👪

Inheritance

1

Autosomal recessive HP:0000007

Disease requires biallelic CFAP44 variants, mostly homozygous truncating or splice alleles in consanguineous North African and Chinese families, with putative compound heterozygous missense alleles in one patient. Parents are heterozygous carriers.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:28552195 SUPPORT Human clinical

"The homozygous frameshift mutation in CFAP44 (M6) was identified in one subject with MMAF (P002). Both of his parents carried the heterozygous mutation."

Homozygous proband with carrier parents.

PMID:29449551 SUPPORT Human clinical

"In addition, six subjects (7.7%) had a homozygous loss-of-function variant in CFAP44 (Table 2)."

Homozygous loss-of-function alleles in six probands.

◈

Mechanistic Hypotheses

2

CFAP44 acts with its paralog CFAP43 in the I1 dynein tether/tether-head complex

cfap43_cfap44_tether CANONICAL

Evidence balance 2 support 1 refute

CFAP44 and CFAP43 are WD-repeat paralogs that interact and form the heterodimeric T/TH complex of the I1 inner dynein arm in ciliates. Biallelic loss of either gene gives the same MMAF phenotype in men and mice, consistent with a shared complex. In T. brucei, however, knockdown of one protein does not displace the other.

Show evidence (3 references)

PMID:29687140 SUPPORT Model organism

"Here, we provide evidence of a novel ciliary complex composed of two conserved WD-repeat proteins, Fap43p and Fap44p."

The two orthologs interact in Tetrahymena.

PMID:29449551 SUPPORT Human clinical

"There was no significant difference between the three groups (Table 1) as illustrated by the similar morphologies of sperm from patient P43-8 and P44-3, mutated for CFAP43 and CFAP44, respectively"

CFAP43 and CFAP44 patients have indistinguishable semen phenotypes.

PMID:29449551 REFUTE Model organism

"Inactivation of TbCFAP43 by RNAi did not alter the amount and localization of TbCFAP44; conversely, inactivation of TbCFAP44 had no impact on TbCFAP43 protein"

In trypanosomes the two proteins do not depend on each other for localization.

CFAP44 loss causes isolated male infertility without motile-cilia disease

cfap44_sperm_restricted CANONICAL

Evidence balance 1 support 1 refute

No reported CFAP44 patient has respiratory symptoms, hydrocephalus or laterality defects, although the Tetrahymena ortholog is needed for normal ciliary beating. The original explanation was that CFAP43 and CFAP44 link the axoneme to sperm-specific peri-axonemal structures; the later finding of airway and brain phenotypes in Cfap43 knockout mice, and of respiratory symptoms in one CFAP43 family, leaves open whether CFAP44 loss could also affect motile cilia. Cfap44 knockout mice have not been reported to have such phenotypes.

Show evidence (2 references)

PMID:29449551 SUPPORT Human clinical

"These observations suggest that mutations in MMAF genes are only responsible for primary infertility without other PCD features and reinforce the presumption that the sperm flagellum is assembled and organized through a specific way, different from other cilia."

CFAP44 patients in the largest cohort had no PCD features.

PMID:29687140 REFUTE INDIRECT Model organism

"Loss of either protein results in altered waveform, beat stroke and reduced swimming speed."

The ciliate ortholog is needed for motile-cilia beating, so a ciliary role in humans is plausible.

⚙

Pathophysiology

3

Loss of the CFAP44 Tether Protein

Nonsense, frameshift, canonical and deep-intronic splice variants abolish or sharply reduce CFAP44; patient sperm show very weak CFAP44 mRNA, and a deep-intronic variant causes exon 15 skipping. CFAP44 is one half of the tether/tether-head (T/TH) complex, which in ciliates links the I1 inner dynein arm motor domains to the A-tubule of the doublet microtubule; loss of this binding function is inferred from the orthologous complex.

CFAP44 hgnc:25631

dynein complex binding GO:0070840 ↓ DECREASED

Axoneme GO:0005930

Downstream

Sperm Axonemal Disorganization Without CFAP44 the sperm axoneme loses its central pair and its doublet arrangement. How loss of a dynein tether leads to this wider collapse is not established.

Show evidence (6 references)

PMID:29277146 SUPPORT Human clinical

"Real-time quantitative polymerase chain reaction assays also demonstrated that CFAP44 expression was very weak in patient (P)1 and P3"

Loss of CFAP44 transcript in patient sperm.

PMID:30904354 SUPPORT Human clinical

"The relative mRNA expression levels of CFAP43 in patients 1 and 9 and the levels of CFAP44 in patient 5 were significantly lower than those in control sperm samples."

Reduced CFAP44 transcript with a homozygous nonsense allele.

PMID:42371530 SUPPORT Human clinical

"Then, exon 15 skipping was identified through minigene assays and RT-PCR in vivo, resulting in a 111-bp deletion within the mutated sequence, thereby indicating a disruption in the normal splicing of the CFAP44 transcript."

A deep-intronic allele disrupts splicing in patient RNA and a minigene.

+ 3 more references

Sperm Axonemal Disorganization

Most flagellar cross-sections lack the central pair (9+0), and the central pair is disassembled or displaced when present; peripheral doublets are disorganized and fibrous sheaths thickened. Central-pair SPAG6 staining is diffuse and fades along the flagellum, and radial-spoke RSPH1 staining is strongly reduced.

Sperm CL:0000019

Sperm axoneme assembly GO:0007288 ↓ DECREASED

Axoneme GO:0005930 Sperm flagellum GO:0036126

Animal models

Cfap44 knockout mouse Mouse recapitulates Knockout sperm reproduce the patients' axonemal defects.

Trypanosoma brucei TbCFAP44 RNAi knockdown Trypanosoma brucei partially recapitulates Axonemal disorganization after knockdown in a flagellated protozoan.

Downstream

Multiple Morphological Abnormalities of the Sperm Flagella

Absent sperm axoneme central pair complex

Abnormal sperm axoneme morphology

Show evidence (3 references)

PMID:28552195 SUPPORT Human clinical

"The cross section shows a thickened fibrous sheath and an absent central pair of microtubules."

Ultrastructure of sperm from the homozygous CFAP44 proband.

PMID:29449551 SUPPORT Human clinical

"In CFAP44-mutated patients’ sperm cells, RSPH1 staining was significantly reduced"

Radial-spoke head protein reduced in CFAP44 patient sperm.

PMID:29449551 SUPPORT Human clinical

"SPAG6 staining was absent in CFAP43 patient sperm cells, whereas in CFAP44 patients’ sperm cells, SPAG6 immunostaining was present but displayed an abnormal and diffuse pattern concentrated in the midpiece of the spermatozoa, quickly diminishing along the flagellum"

Central-pair protein mislocalized in CFAP44 patient sperm.

Multiple Morphological Abnormalities of the Sperm Flagella

The semen phenotype: almost no morphologically normal sperm, mostly short and absent flagella with coiled, bent and irregular-caliber forms, and no progressive motility.

Sperm CL:0000019

Sperm flagellum assembly GO:0120316 ↓ DECREASED

Animal models

Cfap44 knockout mouse Mouse partially recapitulates Sterility and immotility are reproduced, flagellar malformation less so.

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:28552195 SUPPORT Human clinical

"In individual P002, who carries homozygous frameshift mutations in CFAP44, most spermatozoa had short or absent flagella."

MMAF in the first homozygous CFAP44 proband.

PMID:29449551 SUPPORT Human clinical

"Normal spermatozoa | 1.25 ± 3.5 (n′ = 8) | 0 ± 0 (n′ = 6)"

No morphologically normal sperm in six CFAP44 patients.

⬡

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

9

Male infertility OBLIGATE Reproductive HP:0003251

Show evidence (1 reference)

PMID:29277146 SUPPORT Human clinical

"This study demonstrated that biallelic mutations in CFAP44 and CFAP43 cause MMAF."

Biallelic CFAP44 variants in infertile men with MMAF.

Reduced sperm motility OBLIGATE Reproductive HP:0012207

Show evidence (2 references)

PMID:28552195 SUPPORT Human clinical

"All four subjects were shown to have severe to complete asthenospermia according to semen characteristics."

Asthenozoospermia in CFAP43 and CFAP44 probands.

PMID:42371530 SUPPORT Human clinical

"A comprehensive clinical evaluation was conducted on an infertile Chinese male patient from a nonconsanguineous family with sever asthenozoospermia (no progressive sperm)."

No progressive motility with a deep-intronic allele.

Absent sperm flagella Reproductive HP:0032558

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"Absent flagella | 21.8 ± 17.6 (n′ = 5) | 36.8 ± 4.1 (n′ = 5)"

Mean percentage of sperm without a flagellum in CFAP44 patients (second value).

Short sperm flagella Reproductive HP:0032559

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"Short flagella | 65.3 ± 31.7 (n′ = 8) | 52.2 ± 27 (n′ = 6)"

Mean percentage of short flagella in CFAP44 patients (second value).

Coiled sperm flagella Reproductive HP:0032560

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"Coiled flagella | 8.2 ± 6 (n′ = 6) | 14.4 ± 7 (n′ = 5)"

Mean percentage of coiled flagella in CFAP44 patients (second value).

Bent sperm flagella Reproductive HP:0034811

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"Bent flagella | 10.3 ± 6 (n′ = 3) | 9 (n′ = 1)"

Bent flagella in the one CFAP44 patient with data (second value).

Irregularly shaped sperm tail Reproductive HP:0033393

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"Flagella of irregular caliber | 20.2 ± 19.3 (n′ = 5) | 28.4 ± 16.9 (n′ = 5)"

Mean percentage of irregular-caliber flagella in CFAP44 patients (second value).

Absent sperm axoneme central pair complex Reproductive HP:0033525

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"In CFAP43-mutated and CFAP44-mutated patients, approximately 95% of the cross-sections were abnormal and the main defect observed was the absence of the CPC (9+0 conformation) observed in 81.8, and 66.7% of the cases, respectively, compared to 0% in control fertile subject"

Central-pair loss in 66.7% of CFAP44 cross-sections.

Abnormal sperm axoneme morphology Reproductive HP:0033524

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"The lack of central pair defects was associated with peripheral doublets disorganization in 13.6 and 19% for CFAP43 and CFA44, respectively"

Peripheral doublet disorganization in CFAP44 patient sperm.

🧬

Genetic Associations

1

CFAP44 (Causal)

Gene: CFAP44 hgnc:25631

Show evidence (4 references)

PMID:28552195 SUPPORT Human clinical

"Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject."

First report of a biallelic CFAP44 variant in MMAF.

PMID:29449551 SUPPORT Human clinical

"In addition, six subjects (7.7%) had a homozygous loss-of-function variant in CFAP44 (Table 2)."

Independent replication in six unrelated probands.

PMID:29277146 SUPPORT Human clinical

"Whole exome sequencing analysis of the 27 patients with MMAF identified several CFAP44 mutations"

Five further Chinese patients.

+ 1 more reference

💊

Medical Actions

2

Intracytoplasmic Sperm Injection

Action: Intracytoplasmic Sperm Injection NCIT:C185482

Platform: Other

ICSI bypasses the motility defect. In a retrospective series, CFAP44 patients had a 76% fertilization rate, higher than DNAH1 patients, and half of couples achieved a delivery. In knockout mice, Cfap44-deficient sperm supported embryo development better than sperm from Cfap43 and other MMAF knockouts, although still below wild type.

Mechanism Target:

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

Show evidence (1 reference)

PMID:30251428 SUPPORT Human clinical

"For MMAF patients carrying CFAP44 mutations, the recorded rates of fertilisation, transferable embryos, pregnancy and delivery after ICSI were 76.47%, 88.46%, 50.0% and 50.0% respectively."

Fertilization and delivery rates with CFAP44 patient sperm.

Show evidence (3 references)

PMID:30251428 SUPPORT Human clinical

"The fertilisation rate was significantly higher in the CFAP44+ group than in the DNAH1+ group (76.47% vs. 54.5%, p = 0.0196)."

Fertilization compares favourably with another MMAF genotype.

PMID:34529793 SUPPORT Human clinical

"Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect."

A mixed-genotype MMAF series including CFAP44 patients.

PMID:40070084 SUPPORT INDIRECT Model organism

"Sperm from all KO lines exhibited a marked decrease in supporting embryo development compared to the wild-type, with developmental failure rates ranked as follows: Ccdc146 > Cfap43 > Armc2 > Cfap44-deficient sperm."

In mice, Cfap44-deficient sperm have the smallest embryo-development penalty after ICSI.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Counselling for autosomal recessive recurrence and carrier testing of relatives once the familial CFAP44 alleles are known. A molecular diagnosis also predicts a generally good ICSI prognosis.

Show evidence (1 reference)

PMID:29277146 SUPPORT Human clinical

"These results provide researchers with a new insight to understand the genetic etiology of MMAF and to identify new loci for genetic counselling of MMAF."

The authors name genetic counselling as an application of the diagnosis.

🔬

Diagnosis

4

Molecular Genetic Testing

Establishes the diagnosis by exome sequencing or MMAF gene panels with Sanger confirmation. Deep-intronic splice variants need RNA or minigene studies to confirm. DNAH1, CFAP43 and CFAP44 together explain roughly a quarter to a third of MMAF in exome-sequenced cohorts.

Genetic Testing NCIT:C15709

Show evidence (2 references)

PMID:29449551 SUPPORT Human clinical

"Altogether, DNAH1, CFAP43, and CFAP44 mutations were identified in 28.2% of the analyzed subjects (n = 78) originating from North Africa, Europe, and the Middle East."

Diagnostic yield of exome sequencing in MMAF.

PMID:42371530 SUPPORT Human clinical

"Then, exon 15 skipping was identified through minigene assays and RT-PCR in vivo, resulting in a 111-bp deletion within the mutated sequence, thereby indicating a disruption in the normal splicing of the CFAP44 transcript."

Splicing studies confirm a non-coding variant.

Semen Analysis

Shows MMAF with no progressive motility; no sperm are morphologically normal.

Show evidence (1 reference)

PMID:28552195 SUPPORT Human clinical

"light microscopy, which identified severely distorted sperm flagella, including absent, short, coiled, bent, and irregular-caliber flagella"

Light-microscopic semen morphology defines MMAF.

Transmission Electron Microscopy of Sperm Flagella

Flagellar cross-sections show a missing or displaced central pair, disorganized doublets and thickened fibrous sheaths.

Transmission Electron Microscopy NCIT:C18216

Show evidence (1 reference)

PMID:28552195 SUPPORT Human clinical

"The cross section shows a thickened fibrous sheath and an absent central pair of microtubules."

TEM findings in CFAP44 patient sperm.

Immunofluorescence of Sperm Flagella

Reduced RSPH1 and diffuse SPAG6 staining of patient sperm support pathogenicity of CFAP44 variants.

Show evidence (1 reference)

PMID:29449551 SUPPORT Human clinical

"In CFAP44-mutated patients’ sperm cells, RSPH1 staining was significantly reduced"

Radial-spoke staining is reduced in patient sperm.

🐁

Animal Models

2

Cfap44 knockout mouse

Two independent knockout lines. Males are sterile with immotile sperm and disorganized axonemes; females are fertile. Flagellar malformation is milder than in patients, and sperm show a fragmented mitochondrial sheath and some head defects but little chromatin-compaction defect.

Species

Mouse

Genotype

Cfap44-/- (CRISPR/Cas9 frameshift), homozygous

Publication

PMID:29449551

Pathograph links

Sperm Axonemal Disorganization recapitulates fidelity: high observes: cellular Knockout sperm reproduce the patients' axonemal defects.

Show evidence (2 references)

PMID:29449551 SUPPORT Model organism

"Nevertheless, TEM analysis of Cfap44−/− sperm evidenced ultrastructural defects similar to those found in CFAP44 patients, confirming that CFAP44 is necessary for axonemal organization and function both in mouse and human."

Same ultrastructural defect as in patients.

+ 1 more reference

Multiple Morphological Abnormalities of the Sperm Flagella partially recapitulates fidelity: moderate observes: cellular Sterility and immotility are reproduced, flagellar malformation less so.

Limitations: Cfap44-/- sperm are immotile but their flagellar shape defects are subtler than in patients.

Divergences from the human mechanism

species mismatch qualifying

In one knockout line Cfap44-deficient mouse sperm show subtler flagellar shape defects than the mostly short and absent flagella of patients, so the mouse can underestimate the human morphological defect while reproducing the motility loss.

Show evidence (2 references)

PMID:29449551 SUPPORT Model organism

"Cfap44−/− male mice were also infertile due to flagellar immotility, yet presenting subtler flagellar defects than those observed in patients with CFAP44 mutations"

The authors' statement of the partial match.

+ 1 more reference

Trypanosoma brucei TbCFAP44 RNAi knockdown

Knockdown in the protozoan parasite produces abnormal flagellar beating, disorganized axonemes, multiflagellated cells and growth arrest.

Species

Trypanosoma brucei

Genotype

Tetracycline-inducible RNAi against TbCFAP44

Publication

PMID:29449551

Pathograph links

Sperm Axonemal Disorganization partially recapitulates fidelity: moderate observes: cellular Axonemal disorganization after knockdown in a flagellated protozoan.

Limitations: Trypanosome flagella have a paraflagellar rod instead of the fibrous sheath and outer dense fibres of sperm, and knockdown also blocks cytokinesis, which has no human counterpart.

Divergences from the human mechanism

species mismatch qualifying

The trypanosome flagellum is built on a paraflagellar rod rather than the sperm fibrous sheath, so the peri-axonemal partners of CFAP44 differ between the model and human sperm.

Show evidence (1 reference)

PMID:29449551 SUPPORT Model organism

"In all cases, both TbCFAP44RNAi-induced and TbCFAP43RNAi-induced cells showed abnormal beating (Supplementary Movies 2–5) and stopped proliferating after 24 h and eventually died"

Knockdown impairs flagellar beating.

{ }

Source YAML

click to show

name: Spermatogenic Failure 20
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF20
- spermatogenic failure 20
- CFAP44-related multiple morphological abnormalities of the sperm flagella
- CFAP44-related MMAF
description: >-
  Spermatogenic failure 20 (SPGF20) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in CFAP44 (formerly WDR52),
  which encodes a WD-repeat cilia- and flagella-associated protein. CFAP44 and
  its paralog CFAP43 form the heterodimeric tether/tether-head complex that
  anchors the motor domains of the regulatory I1 inner dynein arm to the
  doublet microtubule in ciliates, and in Trypanosoma both proteins sit next
  to doublets 5 and 6. CFAP44 is expressed predominantly in the testis.

  Affected men have asthenoteratozoospermia with multiple morphological
  abnormalities of the sperm flagella (MMAF): mostly short and absent
  flagella, with coiled, bent and irregular-caliber forms, and no
  progressive motility. Electron microscopy shows loss of the central pair in
  most flagella, displaced doublets and thickened fibrous sheaths, and
  radial-spoke staining is reduced. Respiratory or other motile-cilia
  disease has not been reported. Cfap44 knockout mice are sterile with
  immotile sperm but milder flagellar malformation than patients.
  Intracytoplasmic sperm injection (ICSI) gives good fertilization and
  pregnancy rates.
disease_term:
  preferred_term: spermatogenic failure 20
  term:
    id: MONDO:0054724
    label: spermatogenic failure 20
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 617593. ClinGen has no
  gene-disease validity curation for CFAP44 in the 2026-10-14 export, so no
  validity tier is recorded. No GeneReviews chapter covers the disorder.
  Unlike its paralog CFAP43, CFAP44 has no published patient with
  respiratory symptoms, hydrocephalus or laterality defects (PubMed search
  for CFAP44 or WDR52 with respiratory, ciliary dyskinesia, hydrocephalus or
  cilia, October 2026). A peptidase activity was described for an
  alternatively spliced central fragment of Cfap44 in transfected cells
  (PMID:28887034); it has not been linked to sperm or to this disease and is
  not modelled here.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic CFAP44 variants, mostly homozygous truncating
    or splice alleles in consanguineous North African and Chinese families,
    with putative compound heterozygous missense alleles in one patient.
    Parents are heterozygous carriers.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:28552195
    reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The homozygous frameshift mutation in CFAP44 (M6) was identified in one subject with MMAF (P002). Both of his parents carried the heterozygous mutation."
    explanation: Homozygous proband with carrier parents.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, six subjects (7.7%) had a homozygous loss-of-function variant in CFAP44 (Table 2)."
    explanation: Homozygous loss-of-function alleles in six probands.
pathophysiology:
- name: Loss of the CFAP44 Tether Protein
  description: >-
    Nonsense, frameshift, canonical and deep-intronic splice variants abolish
    or sharply reduce CFAP44; patient sperm show very weak CFAP44 mRNA, and a
    deep-intronic variant causes exon 15 skipping. CFAP44 is one half of the
    tether/tether-head (T/TH) complex, which in ciliates links the I1 inner
    dynein arm motor domains to the A-tubule of the doublet microtubule;
    loss of this binding function is inferred from the orthologous complex.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP44
    term:
      id: hgnc:25631
      label: CFAP44
  molecular_functions:
  - preferred_term: dynein complex binding
    modifier: DECREASED
    term:
      id: GO:0070840
      label: dynein complex binding
  cellular_components:
  - preferred_term: Axoneme
    term:
      id: GO:0005930
      label: axoneme
  downstream:
  - target: Sperm Axonemal Disorganization
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Without CFAP44 the sperm axoneme loses its central pair and its doublet
      arrangement. How loss of a dynein tether leads to this wider collapse is
      not established.
    evidence:
    - reference: PMID:29449551
      reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In CFAP43-mutated and CFAP44-mutated patients, approximately 95% of the cross-sections were abnormal and the main defect observed was the absence of the CPC (9+0 conformation) observed in 81.8, and 66.7% of the cases, respectively, compared to 0% in control fertile subject"
      explanation: Loss of CFAP44 is accompanied by central-pair loss in patient sperm.
  evidence:
  - reference: PMID:29277146
    reference_title: "Novel Mutations in CFAP44 and CFAP43 Cause Multiple Morphological Abnormalities of the Sperm Flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Real-time quantitative polymerase chain reaction assays also demonstrated that CFAP44 expression was very weak in patient (P)1 and P3"
    explanation: Loss of CFAP44 transcript in patient sperm.
  - reference: PMID:30904354
    reference_title: "NovelCFAP43 andCFAP44 mutations cause male infertility with multiple morphological abnormalities of the sperm flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The relative mRNA expression levels of CFAP43 in patients 1 and 9 and the levels of CFAP44 in patient 5 were significantly lower than those in control sperm samples."
    explanation: Reduced CFAP44 transcript with a homozygous nonsense allele.
  - reference: PMID:42371530
    reference_title: "A Novel Deep-Intronic CFAP44 Variant Underlies Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Then, exon 15 skipping was identified through minigene assays and RT-PCR in vivo, resulting in a 111-bp deletion within the mutated sequence, thereby indicating a disruption in the normal splicing of the CFAP44 transcript."
    explanation: A deep-intronic allele disrupts splicing in patient RNA and a minigene.
  - reference: PMID:29514928
    reference_title: "The I1 dynein-associated tether and tether head complex is a conserved regulator of ciliary motility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "The tether and tether head (T/TH) complex was hypothesized to provide mechanical feedback during ciliary beating because it links the motor domains of the regulatory I1 dynein to the ciliary doublet microtubule."
    explanation: >-
      Cryo-electron tomography of ciliate axonemes identifies FAP43 and FAP44
      as the T/TH complex that binds the I1 dynein motor domains; the binding
      function of human CFAP44 is inferred from this ortholog.
  - reference: PMID:29514928
    reference_title: "The I1 dynein-associated tether and tether head complex is a conserved regulator of ciliary motility."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "WT-mutant comparisons revealed that the heterodimeric T/TH complex is required for the positional stability of the I1 dynein motor domains, stable anchoring of CK1 kinase, and proper phosphorylation of the regulatory IC138-subunit."
    explanation: Mutants lacking the complex lose stable positioning of the I1 dynein motor domains.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: IN_VITRO
    directness: INDIRECT
    snippet: "Immunoelectron and stimulated-emission-depletion microscopy performed on CFAP43 and CFAP44 orthologs in Trypanosoma brucei evidenced that both proteins are located between the doublet microtubules 5 and 6 and the paraflagellar rod."
    explanation: Localization of the trypanosome ortholog to a specific subset of doublets.
- name: Sperm Axonemal Disorganization
  description: >-
    Most flagellar cross-sections lack the central pair (9+0), and the
    central pair is disassembled or displaced when present; peripheral
    doublets are disorganized and fibrous sheaths thickened. Central-pair
    SPAG6 staining is diffuse and fades along the flagellum, and radial-spoke
    RSPH1 staining is strongly reduced.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Axoneme
    term:
      id: GO:0005930
      label: axoneme
  - preferred_term: Sperm flagellum
    term:
      id: GO:0036126
      label: sperm flagellum
  biological_processes:
  - preferred_term: Sperm axoneme assembly
    modifier: DECREASED
    term:
      id: GO:0007288
      label: sperm axoneme assembly
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: DIRECT
  - target: Absent sperm axoneme central pair complex
    causal_link_type: DIRECT
  - target: Abnormal sperm axoneme morphology
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:28552195
    reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cross section shows a thickened fibrous sheath and an absent central pair of microtubules."
    explanation: Ultrastructure of sperm from the homozygous CFAP44 proband.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In CFAP44-mutated patients’ sperm cells, RSPH1 staining was significantly reduced"
    explanation: Radial-spoke head protein reduced in CFAP44 patient sperm.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SPAG6 staining was absent in CFAP43 patient sperm cells, whereas in CFAP44 patients’ sperm cells, SPAG6 immunostaining was present but displayed an abnormal and diffuse pattern concentrated in the midpiece of the spermatozoa, quickly diminishing along the flagellum"
    explanation: Central-pair protein mislocalized in CFAP44 patient sperm.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The semen phenotype: almost no morphologically normal sperm, mostly short
    and absent flagella with coiled, bent and irregular-caliber forms, and no
    progressive motility.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  biological_processes:
  - preferred_term: Sperm flagellum assembly
    modifier: DECREASED
    term:
      id: GO:0120316
      label: sperm flagellum assembly
  downstream:
  - target: Reduced sperm motility
    causal_link_type: DIRECT
  - target: Male infertility
    causal_link_type: DIRECT
    description: 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:28552195
    reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In individual P002, who carries homozygous frameshift mutations in CFAP44, most spermatozoa had short or absent flagella."
    explanation: MMAF in the first homozygous CFAP44 proband.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Normal spermatozoa | 1.25 ± 3.5 (n′ = 8) | 0 ± 0 (n′ = 6)"
    explanation: No morphologically normal sperm in six CFAP44 patients.
mechanistic_hypotheses:
- hypothesis_group_id: cfap43_cfap44_tether
  hypothesis_label: CFAP44 acts with its paralog CFAP43 in the I1 dynein tether/tether-head complex
  status: CANONICAL
  description: >-
    CFAP44 and CFAP43 are WD-repeat paralogs that interact and form the
    heterodimeric T/TH complex of the I1 inner dynein arm in ciliates.
    Biallelic loss of either gene gives the same MMAF phenotype in men and
    mice, consistent with a shared complex. In T. brucei, however, knockdown
    of one protein does not displace the other.
  evidence:
  - reference: PMID:29687140
    reference_title: "Ciliary proteins Fap43 and Fap44 interact with each other and are essential for proper cilia and flagella beating."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we provide evidence of a novel ciliary complex composed of two conserved WD-repeat proteins, Fap43p and Fap44p."
    explanation: The two orthologs interact in Tetrahymena.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was no significant difference between the three groups (Table 1) as illustrated by the similar morphologies of sperm from patient P43-8 and P44-3, mutated for CFAP43 and CFAP44, respectively"
    explanation: CFAP43 and CFAP44 patients have indistinguishable semen phenotypes.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "Inactivation of TbCFAP43 by RNAi did not alter the amount and localization of TbCFAP44; conversely, inactivation of TbCFAP44 had no impact on TbCFAP43 protein"
    explanation: In trypanosomes the two proteins do not depend on each other for localization.
- hypothesis_group_id: cfap44_sperm_restricted
  hypothesis_label: CFAP44 loss causes isolated male infertility without motile-cilia disease
  status: CANONICAL
  description: >-
    No reported CFAP44 patient has respiratory symptoms, hydrocephalus or
    laterality defects, although the Tetrahymena ortholog is needed for
    normal ciliary beating. The original explanation was that CFAP43 and
    CFAP44 link the axoneme to sperm-specific peri-axonemal structures; the
    later finding of airway and brain phenotypes in Cfap43 knockout mice, and
    of respiratory symptoms in one CFAP43 family, leaves open whether CFAP44
    loss could also affect motile cilia. Cfap44 knockout mice have not been
    reported to have such phenotypes.
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These observations suggest that mutations in MMAF genes are only responsible for primary infertility without other PCD features and reinforce the presumption that the sperm flagellum is assembled and organized through a specific way, different from other cilia."
    explanation: CFAP44 patients in the largest cohort had no PCD features.
  - reference: PMID:29687140
    reference_title: "Ciliary proteins Fap43 and Fap44 interact with each other and are essential for proper cilia and flagella beating."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Loss of either protein results in altered waveform, beat stroke and reduced swimming speed."
    explanation: The ciliate ortholog is needed for motile-cilia beating, so a ciliary role in humans is plausible.
phenotypes:
- category: Reproductive
  name: Male infertility
  description: Primary male infertility; natural conception has not been reported.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Male infertility
    term:
      id: HP:0003251
      label: Male infertility
  evidence:
  - reference: PMID:29277146
    reference_title: "Novel Mutations in CFAP44 and CFAP43 Cause Multiple Morphological Abnormalities of the Sperm Flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study demonstrated that biallelic mutations in CFAP44 and CFAP43 cause MMAF."
    explanation: Biallelic CFAP44 variants in infertile men with MMAF.
- category: Reproductive
  name: Reduced sperm motility
  description: Complete loss of motility in the reported cohorts.
  frequency: OBLIGATE
  phenotype_term:
    preferred_term: Asthenozoospermia
    term:
      id: HP:0012207
      label: Reduced sperm motility
  evidence:
  - reference: PMID:28552195
    reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All four subjects were shown to have severe to complete asthenospermia according to semen characteristics."
    explanation: Asthenozoospermia in CFAP43 and CFAP44 probands.
  - reference: PMID:42371530
    reference_title: "A Novel Deep-Intronic CFAP44 Variant Underlies Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A comprehensive clinical evaluation was conducted on an infertile Chinese male patient from a nonconsanguineous family with sever asthenozoospermia (no progressive sperm)."
    explanation: No progressive motility with a deep-intronic allele.
- category: Reproductive
  name: Absent sperm flagella
  description: About a third of sperm lack a flagellum.
  phenotype_term:
    preferred_term: Absent sperm flagella
    term:
      id: HP:0032558
      label: Absent sperm flagella
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Absent flagella | 21.8 ± 17.6 (n′ = 5) | 36.8 ± 4.1 (n′ = 5)"
    explanation: Mean percentage of sperm without a flagellum in CFAP44 patients (second value).
- category: Reproductive
  name: Short sperm flagella
  description: The commonest anomaly, about half of sperm.
  phenotype_term:
    preferred_term: Short sperm flagella
    term:
      id: HP:0032559
      label: Short sperm flagella
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Short flagella | 65.3 ± 31.7 (n′ = 8) | 52.2 ± 27 (n′ = 6)"
    explanation: Mean percentage of short flagella in CFAP44 patients (second value).
- 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:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Coiled flagella | 8.2 ± 6 (n′ = 6) | 14.4 ± 7 (n′ = 5)"
    explanation: Mean percentage of coiled flagella in CFAP44 patients (second value).
- category: Reproductive
  name: Bent sperm flagella
  description: Recorded in one CFAP44 patient in the largest cohort.
  phenotype_term:
    preferred_term: Bent sperm flagella
    term:
      id: HP:0034811
      label: Bent sperm flagella
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Bent flagella | 10.3 ± 6 (n′ = 3) | 9 (n′ = 1)"
    explanation: Bent flagella in the one CFAP44 patient with data (second value).
- category: Reproductive
  name: Irregularly shaped sperm tail
  description: Irregular-caliber flagella in over a quarter of sperm.
  phenotype_term:
    preferred_term: Irregular-caliber sperm flagella
    term:
      id: HP:0033393
      label: Irregularly shaped sperm tail
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Flagella of irregular caliber | 20.2 ± 19.3 (n′ = 5) | 28.4 ± 16.9 (n′ = 5)"
    explanation: Mean percentage of irregular-caliber flagella in CFAP44 patients (second value).
- category: Reproductive
  name: Absent sperm axoneme central pair complex
  description: The central pair is missing in about two thirds of flagellar cross-sections.
  phenotype_term:
    preferred_term: Absent sperm axoneme central pair complex
    term:
      id: HP:0033525
      label: Absent sperm axoneme central pair complex
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In CFAP43-mutated and CFAP44-mutated patients, approximately 95% of the cross-sections were abnormal and the main defect observed was the absence of the CPC (9+0 conformation) observed in 81.8, and 66.7% of the cases, respectively, compared to 0% in control fertile subject"
    explanation: Central-pair loss in 66.7% of CFAP44 cross-sections.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: Besides central-pair loss, doublets are disorganized and fibrous sheaths thickened.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The lack of central pair defects was associated with peripheral doublets disorganization in 13.6 and 19% for CFAP43 and CFA44, respectively"
    explanation: Peripheral doublet disorganization in CFAP44 patient sperm.
genetic:
- name: CFAP44
  association: Causal
  gene_term:
    preferred_term: CFAP44
    term:
      id: hgnc:25631
      label: CFAP44
  case_fractions:
  - population: North African, Middle Eastern and French MMAF cohort
    case_fraction_percent: 7.7
    cohort_size: 78
    notes: 6 of 78 men with MMAF; all homozygous.
    evidence:
    - reference: PMID:29449551
      reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In addition, six subjects (7.7%) had a homozygous loss-of-function variant in CFAP44 (Table 2)."
      explanation: CFAP44 share of an MMAF cohort.
  - population: Chinese MMAF patients from consanguineous families
    case_fraction_percent: 7.7
    cohort_size: 13
    evidence:
    - reference: PMID:30904354
      reference_title: "NovelCFAP43 andCFAP44 mutations cause male infertility with multiple morphological abnormalities of the sperm flagella (MMAF)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Four novel homozygous CFAP43 mutations in four (30.8%) MMAF patients and one novel homozygous CFAP44 mutation in one (7.7%) other case were identified."
      explanation: CFAP44 share of a small consanguineous Chinese cohort.
  notes: >-
    Reported alleles are mostly homozygous nonsense, frameshift and splice
    variants (including the deep-intronic c.1890+5G>C causing exon 15
    skipping), plus homozygous p.L590Q and putative compound heterozygous
    missense alleles from one Chinese cohort. Not curated by ClinGen; no
    gene-disease validity tier exists to record.
  evidence:
  - reference: PMID:28552195
    reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intriguingly, we identified compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject."
    explanation: First report of a biallelic CFAP44 variant in MMAF.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, six subjects (7.7%) had a homozygous loss-of-function variant in CFAP44 (Table 2)."
    explanation: Independent replication in six unrelated probands.
  - reference: PMID:29277146
    reference_title: "Novel Mutations in CFAP44 and CFAP43 Cause Multiple Morphological Abnormalities of the Sperm Flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing analysis of the 27 patients with MMAF identified several CFAP44 mutations"
    explanation: Five further Chinese patients.
  - reference: PMID:42371530
    reference_title: "A Novel Deep-Intronic CFAP44 Variant Underlies Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As a result, a CFAP44 homozygous deep-intronic variant (NM_001164496.1:c.1890+5G>C) was detected in the proband by WES."
    explanation: A deep-intronic allele detected by exome sequencing.
animal_models:
- name: Cfap44 knockout mouse
  species: Mouse
  genotype: Cfap44-/- (CRISPR/Cas9 frameshift), homozygous
  publication: PMID:29449551
  description: >-
    Two independent knockout lines. Males are sterile with immotile sperm and
    disorganized axonemes; females are fertile. Flagellar malformation is
    milder than in patients, and sperm show a fragmented mitochondrial sheath
    and some head defects but little chromatin-compaction defect.
  modeled_mechanisms:
  - target: Sperm Axonemal Disorganization
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Knockout sperm reproduce the patients' axonemal defects.
    evidence:
    - reference: PMID:29449551
      reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Nevertheless, TEM analysis of Cfap44−/− sperm evidenced ultrastructural defects similar to those found in CFAP44 patients, confirming that CFAP44 is necessary for axonemal organization and function both in mouse and human."
      explanation: Same ultrastructural defect as in patients.
    - reference: PMID:28552195
      reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The flagellar ultrastructures of testicular sperm shown by TEM indicated a lack of the central pair of microtubules, which is consistent with the observations in human MMAF-affected subjects carrying biallelic mutations in CFAP43 or CFAP44."
      explanation: Central-pair loss in a second knockout line.
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Sterility and immotility are reproduced, flagellar malformation less so.
    limitations: >-
      Cfap44-/- sperm are immotile but their flagellar shape defects are
      subtler than in patients.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        In one knockout line Cfap44-deficient mouse sperm show subtler
        flagellar shape defects than the mostly short and absent flagella of
        patients, so the mouse can underestimate the human morphological
        defect while reproducing the motility loss.
    evidence:
    - reference: PMID:29449551
      reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Cfap44−/− male mice were also infertile due to flagellar immotility, yet presenting subtler flagellar defects than those observed in patients with CFAP44 mutations"
      explanation: The authors' statement of the partial match.
    - reference: PMID:28552195
      reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We found that both Cfap43- and Cfap44-deficient male mice were infertile, whereas female mice with corresponding mutants could generate offspring."
      explanation: Male-only infertility in an independent line.
- name: Trypanosoma brucei TbCFAP44 RNAi knockdown
  species: Trypanosoma brucei
  genotype: Tetracycline-inducible RNAi against TbCFAP44
  publication: PMID:29449551
  description: >-
    Knockdown in the protozoan parasite produces abnormal flagellar beating,
    disorganized axonemes, multiflagellated cells and growth arrest.
  modeled_mechanisms:
  - target: Sperm Axonemal Disorganization
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Axonemal disorganization after knockdown in a flagellated protozoan.
    limitations: >-
      Trypanosome flagella have a paraflagellar rod instead of the fibrous
      sheath and outer dense fibres of sperm, and knockdown also blocks
      cytokinesis, which has no human counterpart.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        The trypanosome flagellum is built on a paraflagellar rod rather than
        the sperm fibrous sheath, so the peri-axonemal partners of CFAP44
        differ between the model and human sperm.
    evidence:
    - reference: PMID:29449551
      reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In all cases, both TbCFAP44RNAi-induced and TbCFAP43RNAi-induced cells showed abnormal beating (Supplementary Movies 2–5) and stopped proliferating after 24 h and eventually died"
      explanation: Knockdown impairs flagellar beating.
treatments:
- name: Intracytoplasmic Sperm Injection
  description: >-
    ICSI bypasses the motility defect. In a retrospective series, CFAP44
    patients had a 76% fertilization rate, higher than DNAH1 patients, and
    half of couples achieved a delivery. In knockout mice, Cfap44-deficient
    sperm supported embryo development better than sperm from Cfap43 and
    other MMAF knockouts, although still below wild type.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Intracytoplasmic Sperm Injection
    term:
      id: NCIT:C185482
      label: Intracytoplasmic Sperm Injection
  target_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    description: Direct injection makes flagellar form and motility irrelevant to fertilization.
    evidence:
    - reference: PMID:30251428
      reference_title: "Patients with multiple morphological abnormalities of the sperm flagella harbouring CFAP44 or CFAP43 mutations have a good pregnancy outcome following intracytoplasmic sperm injection."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "For MMAF patients carrying CFAP44 mutations, the recorded rates of fertilisation, transferable embryos, pregnancy and delivery after ICSI were 76.47%, 88.46%, 50.0% and 50.0% respectively."
      explanation: Fertilization and delivery rates with CFAP44 patient sperm.
  evidence:
  - reference: PMID:30251428
    reference_title: "Patients with multiple morphological abnormalities of the sperm flagella harbouring CFAP44 or CFAP43 mutations have a good pregnancy outcome following intracytoplasmic sperm injection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The fertilisation rate was significantly higher in the CFAP44+ group than in the DNAH1+ group (76.47% vs. 54.5%, p = 0.0196)."
    explanation: Fertilization compares favourably with another MMAF genotype.
  - reference: PMID:34529793
    reference_title: "Genetic diagnosis, sperm phenotype and ICSI outcome in case of severe asthenozoospermia with multiple morphological abnormalities of the flagellum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite occasional technical difficulties, ICSI outcomes for couples with MMAF do not differ from those of other couples requiring ICSI, irrespective of the genetic defect."
    explanation: A mixed-genotype MMAF series including CFAP44 patients.
  - reference: PMID:40070084
    reference_title: "A comprehensive study of the sperm head defects in MMAF condition and their impact on embryo development in mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "Sperm from all KO lines exhibited a marked decrease in supporting embryo development compared to the wild-type, with developmental failure rates ranked as follows: Ccdc146 > Cfap43 > Armc2 > Cfap44-deficient sperm."
    explanation: In mice, Cfap44-deficient sperm have the smallest embryo-development penalty after ICSI.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP44 alleles are known. A molecular
    diagnosis also predicts a generally good ICSI prognosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:29277146
    reference_title: "Novel Mutations in CFAP44 and CFAP43 Cause Multiple Morphological Abnormalities of the Sperm Flagella (MMAF)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These results provide researchers with a new insight to understand the genetic etiology of MMAF and to identify new loci for genetic counselling of MMAF."
    explanation: The authors name genetic counselling as an application of the diagnosis.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis by exome sequencing or MMAF gene panels with
    Sanger confirmation. Deep-intronic splice variants need RNA or minigene
    studies to confirm. DNAH1, CFAP43 and CFAP44 together explain roughly a
    quarter to a third of MMAF in exome-sequenced cohorts.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Altogether, DNAH1, CFAP43, and CFAP44 mutations were identified in 28.2% of the analyzed subjects (n = 78) originating from North Africa, Europe, and the Middle East."
    explanation: Diagnostic yield of exome sequencing in MMAF.
  - reference: PMID:42371530
    reference_title: "A Novel Deep-Intronic CFAP44 Variant Underlies Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Then, exon 15 skipping was identified through minigene assays and RT-PCR in vivo, resulting in a 111-bp deletion within the mutated sequence, thereby indicating a disruption in the normal splicing of the CFAP44 transcript."
    explanation: Splicing studies confirm a non-coding variant.
- name: Semen Analysis
  description: Shows MMAF with no progressive motility; no sperm are morphologically normal.
  evidence:
  - reference: PMID:28552195
    reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "light microscopy, which identified severely distorted sperm flagella, including absent, short, coiled, bent, and irregular-caliber flagella"
    explanation: Light-microscopic semen morphology defines MMAF.
- name: Transmission Electron Microscopy of Sperm Flagella
  description: >-
    Flagellar cross-sections show a missing or displaced central pair,
    disorganized doublets and thickened fibrous sheaths.
  diagnosis_term:
    preferred_term: Transmission Electron Microscopy
    term:
      id: NCIT:C18216
      label: Transmission Electron Microscopy
  evidence:
  - reference: PMID:28552195
    reference_title: "Biallelic Mutations in CFAP43 and CFAP44 Cause Male Infertility with Multiple Morphological Abnormalities of the Sperm Flagella."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The cross section shows a thickened fibrous sheath and an absent central pair of microtubules."
    explanation: TEM findings in CFAP44 patient sperm.
- name: Immunofluorescence of Sperm Flagella
  description: >-
    Reduced RSPH1 and diffuse SPAG6 staining of patient sperm support
    pathogenicity of CFAP44 variants.
  evidence:
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In CFAP44-mutated patients’ sperm cells, RSPH1 staining was significantly reduced"
    explanation: Radial-spoke staining is reduced in patient sperm.

📚

References & Deep Research

Deep Research

1

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

Evaluations and curation notes (1)

Create: Spermatogenic Failure 20 (CFAP44) · 2026-10-16T13:31:03Z · View source

New entry for SPGF20 (MONDO:0054724, CFAP44). Deep research run with the claude_code provider (research/Spermatogenic_Failure_20-deep-research-claude_code.md); just preflight-dr returned WARN because the paralog CFAP43 is mentioned, which is expected, and the report was used only for leads. Primary sources fetched with just fetch-reference: Tang 2017, Coutton 2018, Sha 2018/2019, Wu 2019, the 2026 deep-intronic CFAP44 family, the ciliate Fap43/Fap44 and T/TH structural papers, Ferreux 2021 ICSI series and the Muronova 2025 mouse ICSI study. ClinGen has no CFAP44 gene-disease validity curation in the 2026-10-14 export, so gene_disease_validity is left absent. Judgement calls: dynein complex binding (GO:0070840) bound as the molecular function, inferred from the ciliate T/TH complex; a peptidase activity reported for a Cfap44 splice fragment in transfected cells (PMID:28887034) was not modelled; no respiratory phenotype recorded because none has been reported for CFAP44, with a CANONICAL sperm-restricted hypothesis carrying a REFUTE item from the ciliate beating defect; the Cfap44 knockout mouse is PARTIALLY_RECAPITULATES for MMAF with a SPECIES_MISMATCH divergence because its flagellar malformation is subtler than in patients. No GeneReviews chapter. Validated with just validate, validate-terms, count-verified-snippets (all verified), check-entity-refs, check-causal-targets, check-duplicate-keys, snippet/title gates, gene-activity grounding and validate-disorders.

Claude Code ▸

Spermatogenic Failure 20 (SPGF20; CFAP44-related MMAF): Research Report

claude-haiku-5-5, claude-sonnet-5-5 6 citations 2026-10-16T13:13:41.814436

Spermatogenic Failure 20 (SPGF20; CFAP44-related MMAF): Research Report

Evidence status. Verified this session: gene and disease identifiers, the Tang 2017 and Coutton 2018 findings, the ICSI series, and the mouse data. Unverified: items marked [unverified] come from general knowledge or from search snippets I did not open. Check them before curation. I did not verify OMIM prose, HPO frequencies, GO/CL/UBERON identifiers, or ClinGen validity. I also quote no exact abstract text, because I read only the Coutton paper's full text, and only partially. The CLAUDE.md rules require the snippets to be exact quotes, so take snippets from just fetch-reference, not from this report.

1. Disease information

Overview. SPGF20 is an autosomal recessive form of male infertility. The underlying defect is "multiple morphological abnormalities of the sperm flagella" (MMAF), also called asthenoteratozoospermia with flagellar defects. Sperm tails are absent, short, coiled, bent or of irregular caliber. Men are otherwise typically healthy. Sperm count can be normal, but sperm are almost immotile.
Identifiers.
MONDO:0054724 (the repository stub names CFAP44 as MONDO's causal gene).
OMIM phenotype 617593; OMIM gene 617559 (CFAP44, 3q13.2). A search-derived DrugMap record and a PMC 2023 table agree on the pairing.
Orphanet, ICD and MeSH identifiers: not checked.
Synonyms. Spermatogenic failure 20; SPGF20; MMAF type 20 [unverified]. CFAP44 was formerly WDR52 [unverified].
Data source. Disease-level, aggregated from family and cohort sequencing, not EHR.
Repository state. stubs/Spermatogenic_Failure_20.yaml exists, with entry_type: UNDECIDED. No kb/disorders entry exists yet.
Lump/split note. Many SPGF entries share the same MMAF phenotype (CFAP43, DNAH1, CFAP69, ARMC2 and others). A curator should keep SPGF20 as a gene-defined disease entry and consider a covering MMAF grouping.

2. Etiology

Cause. Biallelic loss-of-function variants in CFAP44 (cilia- and flagella-associated protein 44).
Genetic risk factors. No modifier genes are established. Digenic CFAP43/CFAP44 involvement has not been shown. CFAP43 and CFAP44 variants are found in separate patients.
Environmental factors. None established for this form. The known MMAF causes are genetic.
Protective factors and gene-environment interactions. None known.

3. Phenotypes

All items below are for male patients. Female carriers are not reported to be affected.

Phenotype	Suggested HPO	Evidence
Male infertility	HP:0003251	Core feature (PMID:28552195; PMID:29449551)
Asthenozoospermia	HP:0012206	Near-universal [unverified ID]
Teratozoospermia / flagellar abnormalities	HP:0012864	Absent, short, coiled and irregular-caliber flagella
Abnormal sperm tail morphology	HP:0012869 [unverified]	MMAF

Frequencies. In CFAP44 patients from Coutton 2018 (PMID:29449551), mean absent flagella were 36.8%, short flagella 52.2% and irregular-caliber flagella 28.4%.
Onset, progression and quality of life. Onset is at reproductive age and the phenotype is stable. Infertility is the presenting complaint. No quality-of-life data were found.
Verify every HPO CURIE with a lookup before binding. Per CLAUDE.md, I wrote none of these from a source in this session.

4. Genetic/molecular information

Gene. CFAP44, HGNC symbol (lowercase hgnc: form in the KB, number to be looked up), 3q13.2.
Variants (Coutton 2018, PMID:29449551, Table 2). All six patients were homozygous.
c.1890+1G>A (p.Pro631Ile*22), splice site, Tunisia.
c.3175C>T (p.Arg1059Ter), nonsense, Tunisia.
c.2818dupG (p.Glu940GlyfsTer19), frameshift, Morocco.
c.1387G>T (p.Glu463Ter), nonsense, two patients, Algeria.
c.4767delT (p.Ile1589MetfsTer6), frameshift, Algeria.
The paper's text gives the first variant as c.1890+1C>T, which conflicts with the table. Resolve this against the source before curating.
Tang 2017 (PMID:28552195). A homozygous frameshift in CFAP44 was found in 1 of 30 Han Chinese MMAF men. Compound-heterozygous CFAP43 variants were found in 3 other men. These variants were absent in 984 controls.
Functional consequence. Loss of function (nonsense, frameshift, splice). Origin is germline.
Gene share. CFAP44 explained 6 of 78 men (7.7%) in Coutton 2018. CFAP43 and CFAP44 together explained about 20.5%. The cohort was mainly North African, so the share is cohort-dependent.
Epigenetics and chromosomal abnormalities. None reported.
Population frequency (gnomAD) and ClinVar classifications. Not retrieved.

5. Environmental information

None established. Infectious agents are not applicable.

6. Mechanism / pathophysiology

Causal chain

Biallelic loss-of-function variants in CFAP44 produce absent or truncated CFAP44 protein. This is demonstrated by genetics and inferred at the protein level.
CFAP44 is lost from the sperm axoneme. In the T. brucei ortholog, it localizes next to the paraflagellar rod, apposed to doublets 5–6 (PMID:29449551).
Axonemal organization fails. In patient sperm, TEM showed about 95% abnormal cross-sections in one patient, most often lacking the central pair (9+0, 66.7%). Reduced SPAG6 and RSPH1 staining implicates central-pair and radial-spoke components.
Flagellar assembly and beating fail, so tails are absent, short or coiled and motility is reduced. This step is established in humans and mice.
Sperm are immotile and structurally abnormal, which causes male infertility.

Evidence by model system: - Human: MMAF patients with biallelic variants (above). - Mouse: Cfap44 knockout males are infertile with MMAF, and females are fertile (PMID:28552195). - Trypanosome: RNAi knockdown of TbCFAP44 gave abnormal beating, growth arrest and multiflagellated cells. Axonemal defects were found in 27.3% of axonemes versus 0.6% of controls.

Cell and tissue targets: - Cell type: spermatid or sperm (CL term to look up). - Tissue: testis. - Components: axoneme, sperm flagellum (GO terms to look up). - Biological processes: sperm flagellum assembly, spermatid differentiation. - Omics and other mechanisms. No metabolic, immune, proteomic or single-cell findings were retrieved. A 2025 Mol Hum Reprod study (Muroňová et al.) compared mouse knockouts. Cfap44-/- sperm had the mildest nuclear defects and the lowest embryo-developmental failure among the knockouts compared (Cfap43, Armc2, Ccdc146) (per a search summary; paper not opened).

7. Anatomical structures affected

Organ: testis and sperm. Other organs are not involved, and there is no ciliary syndrome in these patients. That statement is from the literature picture, not from a source I checked. Primary ciliary dyskinesia-like features are reported for some other MMAF genes, not for CFAP44 [unverified].
Cell level: spermatids and spermatozoa. Subcellular: axoneme and flagellum.
Lateralization: not applicable (systemic germline).

8. Temporal development

Onset is at reproductive age (detected on infertility workup). Stable, lifelong, with no remission.

9. Inheritance and population

Inheritance: autosomal recessive (HP:0000007 – verify).
Penetrance and sex: limited to males. Females are unaffected in mice.
Consanguinity: the Coutton 2018 CFAP44 patients were all homozygous. Consanguinity is likely in the North African cohort. Verify this against the full text.
Founder effects: none established.
Prevalence: unknown. MMAF is rare, and CFAP44 accounts for about 7.7% of the MMAF cohort studied.

10. Diagnostics

Semen analysis: asthenozoospermia with flagellar abnormalities on morphology.
Electron microscopy and immunostaining: central-pair and axoneme defects (TEM); SPAG6 and RSPH1 staining.
Genetic testing: whole-exome sequencing or an MMAF gene panel. WES in 78 MMAF men gave a diagnosis in 22 (28%) across DNAH1, CFAP43 and CFAP44.
Differential diagnosis: other MMAF genes (DNAH1, CFAP43, CFAP69, ARMC2 and others) and primary ciliary dyskinesia.
Screening: none.

11. Outcome/prognosis

Life expectancy is normal, and the burden is infertility. Assisted reproduction outcomes in a small retrospective series (6 MMAF patients with biallelic CFAP44 or CFAP43 variants; Frontiers in Endocrinology 2024): - For CFAP44, ICSI gave 76.47% fertilization, 88.46% transferable embryos, 50% pregnancy and 50% delivery. - Fertilization was significantly higher than in the DNAH1 group. - Samples were very small. Coutton 2018 does not report ICSI outcomes for CFAP44. - Also check Coutton 2018's own discussion, which says ICSI prognosis is hard to predict for non-DNAH1 genotypes.

12. Treatment

No curative or drug therapy exists.
Intracytoplasmic sperm injection (ICSI) is the main option, with the outcomes above (NCIT term to look up; the repository table suggests a procedure term, but look up the CURIE rather than trusting memory).
Gene therapy and other advanced approaches: none found. Clinical trials: none found, and I did not search ClinicalTrials.gov.

13. Prevention

Genetic counseling for couples. A male partner's biallelic status confers 100% transmission of one pathogenic allele to children, who would be carriers. This is inferred from recessive inheritance.
Preimplantation genetic testing is possible if the variants are known. This is general knowledge and was not verified.

14. Other species

I did not search OMIA or ortholog databases. The mouse ortholog is Cfap44, and the Trypanosoma ortholog is TbCFAP44 (NCBITaxon IDs and NCBI Gene IDs to look up).

15. Model organisms

Mouse: CRISPR/Cas9 Cfap44 knockout. Males are infertile with MMAF and peri-axonemal and axonemal defects. Females are fertile (PMID:28552195). This is MODEL_ORGANISM evidence, and the model recapitulates the human phenotype well. Since 2025, comparative data show milder nuclear and embryo-development defects than other MMAF knockouts.
Trypanosoma brucei: RNAi knockdown with flagellar defects (PMID:29449551). The relevance to human spermatogenesis is by homology only.
Resources: MGI and IMPC (not queried here).

Evidence summary for curation

Claim	PMID	Evidence source
CFAP44 homozygous frameshift in an MMAF man; CFAP43 compound-heterozygous variants; absent in 984 controls	28552195	HUMAN_CLINICAL
22 of 78 MMAF men with biallelic DNAH1, CFAP43 or CFAP44 variants (CFAP44 n=6); Cfap43/44 knockout mice infertile; Trypanosoma RNAi	29449551	HUMAN_CLINICAL, MODEL_ORGANISM
ICSI outcomes for CFAP44 patients	See Frontiers 2024 link above (PMID not retrieved)	HUMAN_CLINICAL
Cfap44 knockout nuclear and embryo-development comparison	Muroňová 2025 (PMID not retrieved)	MODEL_ORGANISM

Next steps before curation. Run just fetch-reference for PMIDs 28552195 and 29449551. Look up every HPO, GO, CL and UBERON CURIE. Resolve the c.1890+1G>A versus C>T discrepancy. Retrieve the PMIDs for the ICSI series and the 2025 knockout comparison. Also check ClinGen validity for CFAP44-MMAF and the GeneReviews baseline (just check-genereviews).

Sources: - DrugMap SPGF20 record - PMC 2023 gene table - Coutton et al. 2018, Nat Commun (PMC5814398) - Tang et al. 2017 AJHG (PMID 28552195) - Frontiers in Endocrinology 2024 review/ICSI series - Muroňová et al. 2025, Mol Hum Reprod (HAL record)

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	5
Resolved	5
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	5
On topic	4
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	6
Resolved	6
Unresolved (possible confabulation)	0
Obsolete	0
Unverifiable	0
Terms whose name was checked	5
Terms named correctly	1
Terms named as a different term	3
Terms whose name is worth a second look	1

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:0012869 (1 mention) - the report calls it "unverified"; HP calls it Acephalic spermatozoa
HP:0000007 (1 mention) - the report calls it "verify"; HP calls it Autosomal recessive inheritance

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:0012864 (1 mention) - the report calls it "Teratozoospermia / flagellar abnormalities"; HP calls it Abnormal sperm morphology, and lists "Teratozoospermia" among its other names

Spermatogenic Failure 20

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Spermatogenic Failure 20 (SPGF20; CFAP44-related MMAF): Research Report

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

15. Model organisms

Evidence summary for curation

Reference Validation

Term Validation

Terms the report names something else

Terms whose name is worth a second look