT.

11. Outcome and prognosis

Fertility is impaired, but general health is not affected as far as is known. Natural fertilization is unlikely. No survival or mortality data are available.

12. Treatment

  • ICSI (intracytoplasmic sperm injection; NCIT term to look up) is the main option. One affected man fathered a healthy baby by ICSI in the J Med Genet cohort (PMID 35387802). The Arcensus report cites 100% fertilization in treated probands, which is a weak source.
  • Genetic counseling. There is no drug, gene or cell therapy and no clinical trial that I found.
  • Possible concern: whether sperm quality can support ICSI success depends on the individual. The outcomes cited are from very small numbers.

13. Prevention

There is no primary prevention. Options are genetic counseling and carrier testing of relatives. For couples using ICSI, preimplantation or prenatal testing is possible, though the heritable risk to a child is that of a carrier (recessive), and a male child homozygous for the variant would also be infertile.

14. Other species and natural disease

I found no natural disease report (not checked in OMIA). The mouse ortholog is Cfap61 (NCBI Gene IDs not retrieved).

15. Model organisms

  • Mouse knockout (Cfap61-/-):
  • Male sterility with MMAF (Liu et al., Development 2021, DOI 10.1242/dev.199805; preprint).
  • An earlier knockout paper (ScienceDirect, "Absence of murine CFAP61 causes male infertility due to MMAF").
  • The J Med Genet cohort paper used knockout mice with an OAT phenotype.
  • The preprint says the mice lack the PCD symptoms usually seen with cilia genes.
  • Fidelity: the mouse reproduces the male-infertility MMAF phenotype well. It is a loss-of-function model and does not cover human genotype-specific variation.
  • Not checked: MGI or IMPC records, zebrafish and other models, and organoids.

Suggested KB follow-ups

  1. Run just fetch-reference for each paper (PMID 35387802 first, then look up the PMIDs of the Ma 2021/2022, Liu 2021 and 2024 splice-variant papers).
  2. Quote evidence snippets only from the cached text.
  3. Look up every ontology CURIE (MONDO:0957301 is from MedGen and MONDO's own listing) and the lowercase hgnc: ID for CFAP61.
  4. Check ClinGen, GeneReviews and Orphanet before adding gene validity or a baseline phenotype.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 7
Resolved 6
Unresolved (possible confabulation) 1
Unverifiable 0
References weighed for topical relevance 6
On topic 4
Off topic 0

Unresolved references

These identifiers did not resolve to a record and may be fabricated. A lookup that failed for transport reasons is indistinguishable from one that failed because the record does not exist, so spot-check before acting on them:

  • DOI:10.1242/dev.199805/2120252/dev199805.pdf (4 mentions) - Identifier did not resolve to a record

Term Validation

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

Outcome Count
Terms checked 1
Resolved 1
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 0

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