Spermatogenic Failure 41

👪

Inheritance

1

Autosomal recessive HP:0000007

All reported probands are homozygous for a CFAP70 variant. In the one family with segregation data, a fertile brother carries the wild-type allele; the parents were not available for testing.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31621862 SUPPORT Human clinical

"we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70, a gene not previously linked to the MMAF phenotype"

Two unrelated homozygous probands.

PMID:37352829 SUPPORT Human clinical

"Sanger sequencing of the CFAP70 gene revealed that the proband (II-1) carried the homozygous nonsense variant, and his fertile brother (II-2) harboured the wild-type allele"

A third homozygous proband, with a fertile wild-type brother.

◈

Mechanistic Hypotheses

1

CFAP70 loss causes isolated male infertility in humans although knockout mice also develop motile-cilia disease

cfap70_sperm_restricted_in_humans EMERGING

Evidence balance 2 support 2 refute

All three reported men have infertility alone, with no respiratory or other ciliary symptoms. Cfap70 knockout mice, by contrast, develop fully penetrant hydrocephalus and sinusitis with central-pair defects in ependymal and tracheal cilia, as do knockouts of the other C2a genes. Whether the human sparing reflects species differences, redundancy or under-ascertainment in three probands is unresolved.

Show evidence (4 references)

PMID:37352829 SUPPORT Human clinical

"Patients carrying CFAP70 variants in Charles Coutton's study23 and our current study have no symptoms other than male sterility, indicating no obvious role or functional redundancy of CFAP70 in the development of ependymal cilia in humans."

No extra-reproductive ciliary disease in the three reported men.

PMID:37352829 SUPPORT Human clinical

"The results of the patient's physical examination revealed normal development of male external genitalia, normal bilateral testicular size, no abnormality in the bilateral spermatic veins, normal hormone levels and no PCD-related symptoms."

The nonsense proband was examined and had no PCD-related symptoms.

PMID:42417609 REFUTE INDIRECT Model organism

"Importantly, the hydrocephalus and sinusitis phenotypes were fully penetrant in the KO mice of each strain (Figure 1K)."

Cfap70 knockout mice have motile-cilia disease, which argues that CFAP70 is not sperm-specific. This is mouse evidence; no affected man has these features.

+ 1 more reference

⚙

Pathophysiology

3

Loss of CFAP70 from the Sperm Axoneme

The splice-site allele removes CFAP70 from the sperm flagellum, and the p.R988X nonsense allele leaves a truncated protein lacking C-terminal tetratricopeptide repeats 5-8. CFAP70 is a structural component of the C2a projection of the central apparatus: in mouse motile cilia, loss of CFAP70, CFAP65 (CCDC108) or MYCBPAP destabilizes the other two and collapses the projection, and in Chlamydomonas the fap70 mutant lacks most of C2a.

CFAP70 hgnc:30726

structural constituent of the axonemal C2a projection GO:0005200 ↓ DECREASED

Axonemal central pair projection (C2a) GO:1990718

Animal models

Cfap70 TPR5-8 truncation mouse Mouse recapitulates Models the C-terminal truncation produced by the patient allele.

Downstream

Failure of Sperm Flagellum Assembly Without CFAP70 the flagellar axoneme is not assembled properly in spermatids; patient sperm lack both outer dynein arm and central pair markers.

Show evidence (5 references)

PMID:31621862 SUPPORT Human clinical

"In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum."

Protein loss in patient sperm with the splice allele.

PMID:37352829 SUPPORT Human clinical

"This nonsense variant generates a truncated CFAP70 protein lacking the C-terminal 5–8 tetratricopeptide repeats (TPRs)."

The nonsense allele truncates the TPR region.

PMID:42417609 SUPPORT Model organism

"The ciliary incorporation of CCDC108, MYCBPAP, and CFAP70 is essential for one another's stability, with the loss of any single component triggering C2a collapse, which destabilizes the central pair microtubules, and ultimately alters the ciliary movement pattern."

Knockout mice show that CFAP70 is a structural component whose loss collapses the C2a projection, which grounds the structural molecular function.

+ 2 more references

Failure of Sperm Flagellum Assembly

Flagellar biogenesis fails in spermatids. In mice, CFAP70 helps to preassemble the calmodulin- and radial spoke-associated complex in the cytoplasm, maintains levels of other MMAF proteins such as QRICH2, and controls the localization of axonemal proteins on the manchette; loss of CFAP70 also causes club-shaped heads and abnormal manchette disassembly.

Spermatid CL:0000018

Sperm flagellum assembly GO:0120316 ↓ DECREASED

Axonemal central apparatus GO:1990716

Animal models

Cfap70 knockout mouse Mouse partially recapitulates The knockout shows the spermatid assembly defect, alongside motile-cilia disease that patients lack.

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella

Show evidence (2 references)

PMID:37352829 SUPPORT Model organism

"CFAP70 is required for the biogenesis of spermatid flagella partially by regulating the expression of OAT-associated proteins (e.g., QRICH2), assisting the cytoplasmic preassembly of the calmodulin- and radial spoke-associated complex (CSC), and controlling the manchette localization of..."

Mechanism of the assembly defect in knockout spermatids.

PMID:37458246 SUPPORT Model organism

"Specifically, the lack of CFAP70 impairs sperm flagellum biogenesis and head shaping during spermiogenesis."

An independent knockout confirms the flagellar biogenesis defect.

Multiple Morphological Abnormalities of the Sperm Flagella

The semen phenotype: coiled, short and absent flagella in the same ejaculate, with no progressively motile sperm.

Sperm CL:0000019

Animal models

Cfap70 knockout mouse Mouse recapitulates The knockout reproduces the human oligoasthenoteratozoospermia with MMAF.

Cfap70-deficient mouse (Chen 2023) Mouse recapitulates Independent confirmation of MMAF in Cfap70-deficient mice.

Downstream

Reduced sperm motility

Coiled sperm flagella

Short sperm flagella

Absent sperm flagella

Male infertility Malformed, immotile sperm cannot reach or fertilize the oocyte in vivo.

Show evidence (2 references)

PMID:31621862 SUPPORT Human clinical

"In conclusion, this work provides the first evidence that loss of CFAP70 function causes MMAF"

MMAF in the first two probands.

PMID:37352829 SUPPORT Human clinical

"The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."

MMAF in the nonsense proband.

⬡

Pathograph

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●

Phenotypes

6

Male infertility Reproductive HP:0003251

Show evidence (1 reference)

PMID:37352829 SUPPORT Human clinical

"A 33-year-old man (II-1) who was diagnosed with primary infertility for five years and his fertile brother (II-2) were recruited for our study"

Primary infertility in the nonsense proband.

Reduced sperm motility Reproductive HP:0012207

Show evidence (1 reference)

PMID:37352829 SUPPORT Human clinical

"A semen analysis of the proband (II-1) revealed normal semen volume (1.8 mL), extremely low sperm concentration (2.8 × 106 spermatozoa/mL), no progressive mobile sperm, and a low percent of morphologically normal sperm (2%)"

No progressively motile sperm.

Oligozoospermia Reproductive HP:0000798

Show evidence (2 references)

PMID:37352829 SUPPORT Human clinical

"A semen analysis of the proband (II-1) revealed normal semen volume (1.8 mL), extremely low sperm concentration (2.8 × 106 spermatozoa/mL), no progressive mobile sperm, and a low percent of morphologically normal sperm (2%)"

Low sperm concentration in the nonsense proband.

PMID:37352829 SUPPORT BACKGROUND Human clinical

"A previous high-throughput sequencing study identified two unrelated MMAF individuals with very low sperm counts carrying two homozygous variants (c.178 T > A/p.F60I and c.1723-1G > T) in CFAP70"

The two earlier probands also had very low sperm counts.

Coiled sperm flagella Reproductive HP:0032560

Show evidence (1 reference)

PMID:37352829 SUPPORT Human clinical

"The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."

Coiled flagella in patient sperm.

Short sperm flagella Reproductive HP:0032559

Show evidence (1 reference)

PMID:37352829 SUPPORT Human clinical

"The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."

Short flagella in patient sperm.

Absent sperm flagella Reproductive HP:0032558

Show evidence (1 reference)

PMID:37352829 SUPPORT Human clinical

"The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."

Absent flagella in patient sperm.

🧬

Genetic Associations

1

CFAP70 (Causal)

Gene: CFAP70 hgnc:30726

Show evidence (2 references)

PMID:31621862 SUPPORT Human clinical

"One patient had a homozygous splice variant c.1723-1G>T, altering a consensus splice acceptor site of CFAP70 exon 16, and one had a likely deleterious missense variant in exon 3 (p.Phe60Ile)."

First two probands.

PMID:37352829 SUPPORT Human clinical

"A homozygous nonsense variant (c.2962C > T/p.R988X) in CFAP70 was identified in a Chinese infertile man with OAT."

Third proband.

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI bypasses the motility defect. The one treated proband had a live birth after two cycles. In mice, ICSI with knockout sperm produced healthy offspring but at lower two-cell and blastocyst rates than with wild-type sperm.

Mechanism Target:

Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar propulsion irrelevant to fertilization.

Show evidence (1 reference)

PMID:37352829 SUPPORT Human clinical

"ICSI using the spermatozoa from the CFAP70-mutated patient (II-1) was applied for two cycles and successfully resulted in a live birth (Table 3)."

Live birth from ICSI with patient sperm.

Show evidence (2 references)

PMID:37352829 SUPPORT Human clinical

"ICSI using the spermatozoa from the CFAP70-mutated patient (II-1) was applied for two cycles and successfully resulted in a live birth (Table 3)."

The only reported human ICSI outcome.

PMID:37352829 SUPPORT Model organism

"However, the rates of two-cell embryos and blastocysts were reduced upon ICSI treatment using spermatozoa from Cfap70-KO mice compared with those using wild-type spermatozoa (Table 2)."

In mice ICSI works but with reduced embryo development, a caveat for counselling that has not been tested in more than one patient.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling for autosomal recessive recurrence and carrier testing of relatives once the familial CFAP70 variants are known. All children conceived by ICSI are obligate heterozygous carriers.

Show evidence (1 reference)

PMID:37352829 SUPPORT INDIRECT Human clinical

"Overall, we demonstrate that CFAP70 is necessary to assemble spermatid flagella and that CFAP70 gene could be used as a diagnostic target for male infertility with OAT in the clinic."

The authors propose CFAP70 as a clinical diagnostic target; genetic counselling follows from a molecular diagnosis.

🔬

Diagnosis

3

Molecular Genetic Testing

Establishes the diagnosis. Probands were identified by whole-exome sequencing with Sanger confirmation. MMAF is genetically heterogeneous, so semen findings alone cannot name the gene.

Genetic Testing NCIT:C15709

Show evidence (2 references)

PMID:37352829 SUPPORT Human clinical

"CFAP70 variants were detected in infertile men with OAT by whole exome sequencing and Sanger sequencing confirmation."

Exome sequencing with Sanger confirmation identified the proband.

PMID:31621862 SUPPORT Human clinical

"Based on whole-exome sequencing data from a large cohort of 167 MMAF-affected subjects, we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70"

Exome screening of an MMAF cohort.

Semen Analysis

Shows severe oligoasthenoteratozoospermia with MMAF (coiled, short and absent flagella) and no progressive motility.

Show evidence (1 reference)

PMID:37352829 SUPPORT Human clinical

"A semen analysis of the proband (II-1) revealed normal semen volume (1.8 mL), extremely low sperm concentration (2.8 × 106 spermatozoa/mL), no progressive mobile sperm, and a low percent of morphologically normal sperm (2%)"

Semen findings in the nonsense proband.

Immunofluorescence of CFAP70 in Sperm

Absent CFAP70, outer dynein arm and central pair staining in sperm flagella supports the diagnosis for loss-of-function alleles.

Show evidence (1 reference)

PMID:31621862 SUPPORT Human clinical

"In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum."

Immunofluorescence demonstrates protein loss in patient sperm.

🐁

Animal Models

3

Cfap70 knockout mouse

Knockout males are sterile with low sperm counts, low motility and MMAF sperm. They also develop neonatal hydrocephalus with premature death, which has not been reported in patients.

Species

Mouse

Genotype

Cfap70-/- (CRISPR knockout), homozygous

Publication

PMID:37352829

Pathograph links

Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high The knockout reproduces the human oligoasthenoteratozoospermia with MMAF.

Show evidence (1 reference)

PMID:37352829 SUPPORT Model organism

"Morphologic analysis of spermatozoa using Papanicolaou staining (Fig. 1f) and SEM (Fig. 1g) revealed that Cfap70-KO spermatozoa were malformed with short and coiled flagella."

MMAF in knockout sperm.

Failure of Sperm Flagellum Assembly partially recapitulates fidelity: moderate The knockout shows the spermatid assembly defect, alongside motile-cilia disease that patients lack.

Limitations: Knockout mice develop hydrocephalus and sinusitis from motile-cilia dysfunction, so they model a broader ciliopathy than the isolated infertility seen in the three reported men.

Divergences from the human mechanism

species mismatch qualifying

Mouse ependymal and airway cilia depend on CFAP70 for central-pair stability, and knockouts develop hydrocephalus; no CFAP70-deficient man has had hydrocephalus or respiratory disease, so the extra-gonadal phenotype does not transfer to humans on present evidence.

Show evidence (1 reference)

PMID:37352829 SUPPORT Model organism

"In this study, we report that Cfap70-KO mice exhibit male infertility with OAT and that CFAP70 is required for the assembly of flagella in mouse early spermatids."

The knockout localizes the defect to flagellar assembly in early spermatids.

Cfap70 TPR5-8 truncation mouse

Mice expressing CFAP70 truncated like the patient's p.R988X protein (the exact allele could not be engineered) are sterile with low sperm count and motility.

Species

Mouse

Genotype

Cfap70 truncation lacking tetratricopeptide repeats 5-8, homozygous

Publication

PMID:37352829

Pathograph links

Loss of CFAP70 from the Sperm Axoneme recapitulates fidelity: moderate Models the C-terminal truncation produced by the patient allele.

Limitations: The patient's exact nonsense codon could not be edited in mouse, so the model approximates rather than reproduces the human allele.

Show evidence (1 reference)

PMID:37352829 SUPPORT Model organism

"Cfap70-truncated mice lacking 5-8 tetratricopeptide repeats (TPRs) mimic the patient's symptoms."

The truncation model reproduces the patient phenotype.

Cfap70-deficient mouse (Chen 2023)

An independent knockout with MMAF, abnormal head shaping and abnormal manchette disassembly; CFAP70 interacts with the ODA intermediate chains DNAI1 and DNAI2.

Species

Mouse

Genotype

Cfap70-deficient (CRISPR), homozygous

Publication

PMID:37458246

Pathograph links

Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high Independent confirmation of MMAF in Cfap70-deficient mice.

Show evidence (1 reference)

PMID:37458246 SUPPORT Model organism

"Our findings show that the loss of CFAP70 leads to multiple morphological abnormalities of the flagella and spermiogenesis defects."

MMAF in the second knockout line.

{ }

Source YAML

click to show

name: Spermatogenic Failure 41
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF41
- spermatogenic failure 41
- CFAP70-related multiple morphological abnormalities of the sperm flagella
- CFAP70-related oligoasthenoteratozoospermia
description: >-
  Spermatogenic failure 41 (SPGF41) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in CFAP70, a
  tetratricopeptide-repeat protein of motile cilia and sperm flagella. CFAP70
  is a component of the C2a projection of the axonemal central apparatus,
  where it is required for the stability of its partner proteins CFAP65 and
  MYCBPAP, and its N-terminus also sits at the base of the outer dynein arm.
  In spermatids it is needed to assemble the flagellum.

  Affected men present with primary infertility and severe
  asthenoteratozoospermia with multiple morphological abnormalities of the
  sperm flagella (MMAF): coiled, short and absent flagella, no progressive
  motility and, in reported men, reduced sperm concentration. Patient sperm
  lack CFAP70 and show loss of outer dynein arm and central pair markers.
  Only three probands have been reported (a splice-site, a missense and a
  nonsense variant), all without respiratory or other ciliary symptoms,
  although Cfap70 knockout mice develop hydrocephalus and sinusitis in
  addition to sterility. Intracytoplasmic sperm injection (ICSI) has produced
  a live birth.
disease_term:
  preferred_term: spermatogenic failure 41
  term:
    id: MONDO:0032863
    label: spermatogenic failure 41
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 618670. ClinGen has no
  gene-disease validity curation for CFAP70 in any disease, so no validity
  tier is recorded. The human evidence rests on three probands from two
  publications (PMID:31621862, two homozygous probands from a 167-patient
  MMAF cohort; PMID:37352829, one homozygous nonsense proband); the
  supporting mouse models are a knockout and a truncation mutant
  (PMID:37352829) and an independent knockout (PMID:37458246). Cfap70 is also
  one of three C2a-projection genes whose mouse knockouts develop
  hydrocephalus and sinusitis (PMID:42417609); no affected man has been
  reported with these features.
  No GeneReviews or StatPearls chapter covers this disorder.
inheritance:
- name: Autosomal recessive
  description: >-
    All reported probands are homozygous for a CFAP70 variant. In the one
    family with segregation data, a fertile brother carries the wild-type
    allele; the parents were not available for testing.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31621862
    reference_title: "CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70, a gene not previously linked to the MMAF phenotype"
    explanation: Two unrelated homozygous probands.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing of the CFAP70 gene revealed that the proband (II-1) carried the homozygous nonsense variant, and his fertile brother (II-2) harboured the wild-type allele"
    explanation: A third homozygous proband, with a fertile wild-type brother.
pathophysiology:
- name: Loss of CFAP70 from the Sperm Axoneme
  description: >-
    The splice-site allele removes CFAP70 from the sperm flagellum, and the
    p.R988X nonsense allele leaves a truncated protein lacking C-terminal
    tetratricopeptide repeats 5-8. CFAP70 is a structural component of the C2a
    projection of the central apparatus: in mouse motile cilia, loss of CFAP70,
    CFAP65 (CCDC108) or MYCBPAP destabilizes the other two and collapses the
    projection, and in Chlamydomonas the fap70 mutant lacks most of C2a.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP70
    term:
      id: hgnc:30726
      label: CFAP70
  molecular_functions:
  - preferred_term: structural constituent of the axonemal C2a projection
    modifier: DECREASED
    term:
      id: GO:0005200
      label: structural constituent of cytoskeleton
  cellular_components:
  - preferred_term: Axonemal central pair projection (C2a)
    term:
      id: GO:1990718
      label: axonemal central pair projection
  downstream:
  - target: Failure of Sperm Flagellum Assembly
    causal_link_type: DIRECT
    description: >-
      Without CFAP70 the flagellar axoneme is not assembled properly in
      spermatids; patient sperm lack both outer dynein arm and central pair
      markers.
    evidence:
    - reference: PMID:31621862
      reference_title: "CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Moreover, IF analysis showed the absence of markers for the ODAs and the central pair complex of the axoneme."
      explanation: Patient sperm lacking CFAP70 also lack ODA and central pair markers.
  evidence:
  - reference: PMID:31621862
    reference_title: "CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum."
    explanation: Protein loss in patient sperm with the splice allele.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This nonsense variant generates a truncated CFAP70 protein lacking the C-terminal 5–8 tetratricopeptide repeats (TPRs)."
    explanation: The nonsense allele truncates the TPR region.
  - reference: PMID:42417609
    reference_title: "Proteomic composition and mutual assembly of the C2a projection in vertebrate motile cilia."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The ciliary incorporation of CCDC108, MYCBPAP, and CFAP70 is essential for one another's stability, with the loss of any single component triggering C2a collapse, which destabilizes the central pair microtubules, and ultimately alters the ciliary movement pattern."
    explanation: >-
      Knockout mice show that CFAP70 is a structural component whose loss
      collapses the C2a projection, which grounds the structural molecular
      function.
  - reference: PMID:33988244
    reference_title: "Chlamydomonas FAP70 is a component of the previously uncharacterized ciliary central apparatus projection C2a."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "We also found that fap70-1 mutant axonemes lack most of the C2a projection."
    explanation: The algal ortholog is required for the C2a projection.
  - reference: PMID:30158508
    reference_title: "CFAP70 Is a Novel Axoneme-Binding Protein That Localizes at the Base of the Outer Dynein Arm and Regulates Ciliary Motility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Cryo-electron tomography revealed that the N-terminus of FAP70 resided stably at the base of the ODA."
    explanation: A second axonemal site for the algal ortholog, at the base of the outer dynein arm.
- name: Failure of Sperm Flagellum Assembly
  description: >-
    Flagellar biogenesis fails in spermatids. In mice, CFAP70 helps to
    preassemble the calmodulin- and radial spoke-associated complex in the
    cytoplasm, maintains levels of other MMAF proteins such as QRICH2, and
    controls the localization of axonemal proteins on the manchette; loss of
    CFAP70 also causes club-shaped heads and abnormal manchette disassembly.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatid
    term:
      id: CL:0000018
      label: spermatid
  cellular_components:
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  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
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CFAP70 is required for the biogenesis of spermatid flagella partially by regulating the expression of OAT-associated proteins (e.g., QRICH2), assisting the cytoplasmic preassembly of the calmodulin- and radial spoke-associated complex (CSC), and controlling the manchette localization of axoneme-related proteins."
    explanation: Mechanism of the assembly defect in knockout spermatids.
  - reference: PMID:37458246
    reference_title: "Experimental and molecular support for Cfap70 as a causative gene of 'multiple morphological abnormalities of the flagella' with male infertility†."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Specifically, the lack of CFAP70 impairs sperm flagellum biogenesis and head shaping during spermiogenesis."
    explanation: An independent knockout confirms the flagellar biogenesis defect.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The semen phenotype: coiled, short and absent flagella in the same
    ejaculate, with no progressively motile sperm.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Coiled sperm flagella
    causal_link_type: DIRECT
  - target: Short sperm flagella
    causal_link_type: DIRECT
  - target: Absent sperm flagella
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: Malformed, immotile sperm cannot reach or fertilize the oocyte in vivo.
  evidence:
  - reference: PMID:31621862
    reference_title: "CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In conclusion, this work provides the first evidence that loss of CFAP70 function causes MMAF"
    explanation: MMAF in the first two probands.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."
    explanation: MMAF in the nonsense proband.
mechanistic_hypotheses:
- hypothesis_group_id: cfap70_sperm_restricted_in_humans
  hypothesis_label: CFAP70 loss causes isolated male infertility in humans although knockout mice also develop motile-cilia disease
  status: EMERGING
  description: >-
    All three reported men have infertility alone, with no respiratory or
    other ciliary symptoms. Cfap70 knockout mice, by contrast, develop fully
    penetrant hydrocephalus and sinusitis with central-pair defects in
    ependymal and tracheal cilia, as do knockouts of the other C2a genes.
    Whether the human sparing reflects species differences, redundancy or
    under-ascertainment in three probands is unresolved.
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients carrying CFAP70 variants in Charles Coutton's study23 and our current study have no symptoms other than male sterility, indicating no obvious role or functional redundancy of CFAP70 in the development of ependymal cilia in humans."
    explanation: No extra-reproductive ciliary disease in the three reported men.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The results of the patient's physical examination revealed normal development of male external genitalia, normal bilateral testicular size, no abnormality in the bilateral spermatic veins, normal hormone levels and no PCD-related symptoms."
    explanation: The nonsense proband was examined and had no PCD-related symptoms.
  - reference: PMID:42417609
    reference_title: "Proteomic composition and mutual assembly of the C2a projection in vertebrate motile cilia."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Importantly, the hydrocephalus and sinusitis phenotypes were fully penetrant in the KO mice of each strain (Figure 1K)."
    explanation: >-
      Cfap70 knockout mice have motile-cilia disease, which argues that
      CFAP70 is not sperm-specific. This is mouse evidence; no affected man
      has these features.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "In addition to OAT, Cfap70-KO mice suffer from neonatal hydrocephalus, which leads to a high ratio of premature lethality."
    explanation: A second knockout with hydrocephalus.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary infertility is the presenting complaint; affected men are otherwise well.
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 33-year-old man (II-1) who was diagnosed with primary infertility for five years and his fertile brother (II-2) were recruited for our study"
    explanation: Primary infertility in the nonsense proband.
- category: Reproductive
  name: Reduced sperm motility
  description: Severe asthenozoospermia with no progressively motile sperm.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A semen analysis of the proband (II-1) revealed normal semen volume (1.8 mL), extremely low sperm concentration (2.8 × 106 spermatozoa/mL), no progressive mobile sperm, and a low percent of morphologically normal sperm (2%)"
    explanation: No progressively motile sperm.
- category: Reproductive
  name: Oligozoospermia
  description: >-
    Reported men have reduced sperm concentration (2.8 million/mL in the
    nonsense proband), and knockout mice have low sperm counts. How CFAP70
    loss reduces sperm output is not established, so this phenotype is not
    linked to the causal chain.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A semen analysis of the proband (II-1) revealed normal semen volume (1.8 mL), extremely low sperm concentration (2.8 × 106 spermatozoa/mL), no progressive mobile sperm, and a low percent of morphologically normal sperm (2%)"
    explanation: Low sperm concentration in the nonsense proband.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "A previous high-throughput sequencing study identified two unrelated MMAF individuals with very low sperm counts carrying two homozygous variants (c.178 T > A/p.F60I and c.1723-1G > T) in CFAP70"
    explanation: The two earlier probands also had very low sperm counts.
- category: Reproductive
  name: Coiled sperm flagella
  description: The most frequent flagellar anomaly (39% of sperm in the nonsense proband).
  phenotype_term:
    preferred_term: Coiled sperm flagella
    term:
      id: HP:0032560
      label: Coiled sperm flagella
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."
    explanation: Coiled flagella in patient sperm.
- category: Reproductive
  name: Short sperm flagella
  description: About a quarter of sperm in the nonsense proband.
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."
    explanation: Short flagella in patient sperm.
- category: Reproductive
  name: Absent sperm flagella
  description: About a quarter of sperm in the nonsense proband.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The spermatozoa of the proband (II-1) exhibited multiple flagellar malformations, including short, coiled, and absent flagella."
    explanation: Absent flagella in patient sperm.
genetic:
- name: CFAP70
  association: Causal
  gene_term:
    preferred_term: CFAP70
    term:
      id: hgnc:30726
      label: CFAP70
  notes: >-
    Reported alleles are homozygous: a splice-acceptor variant
    (c.1723-1G>T) and a missense variant (p.Phe60Ile) from a 167-patient MMAF
    cohort, and a nonsense variant (c.2962C>T, p.R988X) in a Chinese man.
    ClinGen has not curated CFAP70 for any disease, so no gene-disease
    validity tier is recorded.
  evidence:
  - reference: PMID:31621862
    reference_title: "CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One patient had a homozygous splice variant c.1723-1G>T, altering a consensus splice acceptor site of CFAP70 exon 16, and one had a likely deleterious missense variant in exon 3 (p.Phe60Ile)."
    explanation: First two probands.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A homozygous nonsense variant (c.2962C > T/p.R988X) in CFAP70 was identified in a Chinese infertile man with OAT."
    explanation: Third proband.
animal_models:
- name: Cfap70 knockout mouse
  species: Mouse
  genotype: Cfap70-/- (CRISPR knockout), homozygous
  publication: PMID:37352829
  description: >-
    Knockout males are sterile with low sperm counts, low motility and MMAF
    sperm. They also develop neonatal hydrocephalus with premature death,
    which has not been reported in patients.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    description: The knockout reproduces the human oligoasthenoteratozoospermia with MMAF.
    evidence:
    - reference: PMID:37352829
      reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Morphologic analysis of spermatozoa using Papanicolaou staining (Fig. 1f) and SEM (Fig. 1g) revealed that Cfap70-KO spermatozoa were malformed with short and coiled flagella."
      explanation: MMAF in knockout sperm.
  - target: Failure of Sperm Flagellum Assembly
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: The knockout shows the spermatid assembly defect, alongside motile-cilia disease that patients lack.
    limitations: >-
      Knockout mice develop hydrocephalus and sinusitis from motile-cilia
      dysfunction, so they model a broader ciliopathy than the isolated
      infertility seen in the three reported men.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse ependymal and airway cilia depend on CFAP70 for central-pair
        stability, and knockouts develop hydrocephalus; no CFAP70-deficient
        man has had hydrocephalus or respiratory disease, so the extra-gonadal
        phenotype does not transfer to humans on present evidence.
    evidence:
    - reference: PMID:37352829
      reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In this study, we report that Cfap70-KO mice exhibit male infertility with OAT and that CFAP70 is required for the assembly of flagella in mouse early spermatids."
      explanation: The knockout localizes the defect to flagellar assembly in early spermatids.
- name: Cfap70 TPR5-8 truncation mouse
  species: Mouse
  genotype: Cfap70 truncation lacking tetratricopeptide repeats 5-8, homozygous
  publication: PMID:37352829
  description: >-
    Mice expressing CFAP70 truncated like the patient's p.R988X protein
    (the exact allele could not be engineered) are sterile with low sperm
    count and motility.
  modeled_mechanisms:
  - target: Loss of CFAP70 from the Sperm Axoneme
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: Models the C-terminal truncation produced by the patient allele.
    limitations: >-
      The patient's exact nonsense codon could not be edited in mouse, so the
      model approximates rather than reproduces the human allele.
    evidence:
    - reference: PMID:37352829
      reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cfap70-truncated mice lacking 5-8 tetratricopeptide repeats (TPRs) mimic the patient's symptoms."
      explanation: The truncation model reproduces the patient phenotype.
- name: Cfap70-deficient mouse (Chen 2023)
  species: Mouse
  genotype: Cfap70-deficient (CRISPR), homozygous
  publication: PMID:37458246
  description: >-
    An independent knockout with MMAF, abnormal head shaping and abnormal
    manchette disassembly; CFAP70 interacts with the ODA intermediate chains
    DNAI1 and DNAI2.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    description: Independent confirmation of MMAF in Cfap70-deficient mice.
    evidence:
    - reference: PMID:37458246
      reference_title: "Experimental and molecular support for Cfap70 as a causative gene of 'multiple morphological abnormalities of the flagella' with male infertility†."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Our findings show that the loss of CFAP70 leads to multiple morphological abnormalities of the flagella and spermiogenesis defects."
      explanation: MMAF in the second knockout line.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect. The one treated proband had a live
    birth after two cycles. In mice, ICSI with knockout sperm produced
    healthy offspring but at lower two-cell and blastocyst rates than with
    wild-type sperm.
  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 irrelevant to fertilization.
    evidence:
    - reference: PMID:37352829
      reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "ICSI using the spermatozoa from the CFAP70-mutated patient (II-1) was applied for two cycles and successfully resulted in a live birth (Table 3)."
      explanation: Live birth from ICSI with patient sperm.
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ICSI using the spermatozoa from the CFAP70-mutated patient (II-1) was applied for two cycles and successfully resulted in a live birth (Table 3)."
    explanation: The only reported human ICSI outcome.
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, the rates of two-cell embryos and blastocysts were reduced upon ICSI treatment using spermatozoa from Cfap70-KO mice compared with those using wild-type spermatozoa (Table 2)."
    explanation: >-
      In mice ICSI works but with reduced embryo development, a caveat for
      counselling that has not been tested in more than one patient.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP70 variants are known. All children
    conceived by ICSI are obligate heterozygous carriers.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Overall, we demonstrate that CFAP70 is necessary to assemble spermatid flagella and that CFAP70 gene could be used as a diagnostic target for male infertility with OAT in the clinic."
    explanation: >-
      The authors propose CFAP70 as a clinical diagnostic target; genetic
      counselling follows from a molecular diagnosis.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Probands were identified by whole-exome
    sequencing with Sanger confirmation. 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:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP70 variants were detected in infertile men with OAT by whole exome sequencing and Sanger sequencing confirmation."
    explanation: Exome sequencing with Sanger confirmation identified the proband.
  - reference: PMID:31621862
    reference_title: "CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on whole-exome sequencing data from a large cohort of 167 MMAF-affected subjects, we identified two unrelated affected individuals carrying a homozygous deleterious mutation in CFAP70"
    explanation: Exome screening of an MMAF cohort.
- name: Semen Analysis
  description: >-
    Shows severe oligoasthenoteratozoospermia with MMAF (coiled, short and
    absent flagella) and no progressive motility.
  evidence:
  - reference: PMID:37352829
    reference_title: "CFAP70 is a solid and valuable target for the genetic diagnosis of oligo-astheno-teratozoospermia in infertile men."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A semen analysis of the proband (II-1) revealed normal semen volume (1.8 mL), extremely low sperm concentration (2.8 × 106 spermatozoa/mL), no progressive mobile sperm, and a low percent of morphologically normal sperm (2%)"
    explanation: Semen findings in the nonsense proband.
- name: Immunofluorescence of CFAP70 in Sperm
  description: >-
    Absent CFAP70, outer dynein arm and central pair staining in sperm
    flagella supports the diagnosis for loss-of-function alleles.
  evidence:
  - reference: PMID:31621862
    reference_title: "CFAP70 mutations lead to male infertility due to severe astheno-teratozoospermia. A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the sperm cells from the patient carrying the splice variant, immunofluorescence (IF) experiments confirmed the absence of the protein in the sperm flagellum."
    explanation: Immunofluorescence demonstrates protein loss in patient sperm.

📚

References & Deep Research

Deep Research

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Evaluations and curation notes (1)

Create: Spermatogenic Failure 41 (CFAP70) · 2026-10-16T13:41:55Z · View source

New entry for SPGF41 (MONDO:0032863), autosomal recessive MMAF/oligoasthenoteratozoospermia caused by CFAP70. Deep research with the claude_code provider (research/Spermatogenic_Failure_41-deep-research-claude_code.md; preflight-dr matched CFAP70) was used as leads only; a direct PubMed search for CFAP70 added the C2a-projection mouse knockout study (PMID:42417609). Pathograph: CFAP70 loss (GO:0005200 structural constituent of cytoskeleton, DECREASED, grounded in C2a collapse in knockout mice) -> failure of sperm flagellum assembly -> MMAF -> motility, flagellar and infertility phenotypes; oligozoospermia left unlinked. Hypothesis records that the three reported men had isolated infertility while knockout mice develop hydrocephalus and sinusitis (REFUTE items, mouse-only). ClinGen has no CFAP70 curation, so no validity tier. Three mouse models with a typed SPECIES_MISMATCH divergence; ICSI (one live birth, reduced embryo development in mice), genetic counselling, exome testing, semen analysis and immunofluorescence. No GeneReviews/StatPearls chapter. Stub stubs/Spermatogenic_Failure_41.yaml deleted. Validated with just validate, validate-terms, count-verified-snippets, check-entity-refs, check-causal-targets, check-duplicate-keys, check-genereviews, the corpus snippet/title gates, gene-activity grounding and validate-disorders.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-sonnet-5-5 11 citations 2026-10-16T13:14:39.125096

1. Disease Information

Overview. SPGF41 is an autosomal recessive form of male infertility caused by biallelic loss of function of CFAP70. It presents as oligo-astheno-teratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF). Affected men have no other reported symptoms. [Secondary: MGI/OMIM:618670, Disease Ontology DOID:0111912, MalaCards]
Identifiers. MONDO:0032863. OMIM #618670, which two MGI pages agree on. One search result suggested OMIM:619515, but that came from a garbled page layout and is unresolved. DOID:0111912. The Disease Ontology lists it under "spermatogenic failure", which is_a "autosomal recessive disease".
Synonyms. SPGF41; spermatogenic failure 41; CFAP70-related MMAF; male infertility due to CFAP70 deficiency.
Source type. Aggregated, from case reports and small cohorts. These are not EHR-derived.
Suggested classification. DISEASE (a gene-defined Mendelian entry). It is a candidate for the Spermatogenic_Failure / MMAF grouping, but check existing groupings first.

2. Etiology

Causal factor. Biallelic loss-of-function variants in CFAP70 (10q22.2), which encodes an axonemal protein.
Risk and protective factors. None known beyond genotype. No modifier genes, environmental risk factors, protective variants or gene-environment interactions are reported in what I retrieved.

3. Phenotypes

All items below come from the 2019 and 2023 human reports and the OMIM mirrors. Frequencies are not available. Both 2019 patients and the 2023 patient had the core features, and none had extra-genital findings.

Phenotype	Suggested HPO (look up before binding)	Notes
Male infertility	HP:0003251	Sole clinical complaint.
Asthenozoospermia	HP:0012206	Severe.
Oligozoospermia	HP:0000798	Reported in the OMIM description and the 2023 patient.
Teratozoospermia / MMAF	HP:0012864 (multiple flagellar abnormalities); verify	Short, absent, coiled, irregular-caliber flagella.
Tapered sperm head, short flagella	verify	Listed in the MGI phenotype line.

Onset and course. Lifelong, with presentation at the time of attempted conception. Course is stable. No source gave quality-of-life data.
Not reported. No primary ciliary dyskinesia features (respiratory disease, situs inversus) in the retrieved sources. I did not search specifically for them, so treat "absent" as unconfirmed.

4. Genetic / Molecular Information

Gene. CFAP70 (cilia- and flagella-associated protein 70), 10q22.2. Look up the HGNC ID with runoak before writing it; the repo uses lowercase hgnc:.
Reported variants.
Beurois et al. 2019 (PMID:31621862): two unrelated men from a 167-man MMAF exome cohort. Patient 1 had homozygous c.1723-1G>T, a splice-acceptor change at exon 16. Patient 2 had homozygous p.Phe60Ile in exon 3, a missense variant judged likely deleterious.
Jin et al. 2023 (PMID:37352829): one Chinese man with homozygous nonsense c.2962C>T, p.R988X.
Mechanism class. Loss of function. This is supported by the nonsense and splice variants and by the knockout mice.
Gene–disease validity. I did not check ClinGen or GenCC. Check cache/clingen and just check-gene-validity before recording a tier. Do not assign one yourself.
Not found. Allele frequencies, epigenetic data, chromosomal abnormalities and modifier genes.

5. Environmental Information

None identified. There are no infectious agents. No lifestyle or toxicant data were retrieved. Do not add environmental: entries from this report.

6. Mechanism / Pathophysiology

Causal chain (steps 1 to 3 are demonstrated in humans; steps 4 to 6 rest mainly on the mouse and Chlamydomonas work; the last step is inferred):

Biallelic loss-of-function variants (splice, nonsense, missense) in CFAP70 reduce or abolish CFAP70 protein. Demonstrated by immunofluorescence in the splice-variant patient, where CFAP70 was absent from the flagellum.
CFAP70 is lost from the sperm axoneme. In the 2019 report, outer-dynein-arm and central-pair markers were also absent from the same patient's sperm, so loss of CFAP70 co-occurs with loss of those structures. Whether this is cause or consequence is not settled.
CFAP70 normally sits at the base of the outer dynein arm and binds the axoneme (PMID:30158508; in Chlamydomonas it is placed at the C2a central-apparatus projection, PMID:33988244). It interacts with the outer-dynein-arm components DNAI1 and DNAI2 (PMID:37458246).
Without it, flagellum biogenesis and assembly fail during spermiogenesis, with reduced AKAP3 in the flagella (mouse, PMID:37458246). This leads to MMAF and loss of motility.
Spermiogenesis is also disturbed upstream of the flagellum. Cfap70-null mouse late spermatids have club-shaped heads and abnormal manchette disassembly (PMID:37458246), and sperm counts fall, which fits the oligozoospermia (PMID:37352829).
Result: severe asthenozoospermia, teratozoospermia and oligozoospermia, and male infertility. The branch between flagellar and head or manchette defects is shown in mice, and it is inferred that humans share it.
Suggested GO / CL / UBERON (verify each by lookup): GO sperm flagellum assembly / axonemal dynein complex assembly / cilium movement; CL spermatid (CL:0000018); UBERON testis (UBERON:0000473), epididymis semen/sperm flagellum as relevant. Do not write these IDs without a lookup.
Omics, immune, metabolic. None reported.

7. Anatomical Structures Affected

Testis, specifically the post-meiotic germ cells (spermatids and spermatozoa).
Subcellular: the sperm flagellar axoneme, the outer dynein arm and central apparatus, and the manchette.
No other organs reported. Bilateral, as expected for a systemic germline genotype.

8. Temporal Development

Onset is lifelong, from puberty, and is detected in adulthood on infertility work-up. The course is non-progressive from the information available. No remission patterns are known.

9. Inheritance and Population

Inheritance. Autosomal recessive (HP:0000007). Reported cases are homozygous, and OMIM also describes compound heterozygotes.
Consanguinity. Homozygosity in unrelated patients suggests it may matter, but I did not retrieve the parental data.
Epidemiology. Not available. There is no prevalence figure. Cases are described as rare, and the 2019 yield was 2 of 167 MMAF men (about 1%).
Population. Cases came from a mainly North African/European MMAF cohort (2019) and a Chinese man (2023). Founder effects are not established.
Sex. Male only in terms of phenotype, since the phenotype is infertility of spermatogenic origin.

10. Diagnostics

Semen analysis. Oligo-astheno-teratozoospermia with MMAF morphology, scored on sperm morphology.
Genetic testing. Exome sequencing (it identified both 2019 cases), or a male infertility or MMAF gene panel that includes CFAP70. Biallelic variants confirm the diagnosis.
Supportive. Immunofluorescence for CFAP70 and outer dynein arm markers on sperm. Electron microscopy of the axoneme was not confirmed in what I retrieved.
Differential. Other MMAF genes (DNAH1, CFAP43, CFAP44, WDR66, ARMC2, FSIP2), which are other SPGF entries, and primary ciliary dyskinesia. Note that in the 2019 report, WDR66-mutated patients' sperm also lacked CFAP70 staining, while ARMC2, FSIP2 and CFAP43 mutants retained it.
Screening. None established.

11. Outcome / Prognosis

No mortality or morbidity data. Reported patients have no symptoms besides sterility. Prognosis for natural fertility is poor. Prognosis for assisted reproduction is described as better than for natural conception. Per the 2023 report, ICSI may help affected couples, though that is a suggestion and I found no outcome series for CFAP70 specifically.

12. Treatment

No disease-modifying therapy. The only measure indicated is assisted reproduction, namely ICSI with the patient's own sperm. Suggested NCIT: NCIT:C15986 is wrong here, because it is pharmacotherapy. Look up an ICSI or assisted-reproduction term (candidate: intracytoplasmic sperm injection) and bind only if one verifies. Otherwise leave term: off and use a free-text preferred_term.
Genetic counselling. NCIT:C15240, which the repo lists.
Trials. I did not search ClinicalTrials.gov. None known.
Pharmacogenomics, gene therapy. None.

13. Prevention

There is no primary prevention. Carrier screening and genetic counselling for relatives are appropriate in principle, since this is autosomal recessive. Preimplantation genetic testing is possible after a diagnosis, though I found no literature specific to CFAP70. A transmissible risk is unlikely to apply to the offspring phenotype, so counselling needs a clear statement of carrier status.

14. Other Species / Natural Disease

I did not search OMIA. A GWAS in Holstein cattle listed CFAP70 as a candidate for sire fertility traits (PMID:35484513). That is association only, and it is not a naturally occurring Mendelian disease. A hybrid yellow catfish study reported lower CFAP70 expression in sterile hybrids (PMID:38891632); that is a correlation in a different context.

15. Model Organisms

Mouse knockout (Cfap70-/-). Two independent reports.
Jin et al. 2023 (PMID:37352829): sterile, mainly from oligo-astheno-teratozoospermia. A truncating mouse allele modelled the patient's R988X change and reproduced his features, which is the strongest model-to-human link in the set.
Biol Reprod 2023 (PMID:37458246): MMAF, club-shaped heads, abnormal manchette disassembly, and reduced AKAP3.
Fidelity. Good for the reproductive phenotype. A limitation is that mice show head and manchette defects, which are less prominent in the human reports I retrieved.
Other systems. Chlamydomonas FAP70 mutants show impaired outer dynein arm activity and flagellar motility (PMID:30158508), and the central-apparatus placement is in PMID:33988244. Mouse cell knockdown reduced ciliary beating (PMID:30158508). Evidence source for the mouse and Chlamydomonas items is MODEL_ORGANISM; the cell data are IN_VITRO.
Resources not checked. MGI, IMPC and ZFIN allele pages, beyond the MGI disease-association page above.

Curation Notes for the KB Entry

Decision. Record entry_type: DISEASE. Delete the stub in the curation PR, add a history/disorders/Spermatogenic_Failure_41/ record, and put the claim on a claim-labelled issue titled Curate spermatogenic failure 41 (MONDO:0032863).
Evidence work still needed. Run just fetch-reference for PMIDs 31621862, 37352829, 37458246, 30158508 and 33988244. Re-read each abstract and copy exact snippets. Quote the OMIM text from a cached source if one exists, since I could not access OMIM.
Terms to look up, not trust. Every HPO, GO, CL, UBERON and NCIT ID above is a suggestion that I did not verify. The HGNC ID for CFAP70 was not looked up.
Loose ends. Resolve the OMIM:618670 versus 619515 ambiguity. Check ClinGen for a CFAP70 gene-disease validity assertion. Search for a GeneReviews chapter with just check-genereviews. Search for additional CFAP70 case reports after 2023. The latest PubMed hits listed in my search (PMIDs 38891632 through 42417609) were not individually screened.
Lump/split. One gene, one phenotype, so keep it as a single entry. Compare it against the existing MMAF-gene SPGF entries for possible grouping membership.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	7
Resolved	7
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	7
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	13
Resolved	11
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	2
Terms whose name was checked	4
Terms named correctly	2
Terms named as a different term	2

Terms the report names something else

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

HP:0012206 (1 mention) - the report calls it "Asthenozoospermia"; HP calls it Abnormal sperm motility
HP:0012864 (1 mention) - the report calls it "multiple flagellar abnormalities"; HP calls it Abnormal sperm morphology

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.

Spermatogenic Failure 41

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Inheritance

Mechanistic Hypotheses

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

Deep Research

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Curation Notes for the KB Entry

Sources

Reference Validation

Term Validation

Terms the report names something else

Prefixes with no resolver