Spermatogenic Failure 40

👪

Inheritance

1

Autosomal recessive HP:0000007

Disease requires biallelic CFAP65 variants: homozygous variants in consanguineous Chinese, Pakistani, Tunisian and Iranian families, and compound heterozygous variants in non-consanguineous families.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31501240 SUPPORT Human clinical

"CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF."

Homozygous and compound heterozygous variants across six families.

PMID:42875786 SUPPORT Human clinical

"ROH analysis showed increased autosomal homozygosity in the proband (FROH = 7.88%), supporting parental consanguinity."

Homozygous variant within a run of homozygosity in a consanguineous family.

◈

Mechanistic Hypotheses

1

CFAP65 loss disrupts sperm flagella but spares respiratory ciliary function

cfap65_respiratory_cilia_spared EMERGING

Evidence balance 3 support 2 refute

In knockout mice respiratory cilia lose the C2a projection but keep a normal 9+2 arrangement and show no respiratory disease, attributed to the lower structural demand of short cilia; ependymal cilia are partly affected and many mice develop hydrocephalus. Most patients have isolated infertility, including all those in the two most recent reports. Against this, two of three probands in the first report had chronic wet cough, nasal obstruction and pneumonia, one with later bronchitis and rhinosinusitis, but neither had ciliary biopsy or nasal nitric oxide testing, and one had normal sinus and chest CT. The refuting evidence is therefore weak and unconfirmed, and hydrocephalus has not been reported in patients.

Show evidence (5 references)

PMID:39853433 SUPPORT Model organism

"The knockout mice displayed severe sperm flagellar defects (MMAF), high hydrocephalus incidence, but no significant impact on respiratory cilia."

Respiratory cilia are functionally spared in knockout mice.

PMID:39853433 SUPPORT Human clinical

"Similarly, the patients exhibited MMAF and infertility without respiratory symptoms."

Two further patients without respiratory symptoms.

PMID:42477516 SUPPORT Human clinical

"Based on clinical history and chest X-ray, the affected individuals reported no chronic respiratory symptoms and had no situs inversus, suggesting an isolated sperm-specific phenotype."

No respiratory or laterality findings in two homozygous brothers.

+ 2 more references

⚙

Pathophysiology

5

Loss of CFAP65 Protein in Sperm

Biallelic nonsense, frameshift and splice-site variants abolish CFAP65 in patient sperm. CFAP65 binds central apparatus proteins of the C2a projection (CFAP70, MYCBPAP, SPAG16, SPATA4) and anchors at the base of that projection, acting as a structural stabilizer rather than an enzyme.

CFAP65 hgnc:25325

structural molecule activity GO:0005198 ↓ DECREASED

Axonemal central apparatus GO:1990716

Downstream

Disintegration of the Sperm Axonemal Central Apparatus Without CFAP65 the C2a projection it anchors falls apart, taking the central apparatus with it in sperm.

Defective Acrosome Biogenesis and Sperm Head Shaping How CFAP65 loss disturbs the acrosome and manchette is not settled; it may follow from manchette microtubule disorganization or reflect a separate acrosomal role.

Show evidence (3 references)

PMID:31413122 SUPPORT Human clinical

"CFAP65 staining is present in the acrosome and flagellar midpiece of spermatozoa from normal controls (NCs), but absent in spermatozoa from F1: II-2 and F2: II-2."

Protein absent from patient sperm.

PMID:39853433 SUPPORT Model organism

"CFAP65 was found to anchor at the base of the C2a projection of the axoneme, interacting with proteins such as CFAP70 and MYCBPAP."

Structural placement of CFAP65 in the central apparatus from mouse interactome and ultrastructure.

PMID:42875786 SUPPORT In vitro / ex vivo

"The minigene assay demonstrated complete exon 6 skipping, resulting in a 103-bp transcript deletion and a predicted frameshifted truncated protein p.(Pro182ArgfsTer29)."

A splice allele shown to produce a frameshifted, truncated product.

Disintegration of the Sperm Axonemal Central Apparatus

In patient sperm, central apparatus proteins (CFAP70, MYCBPAP, MYCBP, SPAG16, SPATA4, HYDIN) are lost while doublet-associated proteins (dyneins, N-DRC, radial spokes) are retained, and most flagellar cross-sections show a 9+0 axoneme.

Axonemal central apparatus assembly GO:1904158 ↓ DECREASED

Axonemal central apparatus GO:1990716

Animal models

Cfap65 knockout mouse Mouse recapitulates The same central apparatus proteins are lost from knockout and patient sperm.

Downstream

Sperm Flagellar Axoneme and Mitochondrial Sheath Disorganization The long sperm flagellum depends heavily on central apparatus integrity for stability, so its loss leads to wholesale axonemal disorganization.

Absent sperm axoneme central pair complex

Show evidence (2 references)

PMID:39853433 SUPPORT Human clinical

"IF results showed that CA components, including CFAP70, MYCBPAP, MYCBP, SPAG16, SPATA4, and HYDIN, were absent in sperm of the patient, while DMT-associated components such as DRC1 (N-DRC), DNAH1, DNAH5 (dyneins), IQUB, NME5, RSPH9 (RSs), were normally assembled"

Selective loss of central apparatus proteins in patient sperm.

PMID:31413122 SUPPORT Human clinical

"93.3% (28/30) of F1: II-2 and 83.9% (26/31) of F2: II-2 spermatozoa lacked a central pair complex (CPC) in the axoneme (9+0 structure)"

Most flagellar cross-sections lack the central pair.

Sperm Flagellar Axoneme and Mitochondrial Sheath Disorganization

Flagella fail to assemble properly: axonemes are disorganized, the mitochondrial sheath of the midpiece is poorly assembled or missing, and the fibrous sheath is disorganized or hyperplastic.

Sperm CL:0000019

Sperm flagellum assembly GO:0120316 ↓ DECREASED Sperm mitochondrial sheath assembly GO:0120317 ↓ DECREASED

Sperm flagellum GO:0036126

Animal models

Cfap65 knockout mouse Mouse recapitulates Knockout flagella show complete axonemal disorganization.

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella

Abnormal sperm axoneme morphology

Show evidence (3 references)

PMID:42477516 SUPPORT Human clinical

"TEM further demonstrated severe axonemal disorganization, with absent or disrupted microtubule doublets observed in 85% of the cross-sections."

Axonemal disorganization in patient sperm.

PMID:31413122 SUPPORT Human clinical

"The most apparent defects observed in the longitudinal sections of flagella were poorly assembled or missing MS in the midpiece."

Mitochondrial sheath defects in patient sperm.

PMID:34231842 SUPPORT Model organism

"Moreover, subsequent flagellar elongation was also severely affected and characterized by disrupted assembly of the mitochondrial sheath (MS) in Cfap65-/- male mice."

Knockout mice show the defect arises during flagellar elongation in spermatids.

Defective Acrosome Biogenesis and Sperm Head Shaping

Many patient sperm lack an acrosome or carry a thin one with barely recognizable membranes, and heads are amorphous, tapered or small. In knockout mice the manchette develops abnormally, spermatid heads become hyper-constricted, and protamine precursor processing and nuclear condensation are impaired.

Spermatid CL:0000018

Acrosome assembly GO:0001675 ↓ DECREASED

Manchette GO:0002177

Animal models

Cfap65 knockout mouse Mouse partially recapitulates Knockout spermatids show manchette, acrosome and nuclear condensation defects that match the head defects in patients.

Downstream

Acrosomal hypoplasia

Abnormal sperm head morphology

Show evidence (3 references)

PMID:31413122 SUPPORT Human clinical

"Most of the acrosomes were quite thin and showed highly diminished contents with barely recognisable inner and outer acrosomal membranes."

Acrosome hypoplasia on electron microscopy of patient sperm.

PMID:34231842 SUPPORT Model organism

"In Cfap65-/- mouse testes, hyper-constricted sperm heads were apparent in step 9 spermatids accompanied by abnormal manchette development, and acrosome biogenesis was abnormal in the maturation phase."

Knockout spermatids show manchette and acrosome defects.

PMID:39853433 SUPPORT Model organism

"Loss of CFAP65 caused disorganization of the sperm head-shaping microtubule structure and impaired protamine precursor removal, leading to nuclear condensation defects and poor assisted reproductive outcomes."

Manchette and nuclear condensation defects in knockout mice.

Multiple Morphological Abnormalities of the Sperm Flagella

The semen phenotype: absent, short, bent, coiled and irregular flagella in nearly all sperm, usually with complete immotility.

Sperm CL:0000019

Animal models

Cfap65 frameshift mouse Mouse recapitulates The mutant reproduces the human MMAF semen phenotype.

Downstream

Reduced sperm motility

Male infertility Immotile, malformed 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:42477516 SUPPORT Human clinical

"Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."

MMAF in nearly all sperm of two brothers.

PMID:31501240 SUPPORT Human clinical

"CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF."

MMAF in six further families.

⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

13

Genitourinary 12

Male infertility HP:0003251

Show evidence (1 reference)

PMID:31571197 SUPPORT Human clinical

"Here, we report a man with primary infertility, who had a typical MMAF phenotype."

Primary infertility in a homozygous nonsense proband.

Reduced sperm motility HP:0012207

Show evidence (2 references)

PMID:31413122 SUPPORT Human clinical

"To the best of our knowledge, we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile."

Complete immotility in three probands.

PMID:42875786 SUPPORT Human clinical

"Semen analysis showed a sperm concentration of 8.1 × 10⁶/mL, with total and progressive motility of 0%."

Complete asthenozoospermia in a splice-site proband.

Absent sperm flagella HP:0032558

Show evidence (1 reference)

PMID:42477516 SUPPORT Human clinical

"Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."

Absent flagella among MMAF features.

Short sperm flagella HP:0032559

Show evidence (1 reference)

PMID:42477516 SUPPORT Human clinical

"Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."

Short flagella among MMAF features.

Coiled sperm flagella HP:0032560

Show evidence (1 reference)

PMID:42477516 SUPPORT Human clinical

"Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."

Coiled flagella among MMAF features.

Bent sperm flagella HP:0034811

Show evidence (1 reference)

PMID:42477516 SUPPORT Human clinical

"Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."

Bent flagella among MMAF features.

Irregularly shaped sperm tail HP:0033393

Show evidence (1 reference)

PMID:31413122 SUPPORT Human clinical

"Sperm tails displayed unidentifiable or swollen midpieces and shorter principal pieces of highly irregular width, indicating poorly assembled mitochondrial sheaths (MS) and misarranged fibrous sheaths (FS)."

Irregular-width flagella in patient sperm.

Abnormal sperm axoneme morphology HP:0033524

Show evidence (1 reference)

PMID:42477516 SUPPORT Human clinical

"TEM further demonstrated severe axonemal disorganization, with absent or disrupted microtubule doublets observed in 85% of the cross-sections."

Axonemal disorganization on TEM.

Absent sperm axoneme central pair complex HP:0033525

Show evidence (1 reference)

PMID:31413122 SUPPORT Human clinical

"93.3% (28/30) of F1: II-2 and 83.9% (26/31) of F2: II-2 spermatozoa lacked a central pair complex (CPC) in the axoneme (9+0 structure)"

Central pair loss in most cross-sections.

Acrosomal hypoplasia HP:0034913

Show evidence (1 reference)

PMID:31413122 SUPPORT Human clinical

"PSA could bind glycoprotein in the acrosome, but its signal for acrosome was absent in 82.0% (41/50) and 77.6% (45/58) of the spermatozoa from F1: II-2 and F2: II-2."

Acrosome staining absent in most sperm of two probands.

Abnormal sperm head morphology HP:0012865

Show evidence (1 reference)

PMID:31413122 SUPPORT Human clinical

"Of the CFAP65 mutant spermatozoa, 72.3% and 68.6% had misshapen heads (a total of 166 and 172 spermatozoa were observed, respectively)."

Misshapen heads in most sperm of two probands.

Oligozoospermia HP:0000798

Show evidence (2 references)

PMID:42875786 SUPPORT Human clinical

"This study investigated a novel homozygous CFAP65 splice-site variant identified in a consanguineous family in which the proband presented with oligozoospermia and complete asthenozoospermia."

Oligozoospermia in a splice-site proband.

PMID:31413122 SUPPORT Human clinical

"Semen analysis showed a reduced sperm count (5.3–6.9×106/mL) with 100% sperm immobility"

Low count in one of three probands.

Immune 1

Recurrent respiratory infections HP:0002205

Show evidence (3 references)

PMID:31413122 SUPPORT Human clinical

"these symptoms gradually developed into recurrent airway infections, bronchitis and rhinosinusitis"

Recurrent airway infections in one proband.

PMID:42477516 REFUTE Human clinical

"Based on clinical history and chest X-ray, the affected individuals reported no chronic respiratory symptoms and had no situs inversus, suggesting an isolated sperm-specific phenotype."

No respiratory disease in two homozygous brothers.

PMID:39853433 REFUTE Human clinical

"Similarly, the patients exhibited MMAF and infertility without respiratory symptoms."

No respiratory symptoms in two further patients.

🧬

Genetic Associations

1

CFAP65 (Causal)

Gene: CFAP65 hgnc:25325

Show evidence (4 references)

PMID:31413122 SUPPORT Human clinical

"No biallelic deleterious variants of CFAP65 were detected in the control cohort of 637 individuals."

Biallelic variants in three probands and none in 637 controls.

PMID:31501240 SUPPORT Human clinical

"CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF."

Replication in six Chinese families.

PMID:31571197 SUPPORT Human clinical

"Our experimental observations on human subjects suggested that CFAP65 is involved in sperm flagellum structure and assembly and that loss-of-function mutations could lead to male infertility in humans by causing the MMAF phenotype."

A further homozygous nonsense (p.Trp892*) proband with MMAF.

+ 1 more reference

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI is the only route to biological parenthood, and patient sperm can fertilize oocytes, but outcomes have been poor: three couples underwent two cycles each with fertilization rates of 22-69% and only biochemical pregnancies that miscarried, and ICSI outcomes for two further patients were also unfavorable. Head defects, acrosome hypoplasia and impaired nuclear condensation are the proposed reasons. Assisted oocyte activation and other strategies have been suggested but not reported.

Mechanism Target:

Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection bypasses the flagellar defect but not the head and nuclear defects.

Show evidence (1 reference)

PMID:31413122 SUPPORT Human clinical

"Fertilisation rates ranged from 22.2% (2/9) to 69.2% (9/13)."

Injected sperm with MMAF can fertilize oocytes.

Show evidence (2 references)

PMID:31413122 REFUTE Human clinical

"Each couple had undergone two ICSI cycles, but clinical pregnancy was not achieved."

No clinical pregnancy in six ICSI cycles across three couples.

PMID:39853433 REFUTE Human clinical

"Unfortunately, the ICSI outcomes for the patients and Cfap65−/− mice were not favorable"

Unfavorable ICSI outcomes in two further patients.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling on autosomal recessive recurrence and carrier testing of relatives once the familial CFAP65 alleles are known, including the expectation of poor ICSI outcomes.

Show evidence (1 reference)

PMID:31413122 SUPPORT Human clinical

"This finding may also have important clinical implications for genetic and reproductive counselling of affected families."

The authors name genetic and reproductive counselling as the application.

🔬

Diagnosis

3

Molecular Genetic Testing

Establishes the diagnosis. Probands have been identified by whole-exome sequencing with Sanger confirmation; minigene assays can confirm splice effects.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:31501240 SUPPORT Human clinical

"We conducted genetic analysis using whole-exome sequencing in 88 Han Chinese MMAF probands."

Whole-exome sequencing identified the causal alleles.

Semen Analysis

Shows severe asthenozoospermia, usually complete immotility, with MMAF and often misshapen heads; sperm concentration may be low.

Show evidence (1 reference)

PMID:42875786 SUPPORT Human clinical

"Semen analysis showed a sperm concentration of 8.1 × 10⁶/mL, with total and progressive motility of 0%."

Semen analysis reveals the motility defect.

Transmission Electron Microscopy of Sperm

Shows a 9+0 axoneme or disorganized doublets, poorly assembled mitochondrial sheath and, in many patients, thin or absent acrosomes.

Transmission Electron Microscopy NCIT:C18216

Show evidence (1 reference)

PMID:31413122 SUPPORT Human clinical

"Ultrastructural and immunostaining analyses of spermatozoa from two patients showed highly aberrant sperm morphology with severe defects such as acrosome hypoplasia, disruption of the mitochondrial sheath and absence of the central pair complex."

Ultrastructure shows the combined head and flagellar lesion.

🐁

Animal Models

2

Cfap65 frameshift mouse

Male mice homozygous for a CRISPR-induced frameshift in Cfap65 have sperm phenotypes consistent with human MMAF.

Species

Mouse

Genotype

Cfap65 CRISPR-Cas9 frameshift allele, homozygous

Publication

PMID:31501240

Pathograph links

Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high observes: cellular The mutant reproduces the human MMAF semen phenotype.

Divergences from the human mechanism

species mismatch qualifying

Mouse sperm have a hooked head and longer flagellum than human sperm, so head and flagellar defects are scored on a different baseline.

Show evidence (1 reference)

PMID:31501240 SUPPORT Model organism

"Remarkably, the phenotypes of Cfap65-mutated male mice were consistent with human MMAF."

Authors' statement that the mutant matches human MMAF.

Cfap65 knockout mouse

Knockout males have severe MMAF, acrosome and manchette defects and reduced sperm counts; females remain fertile. Respiratory cilia lose the C2a projection without overt disease, and on a pure C57BL/6 background over two-thirds of pups develop hydrocephalus, most dying before three weeks of age.

Species

Mouse

Genotype

Cfap65-/- (knockout), homozygous

Publication

PMID:39853433

Pathograph links

Disintegration of the Sperm Axonemal Central Apparatus recapitulates fidelity: high observes: molecular The same central apparatus proteins are lost from knockout and patient sperm.

Show evidence (1 reference)

PMID:39853433 SUPPORT Model organism

"In motile cilia/flagella of Cfap65−/− mice, the same CA components defects were also observed in the sperm flagella, without DMT proteins defects"

Knockout sperm lose the same central apparatus components as patient sperm.

Defective Acrosome Biogenesis and Sperm Head Shaping partially recapitulates fidelity: moderate observes: cellular Knockout spermatids show manchette, acrosome and nuclear condensation defects that match the head defects in patients.

Limitations: Manchette dynamics and protamine processing were examined only in mice; patients show the end result (thin or absent acrosomes, misshapen heads) but the developmental steps have not been observed in human testis.

Divergences from the human mechanism

species mismatch qualifying

Mouse spermatid head shaping produces a hooked head, unlike the spatulate human head, so the hyper-constricted mouse head is not a direct counterpart of the tapered or small human head.

Show evidence (1 reference)

PMID:39853433 SUPPORT Model organism

"Loss of CFAP65 caused disorganization of the sperm head-shaping microtubule structure and impaired protamine precursor removal, leading to nuclear condensation defects and poor assisted reproductive outcomes."

Manchette and nuclear condensation defects in knockout spermatids.

Sperm Flagellar Axoneme and Mitochondrial Sheath Disorganization recapitulates fidelity: high observes: cellular Knockout flagella show complete axonemal disorganization.

Limitations: Knockout mice also develop hydrocephalus at high frequency on a C57BL/6 background, which has not been reported in patients.

Divergences from the human mechanism

species mismatch immaterial

Hydrocephalus in knockout mice reflects ependymal cilia, which are outside this node; it does not bear on the flagellar claim but shows the mouse is not a clean model of the human whole-body phenotype.

Show evidence (1 reference)

PMID:39853433 SUPPORT Model organism

"The knockout mice displayed severe sperm flagellar defects (MMAF), high hydrocephalus incidence, but no significant impact on respiratory cilia."

Severe flagellar defects in knockout males.

{ }

Source YAML

click to show

name: Spermatogenic Failure 40
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF40
- spermatogenic failure 40
- CFAP65-related multiple morphological abnormalities of the sperm flagella
- CFAP65-related asthenoteratozoospermia with acrosome hypoplasia
description: >-
  Spermatogenic failure 40 (SPGF40) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in CFAP65 (formerly CCDC108),
  which encodes a large testis-enriched cilia- and flagella-associated protein.
  CFAP65 is a structural component at the base of the C2a projection of the
  axonemal central apparatus; without it the C2a projection and the wider
  central apparatus disintegrate in the sperm flagellum. Almost all reported
  alleles are nonsense, frameshift or splice-site variants.

  Affected men have severe asthenoteratozoospermia, usually with completely
  immotile sperm and multiple morphological abnormalities of the sperm
  flagella (MMAF): absent, short, bent, coiled and irregular flagella with
  poorly assembled mitochondrial sheaths and a 9+0 axoneme lacking the
  central pair. Many patients also have acrosome hypoplasia and misshapen
  heads, reflecting a second role in acrosome biogenesis and in head shaping
  by the manchette. Sperm counts are normal to moderately low.

  Most patients have isolated infertility, but a few have reported chronic
  cough, sinusitis or pneumonia; in knockout mice respiratory cilia lose the
  C2a projection without overt disease, while many mice develop
  hydrocephalus. ICSI achieves fertilization, but reported pregnancy outcomes
  are poor.
disease_term:
  preferred_term: spermatogenic failure 40
  term:
    id: MONDO:0032859
    label: spermatogenic failure 40
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 618664; the CFAP65 gene entry
  is OMIM 614270. ClinGen has no gene-disease validity classification for
  CFAP65: the ClinGen gene-validity export snapshot of 2026-10-14
  (data/clingen/gene_validity.csv) has no CFAP65 row. The ClinGen record for
  CFAP47 and X-linked spermatogenic failure 3 mentions CFAP65 only as an
  interacting protein. No GeneReviews chapter covers this disease (Bookshelf
  index snapshot 2026-09-10). Abstract-only caches: PMID:31501240,
  PMID:31571197, PMID:34231842 and PMID:42875786; PMID:31413122,
  PMID:39853433 and PMID:42477516 are full text. Reports disagree on where
  CFAP65 sits in sperm (acrosome and midpiece by immunostaining, or the
  central apparatus by interactome and ultrastructure); this entry follows
  the central apparatus placement for the flagellar defect and keeps the
  acrosomal defect as a separate node.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic CFAP65 variants: homozygous variants in
    consanguineous Chinese, Pakistani, Tunisian and Iranian families, and
    compound heterozygous variants in non-consanguineous families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:31501240
    reference_title: "Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF."
    explanation: Homozygous and compound heterozygous variants across six families.
  - reference: PMID:42875786
    reference_title: "Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ROH analysis showed increased autosomal homozygosity in the proband (FROH = 7.88%), supporting parental consanguinity."
    explanation: Homozygous variant within a run of homozygosity in a consanguineous family.
pathophysiology:
- name: Loss of CFAP65 Protein in Sperm
  description: >-
    Biallelic nonsense, frameshift and splice-site variants abolish CFAP65 in
    patient sperm. CFAP65 binds central apparatus proteins of the C2a
    projection (CFAP70, MYCBPAP, SPAG16, SPATA4) and anchors at the base of
    that projection, acting as a structural stabilizer rather than an enzyme.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP65
    term:
      id: hgnc:25325
      label: CFAP65
  molecular_functions:
  - preferred_term: structural molecule activity
    modifier: DECREASED
    term:
      id: GO:0005198
      label: structural molecule activity
  cellular_components:
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  downstream:
  - target: Disintegration of the Sperm Axonemal Central Apparatus
    causal_link_type: DIRECT
    description: Without CFAP65 the C2a projection it anchors falls apart, taking the central apparatus with it in sperm.
    evidence:
    - reference: PMID:39853433
      reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "However, CFAP65 deficiency led to the disintegration of the C2a projection, compromising ciliary and flagellar integrity."
      explanation: Knockout mice lose the C2a projection when CFAP65 is absent.
  - target: Defective Acrosome Biogenesis and Sperm Head Shaping
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      How CFAP65 loss disturbs the acrosome and manchette is not settled; it
      may follow from manchette microtubule disorganization or reflect a
      separate acrosomal role.
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP65 staining is present in the acrosome and flagellar midpiece of spermatozoa from normal controls (NCs), but absent in spermatozoa from F1: II-2 and F2: II-2."
    explanation: Protein absent from patient sperm.
  - reference: PMID:39853433
    reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CFAP65 was found to anchor at the base of the C2a projection of the axoneme, interacting with proteins such as CFAP70 and MYCBPAP."
    explanation: Structural placement of CFAP65 in the central apparatus from mouse interactome and ultrastructure.
  - reference: PMID:42875786
    reference_title: "Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The minigene assay demonstrated complete exon 6 skipping, resulting in a 103-bp transcript deletion and a predicted frameshifted truncated protein p.(Pro182ArgfsTer29)."
    explanation: A splice allele shown to produce a frameshifted, truncated product.
- name: Disintegration of the Sperm Axonemal Central Apparatus
  description: >-
    In patient sperm, central apparatus proteins (CFAP70, MYCBPAP, MYCBP,
    SPAG16, SPATA4, HYDIN) are lost while doublet-associated proteins
    (dyneins, N-DRC, radial spokes) are retained, and most flagellar
    cross-sections show a 9+0 axoneme.
  biological_scale: MOLECULAR
  cellular_components:
  - preferred_term: Axonemal central apparatus
    term:
      id: GO:1990716
      label: axonemal central apparatus
  biological_processes:
  - preferred_term: Axonemal central apparatus assembly
    modifier: DECREASED
    term:
      id: GO:1904158
      label: axonemal central apparatus assembly
  downstream:
  - target: Sperm Flagellar Axoneme and Mitochondrial Sheath Disorganization
    causal_link_type: DIRECT
    description: >-
      The long sperm flagellum depends heavily on central apparatus integrity
      for stability, so its loss leads to wholesale axonemal disorganization.
  - target: Absent sperm axoneme central pair complex
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:39853433
    reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IF results showed that CA components, including CFAP70, MYCBPAP, MYCBP, SPAG16, SPATA4, and HYDIN, were absent in sperm of the patient, while DMT-associated components such as DRC1 (N-DRC), DNAH1, DNAH5 (dyneins), IQUB, NME5, RSPH9 (RSs), were normally assembled"
    explanation: Selective loss of central apparatus proteins in patient sperm.
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "93.3% (28/30) of F1: II-2 and 83.9% (26/31) of F2: II-2 spermatozoa lacked a central pair complex (CPC) in the axoneme (9+0 structure)"
    explanation: Most flagellar cross-sections lack the central pair.
- name: Sperm Flagellar Axoneme and Mitochondrial Sheath Disorganization
  description: >-
    Flagella fail to assemble properly: axonemes are disorganized, the
    mitochondrial sheath of the midpiece is poorly assembled or missing, and
    the fibrous sheath is disorganized or hyperplastic.
  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
  - preferred_term: Sperm mitochondrial sheath assembly
    modifier: DECREASED
    term:
      id: GO:0120317
      label: sperm mitochondrial sheath assembly
  cellular_components:
  - preferred_term: Sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TEM further demonstrated severe axonemal disorganization, with absent or disrupted microtubule doublets observed in 85% of the cross-sections."
    explanation: Axonemal disorganization in patient sperm.
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most apparent defects observed in the longitudinal sections of flagella were poorly assembled or missing MS in the midpiece."
    explanation: Mitochondrial sheath defects in patient sperm.
  - reference: PMID:34231842
    reference_title: "CFAP65 is required in the acrosome biogenesis and mitochondrial sheath assembly during spermiogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, subsequent flagellar elongation was also severely affected and characterized by disrupted assembly of the mitochondrial sheath (MS) in Cfap65-/- male mice."
    explanation: Knockout mice show the defect arises during flagellar elongation in spermatids.
- name: Defective Acrosome Biogenesis and Sperm Head Shaping
  description: >-
    Many patient sperm lack an acrosome or carry a thin one with barely
    recognizable membranes, and heads are amorphous, tapered or small. In
    knockout mice the manchette develops abnormally, spermatid heads become
    hyper-constricted, and protamine precursor processing and nuclear
    condensation are impaired.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatid
    term:
      id: CL:0000018
      label: spermatid
  biological_processes:
  - preferred_term: Acrosome assembly
    modifier: DECREASED
    term:
      id: GO:0001675
      label: acrosome assembly
  cellular_components:
  - preferred_term: Manchette
    term:
      id: GO:0002177
      label: manchette
  downstream:
  - target: Acrosomal hypoplasia
    causal_link_type: DIRECT
  - target: Abnormal sperm head morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the acrosomes were quite thin and showed highly diminished contents with barely recognisable inner and outer acrosomal membranes."
    explanation: Acrosome hypoplasia on electron microscopy of patient sperm.
  - reference: PMID:34231842
    reference_title: "CFAP65 is required in the acrosome biogenesis and mitochondrial sheath assembly during spermiogenesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In Cfap65-/- mouse testes, hyper-constricted sperm heads were apparent in step 9 spermatids accompanied by abnormal manchette development, and acrosome biogenesis was abnormal in the maturation phase."
    explanation: Knockout spermatids show manchette and acrosome defects.
  - reference: PMID:39853433
    reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of CFAP65 caused disorganization of the sperm head-shaping microtubule structure and impaired protamine precursor removal, leading to nuclear condensation defects and poor assisted reproductive outcomes."
    explanation: Manchette and nuclear condensation defects in knockout mice.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The semen phenotype: absent, short, bent, coiled and irregular flagella in
    nearly all sperm, usually with complete immotility.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: Immotile, malformed 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:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."
    explanation: MMAF in nearly all sperm of two brothers.
  - reference: PMID:31501240
    reference_title: "Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF."
    explanation: MMAF in six further families.
mechanistic_hypotheses:
- hypothesis_group_id: cfap65_respiratory_cilia_spared
  hypothesis_label: CFAP65 loss disrupts sperm flagella but spares respiratory ciliary function
  status: EMERGING
  description: >-
    In knockout mice respiratory cilia lose the C2a projection but keep a
    normal 9+2 arrangement and show no respiratory disease, attributed to the
    lower structural demand of short cilia; ependymal cilia are partly
    affected and many mice develop hydrocephalus. Most patients have isolated
    infertility, including all those in the two most recent reports. Against
    this, two of three probands in the first report had chronic wet cough,
    nasal obstruction and pneumonia, one with later bronchitis and
    rhinosinusitis, but neither had ciliary biopsy or nasal nitric oxide
    testing, and one had normal sinus and chest CT. The refuting evidence is
    therefore weak and unconfirmed, and hydrocephalus has not been reported in
    patients.
  evidence:
  - reference: PMID:39853433
    reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The knockout mice displayed severe sperm flagellar defects (MMAF), high hydrocephalus incidence, but no significant impact on respiratory cilia."
    explanation: Respiratory cilia are functionally spared in knockout mice.
  - reference: PMID:39853433
    reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, the patients exhibited MMAF and infertility without respiratory symptoms."
    explanation: Two further patients without respiratory symptoms.
  - reference: PMID:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on clinical history and chest X-ray, the affected individuals reported no chronic respiratory symptoms and had no situs inversus, suggesting an isolated sperm-specific phenotype."
    explanation: No respiratory or laterality findings in two homozygous brothers.
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "F1: II-2 exhibited classic PCD-like symptoms from early life, including a positive history of chronic wet cough, nasal obstruction and pneumonia"
    explanation: >-
      One homozygous proband had a PCD-like respiratory history. No ciliary
      biopsy or nasal nitric oxide test was performed.
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "F2: II-2 also exhibited a positive history of chronic wet cough, nasal obstruction and pneumonia."
    explanation: A second proband with the same history, though his sinus and chest CT were normal.
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:31571197
    reference_title: "A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report a man with primary infertility, who had a typical MMAF phenotype."
    explanation: Primary infertility in a homozygous nonsense proband.
- category: Reproductive
  name: Reduced sperm motility
  description: Sperm are usually completely immotile; some patients retain low motility.
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To the best of our knowledge, we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile."
    explanation: Complete immotility in three probands.
  - reference: PMID:42875786
    reference_title: "Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semen analysis showed a sperm concentration of 8.1 × 10⁶/mL, with total and progressive motility of 0%."
    explanation: Complete asthenozoospermia in a splice-site proband.
- category: Reproductive
  name: Absent sperm flagella
  description: Flagella are frequently missing.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."
    explanation: Absent flagella among MMAF features.
- category: Reproductive
  name: Short sperm flagella
  description: Short 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:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."
    explanation: Short flagella among MMAF features.
- 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:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."
    explanation: Coiled flagella among MMAF features.
- 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:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Morphological analysis revealed classic MMAF features, including absent, short, bent, and coiled flagella in over 97% of sperm."
    explanation: Bent flagella among MMAF features.
- category: Reproductive
  name: Irregularly shaped sperm tail
  description: Principal pieces are short and of highly irregular width.
  phenotype_term:
    preferred_term: Irregular-caliber sperm flagella
    term:
      id: HP:0033393
      label: Irregularly shaped sperm tail
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sperm tails displayed unidentifiable or swollen midpieces and shorter principal pieces of highly irregular width, indicating poorly assembled mitochondrial sheaths (MS) and misarranged fibrous sheaths (FS)."
    explanation: Irregular-width flagella in patient sperm.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: Axonemes are disorganized with absent or disrupted doublets.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "TEM further demonstrated severe axonemal disorganization, with absent or disrupted microtubule doublets observed in 85% of the cross-sections."
    explanation: Axonemal disorganization on TEM.
- category: Reproductive
  name: Absent sperm axoneme central pair complex
  description: Most flagellar cross-sections show a 9+0 axoneme.
  phenotype_term:
    preferred_term: Absent sperm axoneme central pair complex
    term:
      id: HP:0033525
      label: Absent sperm axoneme central pair complex
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "93.3% (28/30) of F1: II-2 and 83.9% (26/31) of F2: II-2 spermatozoa lacked a central pair complex (CPC) in the axoneme (9+0 structure)"
    explanation: Central pair loss in most cross-sections.
- category: Reproductive
  name: Acrosomal hypoplasia
  description: >-
    Acrosomes are absent or thin in most sperm of some patients; the feature is
    variable and not reported in every family.
  phenotype_term:
    preferred_term: Acrosomal hypoplasia
    term:
      id: HP:0034913
      label: Acrosomal hypoplasia
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PSA could bind glycoprotein in the acrosome, but its signal for acrosome was absent in 82.0% (41/50) and 77.6% (45/58) of the spermatozoa from F1: II-2 and F2: II-2."
    explanation: Acrosome staining absent in most sperm of two probands.
- category: Reproductive
  name: Abnormal sperm head morphology
  description: About 70% of sperm have amorphous, tapered or small heads in affected men.
  phenotype_term:
    preferred_term: Abnormal sperm head morphology
    term:
      id: HP:0012865
      label: Abnormal sperm head morphology
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of the CFAP65 mutant spermatozoa, 72.3% and 68.6% had misshapen heads (a total of 166 and 172 spermatozoa were observed, respectively)."
    explanation: Misshapen heads in most sperm of two probands.
- category: Reproductive
  name: Oligozoospermia
  description: >-
    Sperm concentration is moderately low in several patients but normal in
    others.
  phenotype_term:
    preferred_term: Oligozoospermia
    term:
      id: HP:0000798
      label: Oligozoospermia
  evidence:
  - reference: PMID:42875786
    reference_title: "Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study investigated a novel homozygous CFAP65 splice-site variant identified in a consanguineous family in which the proband presented with oligozoospermia and complete asthenozoospermia."
    explanation: Oligozoospermia in a splice-site proband.
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semen analysis showed a reduced sperm count (5.3–6.9×106/mL) with 100% sperm immobility"
    explanation: Low count in one of three probands.
- category: Respiratory
  name: Recurrent respiratory infections
  description: >-
    Reported in two of three probands in one series (chronic wet cough, nasal
    obstruction, pneumonia), not confirmed by ciliary testing, and absent in
    the other reported patients. Evidence is weak; see the respiratory
    hypothesis.
  phenotype_term:
    preferred_term: Recurrent respiratory infections
    term:
      id: HP:0002205
      label: Recurrent respiratory infections
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "these symptoms gradually developed into recurrent airway infections, bronchitis and rhinosinusitis"
    explanation: Recurrent airway infections in one proband.
  - reference: PMID:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on clinical history and chest X-ray, the affected individuals reported no chronic respiratory symptoms and had no situs inversus, suggesting an isolated sperm-specific phenotype."
    explanation: No respiratory disease in two homozygous brothers.
  - reference: PMID:39853433
    reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Similarly, the patients exhibited MMAF and infertility without respiratory symptoms."
    explanation: No respiratory symptoms in two further patients.
genetic:
- name: CFAP65
  association: Causal
  gene_term:
    preferred_term: CFAP65
    term:
      id: hgnc:25325
      label: CFAP65
  notes: >-
    Reported alleles are predominantly nonsense, frameshift and splice-site
    variants, homozygous or compound heterozygous, with one missense variant
    (p.Asn1007Lys) in trans with a frameshift. Biallelic CFAP65 variants
    accounted for 6.7% (3/45 families) of a severe asthenozoospermia cohort and
    6 of 88 probands in an MMAF cohort. ClinGen has not classified this
    gene-disease pair, so no validity tier is recorded.
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "No biallelic deleterious variants of CFAP65 were detected in the control cohort of 637 individuals."
    explanation: Biallelic variants in three probands and none in 637 controls.
  - reference: PMID:31501240
    reference_title: "Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CFAP65 homozygous mutations were identified in four unrelated consanguineous families, and CFAP65 compound heterozygous mutations were found in two unrelated cases with MMAF."
    explanation: Replication in six Chinese families.
  - reference: PMID:31571197
    reference_title: "A novel homozygous CFAP65 mutation in humans causes male infertility with multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our experimental observations on human subjects suggested that CFAP65 is involved in sperm flagellum structure and assembly and that loss-of-function mutations could lead to male infertility in humans by causing the MMAF phenotype."
    explanation: A further homozygous nonsense (p.Trp892*) proband with MMAF.
  - reference: PMID:42477516
    reference_title: "A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A novel homozygous frameshift mutation in CFAP65 (c.582_587delinsCG; p.Q194Hfs*4) was identified."
    explanation: A Pakistani family extends the ancestry range.
animal_models:
- name: Cfap65 frameshift mouse
  species: Mouse
  genotype: Cfap65 CRISPR-Cas9 frameshift allele, homozygous
  publication: PMID:31501240
  description: >-
    Male mice homozygous for a CRISPR-induced frameshift in Cfap65 have sperm
    phenotypes consistent with human MMAF.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The mutant reproduces the human MMAF semen phenotype.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse sperm have a hooked head and longer flagellum than human sperm,
        so head and flagellar defects are scored on a different baseline.
    evidence:
    - reference: PMID:31501240
      reference_title: "Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Remarkably, the phenotypes of Cfap65-mutated male mice were consistent with human MMAF."
      explanation: Authors' statement that the mutant matches human MMAF.
- name: Cfap65 knockout mouse
  species: Mouse
  genotype: Cfap65-/- (knockout), homozygous
  publication: PMID:39853433
  description: >-
    Knockout males have severe MMAF, acrosome and manchette defects and
    reduced sperm counts; females remain fertile. Respiratory cilia lose the
    C2a projection without overt disease, and on a pure C57BL/6 background
    over two-thirds of pups develop hydrocephalus, most dying before three
    weeks of age.
  modeled_mechanisms:
  - target: Disintegration of the Sperm Axonemal Central Apparatus
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: The same central apparatus proteins are lost from knockout and patient sperm.
    evidence:
    - reference: PMID:39853433
      reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In motile cilia/flagella of Cfap65−/− mice, the same CA components defects were also observed in the sperm flagella, without DMT proteins defects"
      explanation: Knockout sperm lose the same central apparatus components as patient sperm.
  - target: Defective Acrosome Biogenesis and Sperm Head Shaping
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Knockout spermatids show manchette, acrosome and nuclear condensation defects that match the head defects in patients.
    limitations: >-
      Manchette dynamics and protamine processing were examined only in mice;
      patients show the end result (thin or absent acrosomes, misshapen heads)
      but the developmental steps have not been observed in human testis.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mouse spermatid head shaping produces a hooked head, unlike the
        spatulate human head, so the hyper-constricted mouse head is not a
        direct counterpart of the tapered or small human head.
    evidence:
    - reference: PMID:39853433
      reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of CFAP65 caused disorganization of the sperm head-shaping microtubule structure and impaired protamine precursor removal, leading to nuclear condensation defects and poor assisted reproductive outcomes."
      explanation: Manchette and nuclear condensation defects in knockout spermatids.
  - target: Sperm Flagellar Axoneme and Mitochondrial Sheath Disorganization
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Knockout flagella show complete axonemal disorganization.
    limitations: >-
      Knockout mice also develop hydrocephalus at high frequency on a
      C57BL/6 background, which has not been reported in patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: IMMATERIAL
      description: >-
        Hydrocephalus in knockout mice reflects ependymal cilia, which are
        outside this node; it does not bear on the flagellar claim but shows
        the mouse is not a clean model of the human whole-body phenotype.
    evidence:
    - reference: PMID:39853433
      reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The knockout mice displayed severe sperm flagellar defects (MMAF), high hydrocephalus incidence, but no significant impact on respiratory cilia."
      explanation: Severe flagellar defects in knockout males.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI is the only route to biological parenthood, and patient sperm can
    fertilize oocytes, but outcomes have been poor: three couples underwent
    two cycles each with fertilization rates of 22-69% and only biochemical
    pregnancies that miscarried, and ICSI outcomes for two further patients
    were also unfavorable. Head defects, acrosome hypoplasia and impaired
    nuclear condensation are the proposed reasons. Assisted oocyte
    activation and other strategies have been suggested but not reported.
  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 bypasses the flagellar defect but not the head and nuclear defects.
    evidence:
    - reference: PMID:31413122
      reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Fertilisation rates ranged from 22.2% (2/9) to 69.2% (9/13)."
      explanation: Injected sperm with MMAF can fertilize oocytes.
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Each couple had undergone two ICSI cycles, but clinical pregnancy was not achieved."
    explanation: No clinical pregnancy in six ICSI cycles across three couples.
  - reference: PMID:39853433
    reference_title: "CFAP65 is essential for C2a projection integrity in axonemes: implications for organ-specific ciliary dysfunction and infertility."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Unfortunately, the ICSI outcomes for the patients and Cfap65−/− mice were not favorable"
    explanation: Unfavorable ICSI outcomes in two further patients.
- name: Genetic Counseling
  description: >-
    Counselling on autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP65 alleles are known, including the
    expectation of poor ICSI outcomes.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This finding may also have important clinical implications for genetic and reproductive counselling of affected families."
    explanation: The authors name genetic and reproductive counselling as the application.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Probands have been identified by whole-exome
    sequencing with Sanger confirmation; minigene assays can confirm splice
    effects.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:31501240
    reference_title: "Biallelic mutations in CFAP65 cause male infertility with multiple morphological abnormalities of the sperm flagella in humans and mice."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conducted genetic analysis using whole-exome sequencing in 88 Han Chinese MMAF probands."
    explanation: Whole-exome sequencing identified the causal alleles.
- name: Semen Analysis
  description: >-
    Shows severe asthenozoospermia, usually complete immotility, with MMAF and
    often misshapen heads; sperm concentration may be low.
  evidence:
  - reference: PMID:42875786
    reference_title: "Identification and splicing assessment of a novel homozygous CFAP65 splice-site variant associated with oligozoospermia and complete asthenozoospermia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Semen analysis showed a sperm concentration of 8.1 × 10⁶/mL, with total and progressive motility of 0%."
    explanation: Semen analysis reveals the motility defect.
- name: Transmission Electron Microscopy of Sperm
  description: >-
    Shows a 9+0 axoneme or disorganized doublets, poorly assembled
    mitochondrial sheath and, in many patients, thin or absent acrosomes.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:31413122
    reference_title: "Biallelic mutations in CFAP65 lead to severe asthenoteratospermia due to acrosome hypoplasia and flagellum malformations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural and immunostaining analyses of spermatozoa from two patients showed highly aberrant sperm morphology with severe defects such as acrosome hypoplasia, disruption of the mitochondrial sheath and absence of the central pair complex."
    explanation: Ultrastructure shows the combined head and flagellar lesion.

📚

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 40 (CFAP65) · 2026-10-16T13:40:57Z · View source

New entry for spermatogenic failure 40 (MONDO:0032859), CFAP65-related MMAF with acrosome hypoplasia. Deep research with the claude_code provider (research/Spermatogenic_Failure_40-deep-research-claude_code.md); just preflight-dr returned PASS for CFAP65. Snippets taken from references_cache only. Chain: loss of CFAP65 (structural molecule activity, decreased; C2a projection of the central apparatus) -> central apparatus disintegration -> axoneme and mitochondrial sheath disorganization -> MMAF; a separate branch for acrosome biogenesis and head shaping (manchette). Respiratory involvement recorded both ways: two of three probands in PMID:31413122 had PCD-like histories without ciliary testing (REFUTE items on the respiratory-sparing hypothesis and SUPPORT on a Recurrent respiratory infections phenotype), while later patients and knockout mice show no respiratory disease (SUPPORT/REFUTE respectively); mouse hydrocephalus kept in the animal model only. ICSI recorded with mostly REFUTE outcome evidence. ClinGen has no CFAP65 curation and no GeneReviews chapter exists. Stub stubs/Spermatogenic_Failure_40.yaml deleted. Validated with the full gate list and validate-disorders.

Claude Code ▸

1. Disease Information

claude-haiku-5-5, claude-sonnet-5-5 11 citations 2026-10-16T13:14:20.220797

1. Disease Information

Overview. SPGF40 is an autosomal recessive male infertility disorder caused by biallelic variants in CFAP65 (2q35). It is a sperm-specific flagellar disorder, classically "multiple morphological abnormalities of the sperm flagella" (MMAF). Sperm tails are absent, short, bent, coiled or of irregular caliber, so sperm motility is severely reduced or absent. Some patients also have sperm-head defects, including acrosomal hypoplasia or aplasia. Sources: MalaCards and MedGen mirror.

Item	Value	Source
MONDO	MONDO:0032859	Search result; consistent with the template
OMIM	#618664 (phenotype); OMIM directs readers to SPGF1 (258150) for locus heterogeneity	Secondary summaries
UMLS / MedGen	C5231451	MedGen mirror
Gene	CFAP65 (cilia and flagella associated protein 65), 2q35	Multiple
Orphanet, ICD-10/11, MeSH	Not verified	—

Synonyms. SPGF40; spermatogenic failure 40; CFAP65-related MMAF or asthenoteratozoospermia (informal).
Data type. The knowledge is aggregated from case series and families, not from EHR data.
Gene-disease validity. One aggregator lists "Limited" with AR inheritance. I did not confirm whether this is ClinGen, GenCC or another source, so do not record it as a ClinGen tier without checking the CGGV: record. Evidence has grown since the original 2019 reports, so a re-curated tier may differ.
Related disorders. Other MMAF genes (CFAP43, CFAP44, CFAP61, CFAP69, DNAH1, ARMC2, CFAP58, TTC29) are separate OMIM spermatogenic failure entries (Tang 2017, PMID:28552195; Coutton 2019, PMID:30686508).

2. Etiology

Causal factor. Biallelic loss-of-function variants in CFAP65 are the only established cause.
Genetic risk and modifiers. None are described.
Environmental risk, protective factors and gene-environment interactions. No evidence found; the relevant cohort papers did not report any.
Heterogeneity. In the Chinese cohort reported by Li et al., biallelic CFAP-gene variants explained 15 of 80 MMAF cases (19%). Of these, 4 were in CFAP65, 7 in CFAP43, 2 in CFAP44 and 2 in CFAP69. This figure came from a search snippet and should be checked against the source.

3. Phenotypes

All phenotypes are male-specific unless stated.

Phenotype	Suggested HPO (verify)	Frequency and notes
Male infertility	HP:0003251	All reported probands
Asthenozoospermia / absent motility	HP:0012206	Very frequent; severely reduced or complete immotility. Wang et al. report "we are the first to report that CFAP65 mutations may cause spermatozoa to be completely immotile" (PMID:31413122)
Teratozoospermia, MMAF	HP:0012864	Absent, short, bent, coiled flagella in >97% of sperm in the 2026 Pakistani family (PMID:42477516)
Abnormal sperm head, acrosomal hypoplasia	Search HPO ("Abnormal acrosome morphology")	Variable; reported in some patients (PMID:31413122), absent in others
Normal semen volume	—	Reported in the Pakistani family
Normal FSH, testosterone, karyotype	—	46,XY, no Y microdeletion, FSH 9.4 and 5.83 mIU/mL in the two Pakistani brothers

Respiratory features are inconsistent across reports (summarized in Table 2 of the 2026 paper, PMC13383139): - Several compound heterozygotes had chronic cough, sinusitis or pneumonia (for example c.5341G>T, p.E1781X). - One patient with c.5341G>T plus c.1775_1776del had PCD-like features, nasosinusitis and tympanitis. - p.W892X and the 2026 frameshift were isolated MMAF with no PCD symptoms. - Whether the respiratory findings are caused by CFAP65 or are incidental is unresolved.

Characteristics. - Onset is at reproductive age, when infertility is detected. - The condition is stable, with no progression reported. - No quality-of-life data were found.

4. Genetic/Molecular Information

Gene. CFAP65, NM_194302.3, 35 exons, encoding a 1,925-amino-acid protein with an ASH domain, an MSP domain, a transmembrane helix (aa 187–209) and a coiled-coil region (PMC13383139). The HGNC ID was not retrieved; look it up, and use lowercase hgnc: in this repository.
Reported variants. The list below is from Table 2 of the 2026 paper, so check each against its original paper.
c.5341G>T (p.E1781X)
c.2284C>T (p.R762X) with c.1751delC (p.P584fs)
c.3021C>A (p.N1007K) with c.5714_5721del (p.L1905fs)
c.1775_1776del (p.P527Rfs*74)
c.2675G>A (p.W892X)
c.582_587delinsCG (p.Q194Hfs*4); homozygous; first cousins; absent from gnomAD and 1000 Genomes; "likely pathogenic" by the authors' tools.
Types. Predominantly nonsense, frameshift and splice variants, with a few missense (p.N1007K). The mechanism is presumed loss of function.
Somatic vs germline. Germline.
Modifier genes, epigenetics and chromosomal abnormalities. None reported.
Allele frequency. Not retrieved apart from the absence of the 2026 variant from gnomAD.

Key primary papers (all human unless noted): 1. Wang W et al. 2019, J Med Genet, PMID:31413122. Whole-exome sequencing of 47 men with severe asthenozoospermia found CFAP65 variants in three. EM and immunostaining showed acrosome hypoplasia, mitochondrial sheath disruption and missing central pairs. 2. Li W et al. 2020, J Med Genet, PMID:31501240. Of 88 MMAF men, six families carried biallelic CFAP65 variants. A Cfap65 frameshift mouse reproduced MMAF. 3. Zhang X et al. 2019, Clin Genet, PMID:31571197. A homozygous nonsense variant in one MMAF patient. 4. 2026, Basic Clin Androl, PMID:42477516. A Pakistani consanguineous family with the p.Q194Hfs*4 variant.

5. Environmental Information

No environmental, lifestyle or infectious contributors were identified.

6. Mechanism / Pathophysiology

Causal chain (steps 1 and 2 are demonstrated in patients and mouse; steps 3 to 5 are partly inferred): 1. Biallelic loss-of-function variants in CFAP65 lead to loss of functional CFAP65 protein. 2. Loss of CFAP65 leads to axonemal defects. The mouse model shows loss of the C2a projection of the central apparatus (per the 2025 Cell Mol Life Sci abstract and the 2026 paper's citation of it); in patients, EM shows missing central pair or doublet microtubules and a disorganized fibrous sheath or outer dense fibers. 3. Axonemal disorganization results in short, absent, bent and coiled flagella (MMAF), which leads to severely impaired or absent sperm motility. This step is inferred rather than shown directly. 4. In a subset of patients, defective acrosome biogenesis causes head abnormalities. The knockout-mouse abstract also mentions manchette defects. The mechanism is not established, and CFAP65 localization (acrosome, midpiece or whole flagellum) is reported inconsistently across studies. 5. Sperm that cannot swim cannot reach or fertilize the oocyte, which results in male infertility.

Branch: motile cilia. The mouse data show hydrocephalus (ependymal cilia) but no significant respiratory cilia impairment. The human respiratory findings are inconsistent, so involvement of other motile cilia is unresolved.

Suggested terms (verify before binding): - GO: sperm flagellum assembly, axoneme assembly, acrosome assembly, cilium movement (GO:0003341 or similar). - CL: spermatid (CL:0000018), sperm (CL:0000019). - GO CC: sperm flagellum, axoneme, motile cilium.

Molecular profiling, single-cell, spatial and multi-omics data. None found. Expression is reported in the 2025 paper only in the context of localization, so I cannot cite it.

7. Anatomical Structures Affected

Organs. Testis (spermatogenesis, spermiogenesis); sperm.
Cells. Elongating spermatids and spermatozoa.
Subcellular. Sperm flagellum axoneme (central pair, C2a projection, doublet microtubules), fibrous sheath, outer dense fibers, mitochondrial sheath, acrosome.
Lateralization. Bilateral; this is a systemic germ-cell defect.
Possible secondary involvement. Respiratory epithelium and ependyma, which are unproven in humans.

8. Temporal Development

Onset is at puberty or adulthood and is usually detected through a fertility evaluation. The course is lifelong and non-progressive. No remission is reported. No critical periods are described.

9. Inheritance and Population

Inheritance. Autosomal recessive, with homozygous and compound heterozygous cases.
Consanguinity. Present in the Pakistani family and in other homozygous cases.
Sex. Affects males; female carriers are unaffected.
Prevalence, incidence, carrier frequency, founder effects and geography. Not retrieved. Cases are reported from Chinese, Pakistani and North African cohorts, but this is not a systematic distribution. MMAF overall is rare.
Penetrance, anticipation and germline mosaicism. Not reported.

10. Diagnostics

Semen analysis. Asthenoteratozoospermia with MMAF morphology; sperm concentration can be normal.
EM of sperm. Axonemal disorganization, missing central pair or doublets, and fibrous sheath disorganization.
Genetic testing. Whole-exome sequencing or an MMAF/male-infertility gene panel including CFAP65; confirm with Sanger sequencing and segregation.
Exclusions. Karyotype (46,XY) and Y microdeletion testing; assess for PCD symptoms.
Differential diagnosis. Other MMAF genes (DNAH1, CFAP43, CFAP44, CFAP69, CFAP61, ARMC2) and PCD.
Screening. No population screening exists. Cascade testing of relatives is reasonable in consanguineous families.
LOINC. None retrieved.

11. Outcome/Prognosis

No survival effect is reported. The main outcome is infertility. No quality-of-life, complication or prognostic-factor data were found apart from the unresolved respiratory question.

12. Treatment

No curative or disease-specific therapy exists. In the sources I read, the 2026 paper reports no ICSI outcomes for CFAP65 carriers. - Assisted reproduction. ICSI is the usual approach for MMAF. In a CFAP43/CFAP44 context, ICSI outcomes were discussed (ref. 4 in PMC13383139), but I could not verify success rates for CFAP65, so none are stated here. - Gene therapy and others. None. - Counseling. Genetic counseling is appropriate. - Suggested NCIT terms (verify). Assisted reproductive technology and genetic counseling (the CLAUDE.md list gives NCIT:C15240 for Genetic Counseling). - Clinical trials. None identified.

13. Prevention

Primary and secondary prevention. None.
Genetic counseling and reproductive options. These include carrier testing of partners in consanguineous families and preimplantation genetic testing where applicable.
Lifestyle measures. None are evidence-based for this condition.

14. Other Species / Natural Disease

Natural disease. I found no OMIA entry. This was not checked directly.
Comparative biology. The 2026 paper's discussion says chicken CFAP65 is related to sperm motility (also noted in the Zhang 2019 summary). This is unverified.
Zoonotic aspects. Not applicable.

15. Model Organisms

Mouse. Two sources describe a Cfap65 knockout or frameshift mouse:
Li et al. 2020 (PMID:31501240) reported a frameshift mutant that reproduced MMAF.
The 2025 Cell Mol Life Sci paper (DOI 10.1007/s00018-025-05583-2) reports C2a projection loss, severe MMAF and hydrocephalus. It also describes acrosome malformation, abnormal head shape, manchette defects and disorganized axonemes.
Fidelity. The mouse reproduces MMAF and, to a variable extent, head defects. It additionally shows hydrocephalus and no clear respiratory phenotype, which differs from the mixed human respiratory findings. This difference justifies a HUMAN_MODEL_MISMATCH discussion in the KB if the entry is curated.
Database resources. MGI, IMPC and the Alliance of Genome Resources were not checked.

Gaps for curators

Fetch and quote the four primary papers (PMIDs 31413122, 31501240, 31571197, 42477516) from references_cache/.
Look up the current ClinGen/GenCC record for CFAP65 / SPGF40 and copy the tier. The "Limited" tier I found may be out of date.
Resolve every suggested HPO, GO, CL and NCIT term by lookup. None is verified.
Find the PMID for the 2025 mouse paper in PubMed.
Check GeneReviews and Orphanet for an MMAF chapter or entry, and run just check-genereviews.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	9
Resolved	9
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	1
Quoted claims found in source	1
Quoted claims not found in source	0
References weighed for topical relevance	9
On topic	7
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	8
Resolved	8
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	5
Terms named correctly	1
Terms named as a different term	1
Terms whose name is worth a second look	3

Terms the report names something else

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

MONDO:0032859 (2 mentions) - the report calls it "MONDO"; MONDO calls it spermatogenic failure 40

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0012206 (1 mention) - the report calls it "Asthenozoospermia / absent motility"; HP calls it Abnormal sperm motility
HP:0012864 (1 mention) - the report calls it "Teratozoospermia, MMAF"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names
CL:0000018 (1 mention) - the report calls it "CL: spermatid"; CL calls it spermatid

Spermatogenic Failure 40

Ask OpenScientist

OpenScientist Report

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

Gaps for curators

Sources

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look