Spermatogenic Failure 19

Mendelian MONDO:0054723 Pathograph 23 Show in embeddings browser Spermatogenic Failure Genetic Disease

Spermatogenic failure 19 (SPGF19) is autosomal recessive male infertility caused by biallelic loss-of-function variants in CFAP43 (formerly WDR96), which encodes a WD-repeat cilia- and flagella-associated protein. In the axoneme of motile cilia and flagella, CFAP43 and its paralog CFAP44 form the heterodimeric tether/tether-head complex that anchors the motor domains of the regulatory I1 inner dynein arm to the doublet microtubule; in Trypanosoma the two proteins sit next to doublets 5 and 6. CFAP43 is expressed predominantly in the testis. Affected men have asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF): absent, short, coiled, bent and irregular-caliber flagella, with essentially no progressive motility. Electron microscopy shows a missing central pair (9+0) in most flagella, disorganized peripheral doublets and hyperplastic fibrous sheaths. Cfap43 knockout mice reproduce MMAF and also show defective intra-manchette transport during spermiogenesis. Most patients have no respiratory disease, but one family with a homozygous missense variant had chronic sinusitis and wet cough, and knockout mice have impaired tracheal ciliary function and hydrocephalus, so a motile-cilia component is possible. Intracytoplasmic sperm injection (ICSI) gives good fertilization and pregnancy rates.

Ask OpenScientist

Ask a research question about Spermatogenic Failure 19. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

👪

Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic CFAP43 variants: homozygous variants in consanguineous North African, Middle Eastern, Pakistani, Palestinian and Chinese families, and compound heterozygous variants in non-consanguineous Han Chinese and French probands. Parents are heterozygous carriers.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:28552195 SUPPORT Human clinical
"All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations."
Compound heterozygous CFAP43 variants inherited from carrier parents.
PMID:34100391 SUPPORT Human clinical
"Sanger sequencing further confirmed that these mutations were segregated recessively in the families with the MMAF phenotype."
Recessive segregation in two Pakistani families.
◈

Mechanistic Hypotheses

3
CFAP43 loss also impairs airway motile cilia in some patients
cfap43_motile_cilia_involvement EMERGING
Evidence balance 3 support 4 refute
CFAP43 is present in motile cilia, and Cfap43 knockout mice have faster but less effective tracheal ciliary beating, nasal mucus accumulation and hydrocephalus. Almost all patients nonetheless have isolated infertility. One Palestinian family with a homozygous missense variant had chronic sinusitis, wet cough and focal bronchiectasis, without ciliary studies. ClinGen treats that presentation as a separate CFAP43 primary ciliary dyskinesia entity rated Limited.
Pathograph links
Loss of the CFAP43 Tether Protein -> Airway Motile Cilia Dysfunction INDIRECT UNKNOWN INTERMEDIATES Shown in Cfap43 knockout mice and Xenopus; in patients suggested by a single family with chronic respiratory symptoms.
Airway Motile Cilia Dysfunction -> Chronic sinusitis INDIRECT UNKNOWN INTERMEDIATES
Airway Motile Cilia Dysfunction -> Productive cough INDIRECT UNKNOWN INTERMEDIATES
Airway Motile Cilia Dysfunction -> Bronchiectasis INDIRECT UNKNOWN INTERMEDIATES
Show evidence (7 references)
PMID:31884020 SUPPORT Model organism
"In addition, mice mutant for Cfap43 display early onset hydrocephalus."
Knockout mice show a motile-cilia phenotype outside the testis.
PMID:31004071 SUPPORT Model organism
"We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia."
An independent knockout with hydrocephalus and abnormal motile cilia.
PMID:41341611 SUPPORT Human clinical
"Both siblings exhibited classic MMAF features, including asthenospermia with various flagellar abnormalities, in addition to chronic respiratory symptoms including sinusitis and wet cough."
The only biallelic family with respiratory symptoms.
+ 4 more references
CFAP43 missense alleles cause a milder sperm phenotype than truncating alleles
cfap43_missense_severity EMERGING
Evidence balance 1 support 1 refute
Proposed from one compound heterozygous patient with p.Val347Ala who had more normal sperm and fewer short flagella than patients with homozygous truncating alleles. Contradicted by a family homozygous for p.Trp141Arg with complete asthenozoospermia. No missense allele has been studied functionally.
Pathograph links
Partial CFAP43 Loss from Missense Alleles -> Multiple Morphological Abnormalities of the Sperm Flagella INDIRECT UNKNOWN INTERMEDIATES Missense alleles still cause MMAF; whether it is milder is disputed.
Show evidence (2 references)
PMID:29449551 SUPPORT Human clinical
"Interestingly among CFAP43-mutated patients, only one (P43-9) carried a missense variant, with potentially a milder effect (Val347Ala)."
The proposal rests on one patient.
PMID:41341611 REFUTE Human clinical
"However, this was not observed in the studied family, as both siblings suffered from almost complete asthenospermia in addition to the chronic respiratory symptoms."
A homozygous missense family had a severe phenotype.
CFAP43 acts with its paralog CFAP44 in the I1 dynein tether/tether-head complex
cfap43_cfap44_tether CANONICAL
Evidence balance 2 support 1 refute
CFAP43 and CFAP44 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.
⚙

Pathophysiology

7
Loss of the CFAP43 Tether Protein
Nonsense, frameshift, splice-site, multi-exon deletion and some missense alleles abolish or sharply reduce CFAP43. Patient sperm show low CFAP43 mRNA and absent or reduced CFAP43 protein in the flagellum, and splice alleles cause exon skipping. CFAP43 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.
CFAP43 loss also impairs airway motile cilia in some patients
CFAP43 hgnc:26684 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFAP43 (hgnc:26684). hgnc:26684 is a gene from the HUGO Gene Nomenclature Committee.
dynein complex binding GO:0070840 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dynein complex binding (GO:0070840). GO:0070840 is a molecular function from the Gene Ontology.
Axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology.
Downstream
Sperm Axonemal Disorganization Without CFAP43 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; the T. brucei localization between doublets 5-6 and the paraflagellar rod suggests a link between the axoneme and peri-axonemal structures.
Defective Intra-Manchette Transport Shown in Cfap43-deficient mice; not studied in patients.
Airway Motile Cilia Dysfunction Shown in Cfap43 knockout mice and Xenopus; in patients suggested by a single family with chronic respiratory symptoms. CFAP43 loss also impairs airway motile cilia in some patients
Show evidence (6 references)
PMID:30904354 SUPPORT Human clinical
"Immunofluorescence analysis of CFAP43 showed the protein was absent in the sperm flagella of patients 1 and 9."
CFAP43 protein is lost from patient flagella.
PMID:29277146 SUPPORT Human clinical
"Immunofluorescence analysis of CFAP43 showed lower CFAP43 protein expression levels in P6 than in the normal control."
Reduced CFAP43 protein with a splice-acceptor deletion.
PMID:32207550 SUPPORT In vitro / ex vivo
"Here, using a minigene assay, we demonstrated that the c.3661-2delA variant may cause exon-30 to be skipped, thus generating the p.E1221_K1256del protein."
A splice allele causes in-frame exon skipping.
+ 3 more references
Partial CFAP43 Loss from Missense Alleles
Most CFAP43 alleles are truncating. A minority of patients carry missense alleles, homozygous or in trans with a truncating allele. One compound heterozygous patient with p.Val347Ala had a milder semen phenotype than patients with homozygous truncating alleles, but a Palestinian family homozygous for p.Trp141Arg had complete asthenozoospermia. Whether missense alleles are hypomorphic is unresolved, and none has been tested functionally.
CFAP43 missense alleles cause a milder sperm phenotype than truncating alleles
CFAP43 hgnc:26684 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves CFAP43 (hgnc:26684). hgnc:26684 is a gene from the HUGO Gene Nomenclature Committee.
dynein complex binding GO:0070840 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dynein complex binding (GO:0070840). GO:0070840 is a molecular function from the Gene Ontology.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella Missense alleles still cause MMAF; whether it is milder is disputed. CFAP43 missense alleles cause a milder sperm phenotype than truncating alleles
Show evidence (2 references)
PMID:29449551 SUPPORT Human clinical
"Interestingly among CFAP43-mutated patients, only one (P43-9) carried a missense variant, with potentially a milder effect (Val347Ala)."
A missense allele in trans with a truncating allele.
PMID:41341611 SUPPORT Human clinical
"WES identified a novel homozygous missense genetic variation in CFAP43 [c.421T>A p.(Trp141Arg)]."
A homozygous missense allele in the WD-repeat region.
Defective Intra-Manchette Transport
In Cfap43-deficient mice the manchette of elongating spermatids is abnormal and the ectoplasmic specialization is disorganized, which impairs both sperm head shaping and flagellum formation and adds oligozoospermia and head defects to MMAF. Not yet examined in patients.
Spermatid CL:0000018 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Spermatid (CL:0000018). CL:0000018 is a cell type from the Cell Ontology.
Intramanchette transport GO:1990953 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Intramanchette transport (GO:1990953). GO:1990953 is a biological process from the Gene Ontology.
Manchette GO:0002177 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Manchette (GO:0002177). GO:0002177 is a cellular component from the Gene Ontology.
Animal models
Cfap43 knockout mouse Mouse recapitulates The manchette defect has only been studied in mice.
Downstream
Multiple Morphological Abnormalities of the Sperm Flagella
Show evidence (1 reference)
PMID:33046149 SUPPORT Model organism
"Therefore, our findings demonstrated that, in mice, CFAP43-mediated IMT is essential for sperm head shaping and sperm flagellum formation."
Mouse evidence for a role in intra-manchette transport.
Sperm Axonemal Disorganization
Most flagellar cross-sections lack the central pair (9+0), the central pair is misoriented when present, peripheral doublets are displaced, and fibrous sheaths are hypertrophic. Central-pair (SPAG6) staining is absent and radial-spoke (RSPH1) staining is diffuse in patient sperm.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
Sperm axoneme assembly GO:0007288 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Sperm axoneme assembly (GO:0007288). GO:0007288 is a biological process from the Gene Ontology.
Axoneme GO:0005930 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Axoneme (GO:0005930). GO:0005930 is a cellular component from the Gene Ontology. Sperm flagellum GO:0036126 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sperm flagellum (GO:0036126). GO:0036126 is a cellular component from the Gene Ontology.
Animal models
Cfap43 knockout mouse Mouse recapitulates Knockout sperm lack the central pair and have scattered doublets.
Trypanosoma brucei TbCFAP43 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 central microtubules were absent (9+0) in most flagella, and various cytoskeletal components were distorted as well."
Central-pair loss in patient sperm.
PMID:29449551 SUPPORT Human clinical
"In CFAP43-mutated patients, the RSPH1 staining was completely abnormal with a marked diffuse staining, concentrated in the midpiece, whereas the tubulin staining remained restricted to the axoneme"
Radial-spoke head protein mislocalized in CFAP43 patient sperm.
PMID:29449551 SUPPORT Model organism
"Note the specific arrangement of the ODFs around the axoneme in WT sperm and the complete disorganization of the DMTs and the absence of the central pair in Cfap43−/− sperm."
Knockout mouse sperm show the same axonemal collapse.
Sperm Mitochondrial Sheath Disruption
The mitochondrial sheath of the midpiece is disturbed and partly missing, with reduced TOM20, in a compound heterozygous patient. Reported in one family; whether it is primary or secondary to the axonemal defect is not known.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
Sperm mitochondrial sheath GO:0097226 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Sperm mitochondrial sheath (GO:0097226). GO:0097226 is a cellular component from the Gene Ontology.
Downstream
Reduced sperm motility
Show evidence (1 reference)
PMID:41549427 SUPPORT Human clinical
"Additionally, we observed disturbance and partial deletion of the mitochondrial sheath, along with a significant reduction in translocase of outer mitochondrial membrane 20 (TOM20) expression."
Mitochondrial sheath defects in patient sperm.
Multiple Morphological Abnormalities of the Sperm Flagella
The semen phenotype: 80-100% of sperm have absent, short, coiled, bent or irregular-caliber flagella, and progressive motility is absent.
Sperm CL:0000019 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Sperm (CL:0000019). CL:0000019 is a cell type from the Cell Ontology.
Sperm flagellum assembly GO:0120316 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Sperm flagellum assembly (GO:0120316). GO:0120316 is a biological process from the Gene Ontology.
Animal models
Cfap43 knockout mouse Mouse recapitulates The knockout reproduces human MMAF.
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)
CGGV:assertion_a5055c70-e22e-47e5-af3b-04f3f2a0ed34-2022-12-14T200000.000Z SUPPORT REVIEW SYNTHESIS Other
"Individuals with Spermatogenic Failure 19 present with a combination of sperm flagellar malformations (absent, short, coiled, bent, and/or irregular-caliber flagella)"
ClinGen expert-panel summary of the disease phenotype.
PMID:28552195 SUPPORT Human clinical
"The affected spermatozoa with abnormal flagella accounted for 79.5%–99.5% of the spermatozoa analyzed in these individuals carrying biallelic mutations in CFAP43 or CFAP44"
Almost all sperm are affected.
Airway Motile Cilia Dysfunction
Impaired airway ciliary beating and mucus clearance. Shown in Cfap43 knockout mice and Xenopus; in patients inferred from chronic respiratory symptoms in one family, without ciliary beat, ultrastructure or nasal nitric oxide studies.
CFAP43 loss also impairs airway motile cilia in some patients
Mucociliary clearance GO:0120197 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Mucociliary clearance (GO:0120197). GO:0120197 is a biological process from the Gene Ontology.
Animal models
Cfap43 knockout mouse Mouse partially recapitulates Knockouts have airway mucus accumulation and hydrocephalus.
Downstream
Chronic sinusitis CFAP43 loss also impairs airway motile cilia in some patients
Productive cough CFAP43 loss also impairs airway motile cilia in some patients
Bronchiectasis CFAP43 loss also impairs airway motile cilia in some patients
Show evidence (2 references)
PMID:31884020 SUPPORT Model organism
"CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity."
Airway clearance defect in knockout mice.
PMID:41341611 SUPPORT INDIRECT Human clinical
"Both siblings exhibited classic MMAF features, including asthenospermia with various flagellar abnormalities, in addition to chronic respiratory symptoms including sinusitis and wet cough."
Symptoms consistent with impaired mucociliary clearance in one family.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spermatogenic Failure 19 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

12
Genitourinary 9
Male infertility OBLIGATE HP:0003251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Male infertility (HP:0003251). HP:0003251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29449551 SUPPORT Human clinical
"Altogether the above-identified mutations clearly indicate that in humans, loss of function of CFAP43 is associated with asthenozoospermia and sperm flagellum defects."
Ten infertile men with biallelic CFAP43 variants.
Reduced sperm motility OBLIGATE HP:0012207 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Asthenozoospermia, annotated with Reduced sperm motility (HP:0012207). HP:0012207 is a phenotype from the Human Phenotype Ontology.
Show evidence (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:29449551 SUPPORT Human clinical
"Motility (a + b + c) 1 h | 0 ± 0 (n′ = 9)"
Zero motility in nine CFAP43 patients.
Absent sperm flagella HP:0032558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent sperm flagella (HP:0032558). HP:0032558 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29449551 SUPPORT Human clinical
"Absent flagella | 21.8 ± 17.6 (n′ = 5)"
Mean percentage of sperm without a flagellum in CFAP43 patients.
Short sperm flagella HP:0032559 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short sperm flagella (HP:0032559). HP:0032559 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29449551 SUPPORT Human clinical
"Short flagella | 65.3 ± 31.7 (n′ = 8)"
Mean percentage of short flagella in CFAP43 patients.
Coiled sperm flagella HP:0032560 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Coiled sperm flagella (HP:0032560). HP:0032560 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29449551 SUPPORT Human clinical
"Coiled flagella | 8.2 ± 6 (n′ = 6)"
Mean percentage of coiled flagella in CFAP43 patients.
Bent sperm flagella HP:0034811 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bent sperm flagella (HP:0034811). HP:0034811 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29449551 SUPPORT Human clinical
"Bent flagella | 10.3 ± 6 (n′ = 3)"
Mean percentage of bent flagella in CFAP43 patients.
Irregularly shaped sperm tail HP:0033393 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Irregular-caliber sperm flagella, annotated with Irregularly shaped sperm tail (HP:0033393). HP:0033393 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29449551 SUPPORT Human clinical
"Flagella of irregular caliber | 20.2 ± 19.3 (n′ = 5)"
Mean percentage of irregular-caliber flagella in CFAP43 patients.
Absent sperm axoneme central pair complex HP:0033525 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent sperm axoneme central pair complex (HP:0033525). HP:0033525 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID: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 is the main ultrastructural defect.
Abnormal sperm axoneme morphology HP:0033524 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal sperm axoneme morphology (HP:0033524). HP:0033524 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28552195 SUPPORT Human clinical
"Cross sections showed hypertrophy and hyperplasia of fibrous sheaths."
Peri-axonemal fibrous-sheath defects in patient sperm.
Head and Neck 1
Chronic sinusitis VERY_RARE HP:0011109 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic sinusitis (HP:0011109). HP:0011109 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:41341611 SUPPORT Human clinical
"Importantly, both patients reported that they also suffer from respiratory symptoms characterized by chronic sinusitis and chronic wet cough since infancy"
Chronic sinusitis in both brothers.
PMID:39572557 REFUTE BACKGROUND Human clinical
"The biallelic CFAP43 pathogenic variant causes male infertility with MMAF; however, these patients do not present with any PCD-associated symptoms, such as sinusitis, rhinitis or chronic bronchitis"
Earlier biallelic patients had no sinusitis.
Respiratory 2
Productive cough VERY_RARE HP:0031245 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic wet cough, annotated with Productive cough (HP:0031245). HP:0031245 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41341611 SUPPORT Human clinical
"Importantly, both patients reported that they also suffer from respiratory symptoms characterized by chronic sinusitis and chronic wet cough since infancy"
Chronic wet cough in both brothers.
Bronchiectasis VERY_RARE HP:0002110 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bronchiectasis (HP:0002110). HP:0002110 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:41341611 SUPPORT Human clinical
"As shown in Figure 2, a chest computerised tomography (CT) scan of patient 2 revealed a localized area of bronchiectasis in the medial segment of the right middle lobe of the lung."
Focal bronchiectasis in one patient.
🧬

Genetic Associations

1
CFAP43 (Causal)
Gene: CFAP43 hgnc:26684 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is CFAP43 (hgnc:26684). hgnc:26684 is a gene from the HUGO Gene Nomenclature Committee.
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 biallelic CFAP43 variants in MMAF.
PMID:29449551 SUPPORT Human clinical
"We identified 9 different pathogenic variants in CFAP43 in 10 unrelated individuals from the cohort."
Independent replication in a multi-ethnic cohort.
PMID:36960497 SUPPORT Human clinical
"After systematic analysis, seven mutations in CFAP43 , including five novel mutations and two previously reported mutations, were identified from four families and related to MMAF in an autosomal recessive pattern."
Further families from a panel-sequenced cohort.
+ 1 more reference
💊

Medical Actions

2
Intracytoplasmic Sperm Injection
Action: Intracytoplasmic Sperm InjectionNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Intracytoplasmic Sperm Injection (NCIT:C185482). NCIT:C185482 is a clinical intervention from the NCI Thesaurus. NCIT:C185482
Platform: Other
ICSI bypasses the motility defect. Reported fertilization and blastocyst rates are similar to other ICSI cycles, and pregnancies and live births are reported after ICSI without oocyte activation. The Palestinian brothers each had one live-born son but needed 8 and 4 ICSI cycles. In knockout mice, Cfap43-deficient sperm have chromatin compaction defects and support embryo development less well than Cfap44-deficient sperm; whether this applies to patients is unknown.
Mechanism Target:
Multiple Morphological Abnormalities of the Sperm Flagella — Direct injection makes flagellar form and motility irrelevant to fertilization.
Show evidence (1 reference)
PMID:36960497 SUPPORT Human clinical
"The rate of fertilization was 66.7% and 75.0%, the rate of embryo cleavage was 100.0% and 86.7%, and the rate of blastocyst formation was 41.7% and 46.2%."
Normal-range fertilization and blastocyst rates with patient sperm.
Show evidence (5 references)
PMID:36960497 SUPPORT Human clinical
"Following frozen-thawed embryo transfer, the female partner of F3-II-1 proband became pregnant and gave birth to a full-term healthy boy, while the partner of F4-II-1 proband was in a good state of clinical pregnancy."
Pregnancies after ICSI in two couples.
PMID:41549427 SUPPORT Human clinical
"Finally, assisted reproductive technology using intracytoplasmic sperm injection (ICSI) resulted in a successful pregnancy and live birth."
A further live birth.
PMID:30251428 SUPPORT Human clinical
"Our results support a good ICSI prognosis for MMAF patients carrying CFAP44 or CFAP43 mutations."
Retrospective cohort including CFAP43 patients.
+ 2 more references
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Behavioral / lifestyle
Counselling for autosomal recessive recurrence and carrier testing of relatives once the familial CFAP43 alleles are known. A molecular diagnosis also predicts a generally good ICSI prognosis.
Show evidence (2 references)
PMID:41549427 SUPPORT Human clinical
"Our study expands the spectrum of pathogenic CFAP43 mutations and provides valuable insights for genetic counseling and personalized reproductive strategies in patients with MMAF."
The authors name genetic counselling as an application of the diagnosis.
PMID:36960497 SUPPORT Human clinical
"This study significantly expands the mutant spectrum of CFAP43 , and together with the available information regarding male infertility and MMAF, provides new information for the genetic diagnosis and counseling of MMAF in the future."
A second cohort drawing the same conclusion.
🔬

Diagnosis

5
Molecular Genetic Testing
Establishes the diagnosis. Probands are identified by exome sequencing or MMAF gene panels with Sanger confirmation; copy-number analysis can be needed, as one allele was a 3.3-kb intragenic deletion. MMAF is genetically heterogeneous, and DNAH1, CFAP43 and CFAP44 together explain roughly a quarter to a third of cases in exome-sequenced cohorts.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
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:28552195 SUPPORT Human clinical
"In addition to this point mutation revealed by WES, we also identified a 3.3-kb heterozygous deletion within CFAP43 in P028 by using aCGH and long-range PCR assays"
Copy-number analysis found an allele missed by exome sequencing.
Semen Analysis
Shows MMAF with near-total loss of motility; sperm concentration is usually preserved.
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 misoriented central pair, displaced doublets and fibrous-sheath hyperplasia.
Transmission Electron Microscopy NCIT:C18216 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28552195 SUPPORT Human clinical
"The central microtubules were absent (9+0) in most flagella, and various cytoskeletal components were distorted as well."
TEM findings in patient sperm.
Immunofluorescence of Sperm Flagella
Absent or reduced CFAP43 staining, and absent SPAG6 and diffuse RSPH1 staining, support pathogenicity of CFAP43 variants.
Show evidence (1 reference)
PMID:30904354 SUPPORT Human clinical
"Immunofluorescence analysis of CFAP43 showed the protein was absent in the sperm flagella of patients 1 and 9."
Immunofluorescence demonstrates protein loss.
Respiratory Evaluation
Not routinely needed, but chronic sinusitis, wet cough or bronchiectasis in a man with CFAP43-related MMAF should prompt evaluation for motile-cilia disease, as reported in one family.
Show evidence (1 reference)
PMID:41341611 SUPPORT Human clinical
"As shown in Figure 2, a chest computerised tomography (CT) scan of patient 2 revealed a localized area of bronchiectasis in the medial segment of the right middle lobe of the lung."
Chest CT found bronchiectasis in a symptomatic patient.
🐁

Animal Models

2
Cfap43 knockout mouse
Several independent Cfap43 knockout lines have been made. Males are sterile with immotile MMAF sperm and disorganized axonemes; females are fertile. The mice also have oligozoospermia, sperm head and chromatin compaction defects, impaired tracheal ciliary function and hydrocephalus, which are not part of the human disease as usually reported.
Species
Mouse
Genotype
Cfap43-/- (CRISPR/Cas9 frameshift), homozygous
Publication
PMID:29449551
Pathograph links
Multiple Morphological Abnormalities of the Sperm Flagella recapitulates fidelity: high observes: cellular The knockout reproduces human MMAF.
Show evidence (2 references)
PMID:29449551 SUPPORT Model organism
"Cfap43−/− males were infertile and 100% of their spermatozoa were immotile and morphologically abnormal with short and coiled tail, a phenotype very similar to human MMAF"
Knockout males reproduce the human sperm phenotype.
+ 1 more reference
Sperm Axonemal Disorganization recapitulates fidelity: high observes: cellular Knockout sperm lack the central pair and have scattered doublets.
Show evidence (1 reference)
PMID:29449551 SUPPORT Model organism
"Note the specific arrangement of the ODFs around the axoneme in WT sperm and the complete disorganization of the DMTs and the absence of the central pair in Cfap43−/− sperm."
Same ultrastructural defect as in patients.
Defective Intra-Manchette Transport recapitulates fidelity: unknown observes: cellular The manchette defect has only been studied in mice.
Limitations: Spermatid manchette structure has not been examined in patients, so it is unknown whether the mouse finding applies to human SPGF19.
Divergences from the human mechanism
species mismatch qualifying
Knockout mice add oligozoospermia and strong sperm head and DNA compaction defects to MMAF, whereas reported patients usually have normal sperm counts and the head defects have not been measured, so the weight of the manchette pathway in the human disease may be smaller than in mice.
Show evidence (1 reference)
PMID:33046149 SUPPORT Model organism
"Furthermore, both abnormal manchette and disorganized ectoplasmic specialization (ES) could be observed at the elongated spermatids in Cfap43-deficient mice."
Manchette defects in the knockout.
Airway Motile Cilia Dysfunction partially recapitulates fidelity: low observes: organism Knockouts have airway mucus accumulation and hydrocephalus.
Limitations: Airway and brain phenotypes are prominent in knockout mice but almost absent from patients; one family has respiratory symptoms and none has hydrocephalus.
Divergences from the human mechanism
species mismatch qualifying
Mice are prone to hydrocephalus from ependymal ciliary defects that rarely cause hydrocephalus in humans, and the mouse tracheal phenotype has no counterpart in nearly all CFAP43 patients, so the knockout overstates motile-cilia involvement in the human disease.
Show evidence (1 reference)
PMID:31884020 SUPPORT Model organism
"CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity."
Airway ciliary dysfunction in the knockout.
Trypanosoma brucei TbCFAP43 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 TbCFAP43
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 CFAP43 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 19
creation_date: "2026-10-16T00:00:00Z"
category: Mendelian
synonyms:
- SPGF19
- spermatogenic failure 19
- CFAP43-related multiple morphological abnormalities of the sperm flagella
- CFAP43-related MMAF
description: >-
  Spermatogenic failure 19 (SPGF19) is autosomal recessive male infertility
  caused by biallelic loss-of-function variants in CFAP43 (formerly WDR96),
  which encodes a WD-repeat cilia- and flagella-associated protein. In the
  axoneme of motile cilia and flagella, CFAP43 and its paralog CFAP44 form the
  heterodimeric tether/tether-head complex that anchors the motor domains of
  the regulatory I1 inner dynein arm to the doublet microtubule; in
  Trypanosoma the two proteins sit next to doublets 5 and 6. CFAP43 is
  expressed predominantly in the testis.

  Affected men have asthenoteratozoospermia with multiple morphological
  abnormalities of the sperm flagella (MMAF): absent, short, coiled, bent and
  irregular-caliber flagella, with essentially no progressive motility.
  Electron microscopy shows a missing central pair (9+0) in most flagella,
  disorganized peripheral doublets and hyperplastic fibrous sheaths. Cfap43
  knockout mice reproduce MMAF and also show defective intra-manchette
  transport during spermiogenesis. Most patients have no respiratory disease,
  but one family with a homozygous missense variant had chronic sinusitis and
  wet cough, and knockout mice have impaired tracheal ciliary function and
  hydrocephalus, so a motile-cilia component is possible. Intracytoplasmic
  sperm injection (ICSI) gives good fertilization and pregnancy rates.
disease_term:
  preferred_term: spermatogenic failure 19
  term:
    id: MONDO:0054723
    label: spermatogenic failure 19
parents:
- Spermatogenic Failure
- Genetic Disease
notes: >-
  MONDO cross-references the phenotype as OMIM 617592. ClinGen classifies
  CFAP43 in SPGF19 as Definitive (2022). ClinGen curates two further CFAP43
  pairs as separate disease entities: primary ciliary dyskinesia (Limited,
  2026), based on the one family with MMAF and chronic respiratory symptoms
  that is also recorded here, and autosomal dominant normal-pressure
  hydrocephalus (Disputed, 2026), based on one Japanese family heterozygous
  for p.Trp1502Ter (PMID:31004071). The NPH family and a heterozygous carrier
  with respiratory symptoms after haematopoietic cell transplantation
  (PMID:39572557) are monoallelic, did not have fertility assessed, and are
  not part of this entry. No GeneReviews chapter covers the disorder.
inheritance:
- name: Autosomal recessive
  description: >-
    Disease requires biallelic CFAP43 variants: homozygous variants in
    consanguineous North African, Middle Eastern, Pakistani, Palestinian and
    Chinese families, and compound heterozygous variants in
    non-consanguineous Han Chinese and French probands. 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: "All of these recessive mutations were parentally inherited from heterozygous carriers but were absent in 984 individuals from three Han Chinese control populations."
    explanation: Compound heterozygous CFAP43 variants inherited from carrier parents.
  - reference: PMID:34100391
    reference_title: "Novel biallelic loss-of-function mutations in CFAP43 cause multiple morphological abnormalities of the sperm flagellum in Pakistani families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sanger sequencing further confirmed that these mutations were segregated recessively in the families with the MMAF phenotype."
    explanation: Recessive segregation in two Pakistani families.
pathophysiology:
- name: Loss of the CFAP43 Tether Protein
  description: >-
    Nonsense, frameshift, splice-site, multi-exon deletion and some missense
    alleles abolish or sharply reduce CFAP43. Patient sperm show low CFAP43
    mRNA and absent or reduced CFAP43 protein in the flagellum, and splice
    alleles cause exon skipping. CFAP43 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: CFAP43
    term:
      id: hgnc:26684
      label: CFAP43
  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 CFAP43 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; the T. brucei localization between doublets 5-6 and
      the paraflagellar rod suggests a link between the axoneme and
      peri-axonemal structures.
    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 CFAP43 is accompanied by central-pair loss in patient sperm.
  - target: Defective Intra-Manchette Transport
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Shown in Cfap43-deficient mice; not studied in patients.
    evidence:
    - reference: PMID:33046149
      reference_title: "CFAP43-mediated intra-manchette transport is required for sperm head shaping and flagella formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Furthermore, both abnormal manchette and disorganized ectoplasmic specialization (ES) could be observed at the elongated spermatids in Cfap43-deficient mice."
      explanation: Manchette defects in knockout spermatids.
  - target: Airway Motile Cilia Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cfap43_motile_cilia_involvement
    description: >-
      Shown in Cfap43 knockout mice and Xenopus; in patients suggested by a
      single family with chronic respiratory symptoms.
    evidence:
    - reference: PMID:31884020
      reference_title: "CFAP43 modulates ciliary beating in mouse and Xenopus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity."
      explanation: Loss of Cfap43 impairs airway ciliary function in mice.
  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: "Immunofluorescence analysis of CFAP43 showed the protein was absent in the sperm flagella of patients 1 and 9."
    explanation: CFAP43 protein is lost from patient flagella.
  - 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: "Immunofluorescence analysis of CFAP43 showed lower CFAP43 protein expression levels in P6 than in the normal control."
    explanation: Reduced CFAP43 protein with a splice-acceptor deletion.
  - reference: PMID:32207550
    reference_title: "Mutational effect of human CFAP43 splice-site variant causing multiple morphological abnormalities of the sperm flagella."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, using a minigene assay, we demonstrated that the c.3661-2delA variant may cause exon-30 to be skipped, thus generating the p.E1221_K1256del protein."
    explanation: A splice allele causes in-frame exon skipping.
  - 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 CFAP43 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: Partial CFAP43 Loss from Missense Alleles
  description: >-
    Most CFAP43 alleles are truncating. A minority of patients carry
    missense alleles, homozygous or in trans with a truncating allele. One
    compound heterozygous patient with p.Val347Ala had a milder semen
    phenotype than patients with homozygous truncating alleles, but a
    Palestinian family homozygous for p.Trp141Arg had complete
    asthenozoospermia. Whether missense alleles are hypomorphic is
    unresolved, and none has been tested functionally.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: CFAP43
    term:
      id: hgnc:26684
      label: CFAP43
  molecular_functions:
  - preferred_term: dynein complex binding
    modifier: DECREASED
    term:
      id: GO:0070840
      label: dynein complex binding
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cfap43_missense_severity
    description: Missense alleles still cause MMAF; whether it is milder is disputed.
    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: "This patient has the lowest percentage of sperm with short flagella (22%) with 10% of morphologically normal spermatozoa (versus 0% for the other CFAP43-mutated subjects) and therefore presents a milder phenotype compared to the others with homozygous truncating mutations."
      explanation: The one patient with a missense allele had a milder phenotype.
    - reference: PMID:41341611
      reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
      supports: REFUTE
      evidence_source: HUMAN_CLINICAL
      snippet: "However, this was not observed in the studied family, as both siblings suffered from almost complete asthenospermia in addition to the chronic respiratory symptoms."
      explanation: A homozygous missense allele gave a severe phenotype.
  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: "Interestingly among CFAP43-mutated patients, only one (P43-9) carried a missense variant, with potentially a milder effect (Val347Ala)."
    explanation: A missense allele in trans with a truncating allele.
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES identified a novel homozygous missense genetic variation in CFAP43 [c.421T>A p.(Trp141Arg)]."
    explanation: A homozygous missense allele in the WD-repeat region.
- name: Defective Intra-Manchette Transport
  description: >-
    In Cfap43-deficient mice the manchette of elongating spermatids is
    abnormal and the ectoplasmic specialization is disorganized, which
    impairs both sperm head shaping and flagellum formation and adds
    oligozoospermia and head defects to MMAF. Not yet examined in patients.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Spermatid
    term:
      id: CL:0000018
      label: spermatid
  cellular_components:
  - preferred_term: Manchette
    term:
      id: GO:0002177
      label: manchette
  biological_processes:
  - preferred_term: Intramanchette transport
    modifier: DECREASED
    term:
      id: GO:1990953
      label: intramanchette transport
  downstream:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33046149
      reference_title: "CFAP43-mediated intra-manchette transport is required for sperm head shaping and flagella formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      directness: INDIRECT
      snippet: "Depletion of Cfap43 led to abnormal spermiogenesis and caused MMAF, sperm head abnormality and oligozoospermia."
      explanation: Mouse knockout data link the manchette defect to MMAF.
  evidence:
  - reference: PMID:33046149
    reference_title: "CFAP43-mediated intra-manchette transport is required for sperm head shaping and flagella formation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Therefore, our findings demonstrated that, in mice, CFAP43-mediated IMT is essential for sperm head shaping and sperm flagellum formation."
    explanation: Mouse evidence for a role in intra-manchette transport.
- name: Sperm Axonemal Disorganization
  description: >-
    Most flagellar cross-sections lack the central pair (9+0), the central
    pair is misoriented when present, peripheral doublets are displaced, and
    fibrous sheaths are hypertrophic. Central-pair (SPAG6) staining is absent
    and radial-spoke (RSPH1) staining is diffuse in patient sperm.
  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 central microtubules were absent (9+0) in most flagella, and various cytoskeletal components were distorted as well."
    explanation: Central-pair loss in 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: "In CFAP43-mutated patients, the RSPH1 staining was completely abnormal with a marked diffuse staining, concentrated in the midpiece, whereas the tubulin staining remained restricted to the axoneme"
    explanation: Radial-spoke head protein mislocalized in CFAP43 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: MODEL_ORGANISM
    snippet: "Note the specific arrangement of the ODFs around the axoneme in WT sperm and the complete disorganization of the DMTs and the absence of the central pair in Cfap43−/− sperm."
    explanation: Knockout mouse sperm show the same axonemal collapse.
- name: Sperm Mitochondrial Sheath Disruption
  description: >-
    The mitochondrial sheath of the midpiece is disturbed and partly missing,
    with reduced TOM20, in a compound heterozygous patient. Reported in one
    family; whether it is primary or secondary to the axonemal defect is not
    known.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: Sperm
    term:
      id: CL:0000019
      label: sperm
  cellular_components:
  - preferred_term: Sperm mitochondrial sheath
    term:
      id: GO:0097226
      label: sperm mitochondrial sheath
  downstream:
  - target: Reduced sperm motility
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:41549427
    reference_title: "Novel biallelic CFAP43 mutations induce MMAF with mitochondrial abnormalities and successful ICSI outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we observed disturbance and partial deletion of the mitochondrial sheath, along with a significant reduction in translocase of outer mitochondrial membrane 20 (TOM20) expression."
    explanation: Mitochondrial sheath defects in patient sperm.
- name: Multiple Morphological Abnormalities of the Sperm Flagella
  description: >-
    The semen phenotype: 80-100% of sperm have absent, short, coiled, bent or
    irregular-caliber flagella, and progressive motility is absent.
  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: CGGV:assertion_a5055c70-e22e-47e5-af3b-04f3f2a0ed34-2022-12-14T200000.000Z
    reference_title: "CFAP43 / spermatogenic failure 19 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Individuals with Spermatogenic Failure 19 present with a combination of sperm flagellar malformations (absent, short, coiled, bent, and/or irregular-caliber flagella)"
    explanation: ClinGen expert-panel summary of the disease phenotype.
  - 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 affected spermatozoa with abnormal flagella accounted for 79.5%–99.5% of the spermatozoa analyzed in these individuals carrying biallelic mutations in CFAP43 or CFAP44"
    explanation: Almost all sperm are affected.
- name: Airway Motile Cilia Dysfunction
  description: >-
    Impaired airway ciliary beating and mucus clearance. Shown in Cfap43
    knockout mice and Xenopus; in patients inferred from chronic
    respiratory symptoms in one family, without ciliary beat, ultrastructure
    or nasal nitric oxide studies.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: Mucociliary clearance
    modifier: DECREASED
    term:
      id: GO:0120197
      label: mucociliary clearance
  downstream:
  - target: Chronic sinusitis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cfap43_motile_cilia_involvement
  - target: Productive cough
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cfap43_motile_cilia_involvement
  - target: Bronchiectasis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - cfap43_motile_cilia_involvement
  evidence:
  - reference: PMID:31884020
    reference_title: "CFAP43 modulates ciliary beating in mouse and Xenopus."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity."
    explanation: Airway clearance defect in knockout mice.
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Both siblings exhibited classic MMAF features, including asthenospermia with various flagellar abnormalities, in addition to chronic respiratory symptoms including sinusitis and wet cough."
    explanation: Symptoms consistent with impaired mucociliary clearance in one family.
mechanistic_hypotheses:
- hypothesis_group_id: cfap43_motile_cilia_involvement
  hypothesis_label: CFAP43 loss also impairs airway motile cilia in some patients
  status: EMERGING
  description: >-
    CFAP43 is present in motile cilia, and Cfap43 knockout mice have faster
    but less effective tracheal ciliary beating, nasal mucus accumulation and
    hydrocephalus. Almost all patients nonetheless have isolated infertility.
    One Palestinian family with a homozygous missense variant had chronic
    sinusitis, wet cough and focal bronchiectasis, without ciliary studies.
    ClinGen treats that presentation as a separate CFAP43 primary ciliary
    dyskinesia entity rated Limited.
  evidence:
  - reference: PMID:31884020
    reference_title: "CFAP43 modulates ciliary beating in mouse and Xenopus."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In addition, mice mutant for Cfap43 display early onset hydrocephalus."
    explanation: Knockout mice show a motile-cilia phenotype outside the testis.
  - reference: PMID:31004071
    reference_title: "Nonsense mutation in CFAP43 causes normal-pressure hydrocephalus with ciliary abnormalities."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We knocked out mouse ortholog Cfap43 using CRISPR/Cas9 technology, resulting in Cfap43-deficient mice that exhibited a hydrocephalus phenotype with morphologic abnormality of motile cilia."
    explanation: An independent knockout with hydrocephalus and abnormal motile cilia.
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both siblings exhibited classic MMAF features, including asthenospermia with various flagellar abnormalities, in addition to chronic respiratory symptoms including sinusitis and wet cough."
    explanation: The only biallelic family with respiratory symptoms.
  - reference: CGGV:assertion_f2622390-3981-4f40-8c28-194fb13dd35a-2026-04-09T190000.000Z
    reference_title: "CFAP43 / primary ciliary dyskinesia (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "Previous studies have reported no respiratory phenotype with Spermatogenic Failure 19."
    explanation: ClinGen notes that the respiratory presentation is absent from other SPGF19 reports.
  - reference: CGGV:assertion_f2622390-3981-4f40-8c28-194fb13dd35a-2026-04-09T190000.000Z
    reference_title: "CFAP43 / primary ciliary dyskinesia (Limited)"
    supports: REFUTE
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: "In summary, there is Limited evidence of association between variants in CFAP43 and Primary Ciliary Dyskinesia, despite compelling experimental evidence of a role for CFAP43 in motile ciliary function."
    explanation: ClinGen rates the human respiratory association as Limited.
  - reference: PMID:29449551
    reference_title: "Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human."
    supports: REFUTE
    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: The ten CFAP43 patients in the largest cohort had no PCD features.
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Although direct evaluation of the functional and structural impact of the p.(Trp141Arg) missense variation on patients' spermatozoa was not feasible due to the lack of fresh biological samples"
    explanation: The supporting family has no functional or ciliary studies.
- hypothesis_group_id: cfap43_missense_severity
  hypothesis_label: CFAP43 missense alleles cause a milder sperm phenotype than truncating alleles
  status: EMERGING
  description: >-
    Proposed from one compound heterozygous patient with p.Val347Ala who had
    more normal sperm and fewer short flagella than patients with homozygous
    truncating alleles. Contradicted by a family homozygous for p.Trp141Arg
    with complete asthenozoospermia. No missense allele has been studied
    functionally.
  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: "Interestingly among CFAP43-mutated patients, only one (P43-9) carried a missense variant, with potentially a milder effect (Val347Ala)."
    explanation: The proposal rests on one patient.
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, this was not observed in the studied family, as both siblings suffered from almost complete asthenospermia in addition to the chronic respiratory symptoms."
    explanation: A homozygous missense family had a severe phenotype.
- hypothesis_group_id: cfap43_cfap44_tether
  hypothesis_label: CFAP43 acts with its paralog CFAP44 in the I1 dynein tether/tether-head complex
  status: CANONICAL
  description: >-
    CFAP43 and CFAP44 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.
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: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 the above-identified mutations clearly indicate that in humans, loss of function of CFAP43 is associated with asthenozoospermia and sperm flagellum defects."
    explanation: Ten infertile men with biallelic CFAP43 variants.
- category: Reproductive
  name: Reduced sperm motility
  description: Severe to complete asthenozoospermia; no progressively motile sperm.
  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: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: "Motility (a + b + c) 1 h | 0 ± 0 (n′ = 9)"
    explanation: Zero motility in nine CFAP43 patients.
- category: Reproductive
  name: Absent sperm flagella
  description: About a fifth 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)"
    explanation: Mean percentage of sperm without a flagellum in CFAP43 patients.
- category: Reproductive
  name: Short sperm flagella
  description: The commonest anomaly, about two thirds 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)"
    explanation: Mean percentage of short flagella in CFAP43 patients.
- 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)"
    explanation: Mean percentage of coiled flagella in CFAP43 patients.
- category: Reproductive
  name: Bent sperm flagella
  description: Bent (angulated) 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: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)"
    explanation: Mean percentage of bent flagella in CFAP43 patients.
- category: Reproductive
  name: Irregularly shaped sperm tail
  description: Irregular-caliber flagella are part of the MMAF mosaic.
  phenotype_term:
    preferred_term: Irregular-caliber sperm flagella
    term:
      id: HP:0033393
      label: Irregularly shaped sperm tail
  evidence:
  - reference: PMID: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)"
    explanation: Mean percentage of irregular-caliber flagella in CFAP43 patients.
- category: Reproductive
  name: Absent sperm axoneme central pair complex
  description: The central pair is missing in about 80% 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 is the main ultrastructural defect.
- category: Reproductive
  name: Abnormal sperm axoneme morphology
  description: Besides central-pair loss, doublets are displaced and fibrous sheaths hypertrophic.
  phenotype_term:
    preferred_term: Abnormal sperm axoneme morphology
    term:
      id: HP:0033524
      label: Abnormal sperm axoneme morphology
  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: "Cross sections showed hypertrophy and hyperplasia of fibrous sheaths."
    explanation: Peri-axonemal fibrous-sheath defects in patient sperm.
- category: Respiratory
  name: Chronic sinusitis
  description: >-
    Reported only in one family (two brothers homozygous for p.Trp141Arg),
    and absent from other reported patients.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Chronic sinusitis
    term:
      id: HP:0011109
      label: Chronic sinusitis
  evidence:
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, both patients reported that they also suffer from respiratory symptoms characterized by chronic sinusitis and chronic wet cough since infancy"
    explanation: Chronic sinusitis in both brothers.
  - reference: PMID:39572557
    reference_title: "CFAP43 variant in persistent respiratory symptoms after hematopoietic cell transplantation."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "The biallelic CFAP43 pathogenic variant causes male infertility with MMAF; however, these patients do not present with any PCD-associated symptoms, such as sinusitis, rhinitis or chronic bronchitis"
    explanation: Earlier biallelic patients had no sinusitis.
- category: Respiratory
  name: Productive cough
  description: Chronic wet cough since infancy in the same family.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Chronic wet cough
    term:
      id: HP:0031245
      label: Productive cough
  evidence:
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Importantly, both patients reported that they also suffer from respiratory symptoms characterized by chronic sinusitis and chronic wet cough since infancy"
    explanation: Chronic wet cough in both brothers.
- category: Respiratory
  name: Bronchiectasis
  description: Focal bronchiectasis in one of the two brothers; the other was not imaged.
  frequency: VERY_RARE
  phenotype_term:
    preferred_term: Bronchiectasis
    term:
      id: HP:0002110
      label: Bronchiectasis
  evidence:
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As shown in Figure 2, a chest computerised tomography (CT) scan of patient 2 revealed a localized area of bronchiectasis in the medial segment of the right middle lobe of the lung."
    explanation: Focal bronchiectasis in one patient.
genetic:
- name: CFAP43
  association: Causal
  gene_term:
    preferred_term: CFAP43
    term:
      id: hgnc:26684
      label: CFAP43
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_a5055c70-e22e-47e5-af3b-04f3f2a0ed34-2022-12-14T200000.000Z
    evidence:
    - reference: CGGV:assertion_a5055c70-e22e-47e5-af3b-04f3f2a0ed34-2022-12-14T200000.000Z
      reference_title: "CFAP43 / spermatogenic failure 19 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "CFAP43 | HGNC:26684 | spermatogenic failure 19 | MONDO:0054723 | AR | Definitive"
      explanation: ClinGen gene-disease validity record classifying this gene-disease pair as Definitive.
  case_fractions:
  - population: North African, Middle Eastern and French MMAF cohort
    case_fraction_percent: 12.8
    cohort_size: 78
    notes: 10 of 78 men with MMAF; mostly consanguineous families.
    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: "We subsequently identified 10 subjects with variants in CFAP43 (12.8%), eight of which had a homozygous loss-of-function variant and two with two likely deleterious variants (Table 2)."
      explanation: CFAP43 share of an MMAF cohort.
  - population: Chinese MMAF patients from consanguineous families
    case_fraction_percent: 30.8
    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: CFAP43 share of a small consanguineous Chinese cohort.
  notes: >-
    Reported alleles are mostly nonsense, frameshift and splice-site variants,
    plus a 3.3-kb deletion of exons 32-34 and several missense variants, in
    homozygous or compound heterozygous state, distributed along the whole
    gene. ClinGen's 2022 curation reached the maximum genetic score with 15
    probands in 3 publications (16 variants); its summary names Tang 2017
    (PMID:28552195), cited here. The other two counted publications are not
    named in the cached summary, so which of the cited papers ClinGen used
    could not be confirmed.
  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 biallelic CFAP43 variants 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: "We identified 9 different pathogenic variants in CFAP43 in 10 unrelated individuals from the cohort."
    explanation: Independent replication in a multi-ethnic cohort.
  - reference: PMID:36960497
    reference_title: "Patients with MMAF induced by novel biallelic CFAP43 mutations have good fertility outcomes after intracytoplasmic sperm injection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After systematic analysis, seven mutations in CFAP43 , including five novel mutations and two previously reported mutations, were identified from four families and related to MMAF in an autosomal recessive pattern."
    explanation: Further families from a panel-sequenced cohort.
  - reference: PMID:34100391
    reference_title: "Novel biallelic loss-of-function mutations in CFAP43 cause multiple morphological abnormalities of the sperm flagellum in Pakistani families."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES analysis reflected novel biallelic loss-of-function mutations in CFAP43 in both families"
    explanation: Pakistani families.
animal_models:
- name: Cfap43 knockout mouse
  species: Mouse
  genotype: Cfap43-/- (CRISPR/Cas9 frameshift), homozygous
  publication: PMID:29449551
  description: >-
    Several independent Cfap43 knockout lines have been made. Males are
    sterile with immotile MMAF sperm and disorganized axonemes; females are
    fertile. The mice also have oligozoospermia, sperm head and chromatin
    compaction defects, impaired tracheal ciliary function and
    hydrocephalus, which are not part of the human disease as usually
    reported.
  modeled_mechanisms:
  - target: Multiple Morphological Abnormalities of the Sperm Flagella
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: The knockout reproduces human MMAF.
    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: "Cfap43−/− males were infertile and 100% of their spermatozoa were immotile and morphologically abnormal with short and coiled tail, a phenotype very similar to human MMAF"
      explanation: Knockout males reproduce the human sperm phenotype.
    - 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: An independent knockout line with male-only infertility.
  - target: Sperm Axonemal Disorganization
    relationship: RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Knockout sperm lack the central pair and have scattered doublets.
    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: "Note the specific arrangement of the ODFs around the axoneme in WT sperm and the complete disorganization of the DMTs and the absence of the central pair in Cfap43−/− sperm."
      explanation: Same ultrastructural defect as in patients.
  - target: Defective Intra-Manchette Transport
    relationship: RECAPITULATES
    fidelity: UNKNOWN
    model_scale: CELLULAR
    description: The manchette defect has only been studied in mice.
    limitations: >-
      Spermatid manchette structure has not been examined in patients, so it
      is unknown whether the mouse finding applies to human SPGF19.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Knockout mice add oligozoospermia and strong sperm head and DNA
        compaction defects to MMAF, whereas reported patients usually have
        normal sperm counts and the head defects have not been measured,
        so the weight of the manchette pathway in the human disease may be
        smaller than in mice.
    evidence:
    - reference: PMID:33046149
      reference_title: "CFAP43-mediated intra-manchette transport is required for sperm head shaping and flagella formation."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Furthermore, both abnormal manchette and disorganized ectoplasmic specialization (ES) could be observed at the elongated spermatids in Cfap43-deficient mice."
      explanation: Manchette defects in the knockout.
  - target: Airway Motile Cilia Dysfunction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Knockouts have airway mucus accumulation and hydrocephalus.
    limitations: >-
      Airway and brain phenotypes are prominent in knockout mice but almost
      absent from patients; one family has respiratory symptoms and none has
      hydrocephalus.
    divergences:
    - divergence_type: SPECIES_MISMATCH
      materiality: QUALIFYING
      description: >-
        Mice are prone to hydrocephalus from ependymal ciliary defects that
        rarely cause hydrocephalus in humans, and the mouse tracheal phenotype
        has no counterpart in nearly all CFAP43 patients, so the knockout
        overstates motile-cilia involvement in the human disease.
    evidence:
    - reference: PMID:31884020
      reference_title: "CFAP43 modulates ciliary beating in mouse and Xenopus."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "CFAP43 is involved in the regulation of the beating frequency of tracheal cilia and loss of CFAP43 causes severe mucus accumulation in the nasal cavity."
      explanation: Airway ciliary dysfunction in the knockout.
- name: Trypanosoma brucei TbCFAP43 RNAi knockdown
  species: Trypanosoma brucei
  genotype: Tetracycline-inducible RNAi against TbCFAP43
  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 CFAP43
        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. Reported fertilization and blastocyst
    rates are similar to other ICSI cycles, and pregnancies and live births
    are reported after ICSI without oocyte activation. The Palestinian
    brothers each had one live-born son but needed 8 and 4 ICSI cycles. In
    knockout mice, Cfap43-deficient sperm have chromatin compaction defects
    and support embryo development less well than Cfap44-deficient sperm;
    whether this applies to patients is unknown.
  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:36960497
      reference_title: "Patients with MMAF induced by novel biallelic CFAP43 mutations have good fertility outcomes after intracytoplasmic sperm injection."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The rate of fertilization was 66.7% and 75.0%, the rate of embryo cleavage was 100.0% and 86.7%, and the rate of blastocyst formation was 41.7% and 46.2%."
      explanation: Normal-range fertilization and blastocyst rates with patient sperm.
  evidence:
  - reference: PMID:36960497
    reference_title: "Patients with MMAF induced by novel biallelic CFAP43 mutations have good fertility outcomes after intracytoplasmic sperm injection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following frozen-thawed embryo transfer, the female partner of F3-II-1 proband became pregnant and gave birth to a full-term healthy boy, while the partner of F4-II-1 proband was in a good state of clinical pregnancy."
    explanation: Pregnancies after ICSI in two couples.
  - reference: PMID:41549427
    reference_title: "Novel biallelic CFAP43 mutations induce MMAF with mitochondrial abnormalities and successful ICSI outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Finally, assisted reproductive technology using intracytoplasmic sperm injection (ICSI) resulted in a successful pregnancy and live birth."
    explanation: A further live birth.
  - 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: "Our results support a good ICSI prognosis for MMAF patients carrying CFAP44 or CFAP43 mutations."
    explanation: Retrospective cohort including CFAP43 patients.
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 1 (Figure 1A, IV2), who is now 54 years old, has a history of 8 ICSI trials, and one of them was successful."
    explanation: Success after repeated cycles in the homozygous missense family.
  - 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: REFUTE
    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, ICSI with Cfap43-deficient sperm gives poorer embryo
      development than wild-type sperm, a possible limit not yet seen in
      patients.
- name: Genetic Counseling
  description: >-
    Counselling for autosomal recessive recurrence and carrier testing of
    relatives once the familial CFAP43 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:41549427
    reference_title: "Novel biallelic CFAP43 mutations induce MMAF with mitochondrial abnormalities and successful ICSI outcomes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study expands the spectrum of pathogenic CFAP43 mutations and provides valuable insights for genetic counseling and personalized reproductive strategies in patients with MMAF."
    explanation: The authors name genetic counselling as an application of the diagnosis.
  - reference: PMID:36960497
    reference_title: "Patients with MMAF induced by novel biallelic CFAP43 mutations have good fertility outcomes after intracytoplasmic sperm injection."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study significantly expands the mutant spectrum of CFAP43 , and together with the available information regarding male infertility and MMAF, provides new information for the genetic diagnosis and counseling of MMAF in the future."
    explanation: A second cohort drawing the same conclusion.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Establishes the diagnosis. Probands are identified by exome sequencing or
    MMAF gene panels with Sanger confirmation; copy-number analysis can be
    needed, as one allele was a 3.3-kb intragenic deletion. MMAF is
    genetically heterogeneous, and DNAH1, CFAP43 and CFAP44 together explain
    roughly a quarter to a third of cases 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: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 addition to this point mutation revealed by WES, we also identified a 3.3-kb heterozygous deletion within CFAP43 in P028 by using aCGH and long-range PCR assays"
    explanation: Copy-number analysis found an allele missed by exome sequencing.
- name: Semen Analysis
  description: >-
    Shows MMAF with near-total loss of motility; sperm concentration is
    usually preserved.
  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 misoriented central pair,
    displaced doublets and fibrous-sheath hyperplasia.
  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 central microtubules were absent (9+0) in most flagella, and various cytoskeletal components were distorted as well."
    explanation: TEM findings in patient sperm.
- name: Immunofluorescence of Sperm Flagella
  description: >-
    Absent or reduced CFAP43 staining, and absent SPAG6 and diffuse RSPH1
    staining, support pathogenicity of CFAP43 variants.
  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: "Immunofluorescence analysis of CFAP43 showed the protein was absent in the sperm flagella of patients 1 and 9."
    explanation: Immunofluorescence demonstrates protein loss.
- name: Respiratory Evaluation
  description: >-
    Not routinely needed, but chronic sinusitis, wet cough or bronchiectasis
    in a man with CFAP43-related MMAF should prompt evaluation for
    motile-cilia disease, as reported in one family.
  evidence:
  - reference: PMID:41341611
    reference_title: "Expanding the phenotypic spectrum associated with CFAP43 mutations: a case report of familial male infertility with respiratory manifestations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As shown in Figure 2, a chest computerised tomography (CT) scan of patient 2 revealed a localized area of bronchiectasis in the medial segment of the right middle lobe of the lung."
    explanation: Chest CT found bronchiectasis in a symptomatic patient.
📚

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 19 (CFAP43) · 2026-10-16T13:31:02Z · View source

New entry for SPGF19 (MONDO:0054723, CFAP43). Deep research run with the claude_code provider (research/Spermatogenic_Failure_19-deep-research-claude_code.md); just preflight-dr returned WARN because the paralog CFAP44 is mentioned, which is expected for this gene pair, 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 Pakistani, Palestinian (Awad 2025) and 2023/2026 Chinese families, the ciliate T/TH structural papers, the mouse IMT, airway and hydrocephalus papers, the Muronova 2025 mouse ICSI study, and the ClinGen CGGV records for SPGF19 (Definitive), PCD (Limited) and NPH (Disputed). Judgement calls: dynein complex binding (GO:0070840) bound as the molecular function, inferred from the ciliate T/TH complex; respiratory phenotypes recorded at VERY_RARE frequency from the single Palestinian family with SUPPORT and REFUTE evidence and an EMERGING motile-cilia hypothesis; missense alleles given a separate node and an EMERGING severity hypothesis because one compound-heterozygous missense patient was milder but a homozygous missense family was severe; monoallelic NPH and post-transplant respiratory reports kept out of the entry and described in notes. ClinGen named only Tang 2017 among its counted papers, so the other two counted publications could not be identified. 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 19 (SPGF19; CFAP43-related MMAF): Research Report
claude-haiku-5-5, claude-sonnet-5-5 16 citations 2026-10-16T13:13:15.978814

Spermatogenic Failure 19 (SPGF19; CFAP43-related MMAF): Research Report

Scope and verification. This report rests on a limited web pass, not a full literature review. Each claim is marked [verified] (seen in a search result or page fetch this session) or [background] (from general knowledge, not re-checked here). Sections 7–15 are mostly [background] with no PMIDs, because I did not find primary sources for them. Check the PMIDs and quotes below against references_cache/ (just fetch-reference) before using them as evidence snippets. Sources are linked in the text.

1. Disease information

Overview. SPGF19 is an autosomal recessive form of male infertility. Sperm show multiple morphological abnormalities of the flagella (MMAF), described as absent, short, coiled, bent and irregular-caliber flagella. This is a non-syndromic asthenoteratozoospermia phenotype. [verified: MalaCards/OMIM summary, LOVD]

Identifiers. - OMIM: 617592. [verified: LOVD, MGI] - MONDO: MONDO:0054723. [verified: DrugMap entry] - Parent class: spermatogenic failure (MONDO:0004983). [verified: same DrugMap entry] - UMLS CUI: C4539818. [verified: same DrugMap entry] - DOID:0070170. [verified: GlyCosmos] - MedGen: 1614356. [verified: appears in search results] - Orphanet, ICD-10/11 and MeSH: not checked. Orphanet likely lists the MMAF/asthenoteratozoospermia group rather than a separate SPGF19 entry [background, unverified].

Synonyms. SPGF19; "spermatogenic failure, type 19"; MMAF associated with CFAP43 (cilia- and flagella-associated protein 43; the older gene name is WDR96). [verified]

Data source. The entry is a disease-level, gene-defined entity derived from patient exome studies. It is not aggregated EHR data.

Gene attribution discrepancy. The LOVD page lists the gene as WDR96. That is the old symbol for CFAP43, so it is a nomenclature difference, not a conflict. OMIM, MedGen and the Disease Ontology all link the disease to CFAP43. DrugMap lists the gene–disease relationship as definitive with AR inheritance. [verified]

Sibling entities. SPGF20 (MONDO:0054724) is the CFAP44 counterpart and is also AR. [verified: DrugMap] The two are clinically near-identical. Both belong to a wider MMAF family that includes DNAH1 and CFAP47 (X-linked).

2. Etiology

  • Causal factor: genetic. Biallelic (homozygous or compound heterozygous) loss-of-function variants in CFAP43 (10q25.1). [verified]
  • Foundational study. Tang et al. 2017 (PMID:28552195) found compound-heterozygous CFAP43 mutations in three Han Chinese men with MMAF (P003, P028, P029), plus a homozygous frameshift in CFAP44 in a fourth. The mutations were inherited from heterozygous carriers and absent from 984 Han Chinese controls. [verified]
  • Independent replication. Auguste/Coutton et al. (Nat Commun 2018) screened 78 MMAF patients by exome sequencing. They found bi-allelic mutations in DNAH1 (n=6), CFAP43 (n=10) and CFAP44 (n=6), and showed the proteins are needed for flagellogenesis in mouse and Trypanosoma brucei. [verified via search summary; PMID not retrieved]
  • Environmental risk factors. None established for this monogenic form. General environmental and lifestyle factors affect sperm count and motility, but nothing specific to CFAP43 is known. [background]
  • Protective factors and gene–environment interactions. None known. [not available]
  • Modifier genes. No data located.

3. Phenotypes

Phenotype Suggested HPO Notes
Male infertility HP:0003251 Primary presentation [verified]
Asthenozoospermia HP:0012206 Reduced motility; typically severe, often near-total immotility [background]
Teratozoospermia / abnormal sperm morphology HP:0012864 (verify) Short, absent, coiled, bent, irregular-caliber flagella [verified]
Abnormal sperm flagellum morphology / MMAF HP:0012207 (verify) Defining phenotype [verified]
Abnormal sperm head morphology verify Seen in some patients and the mouse model (PMID:33046149, title only)
  • Frequency. Essentially penetrant in affected males: by definition they have MMAF. Exact percentages of each flagellar subtype were not retrieved.
  • Onset and course. Congenital genetic defect, recognized in adulthood on infertility work-up. Stable and non-progressive. [background]
  • Quality of life. No data located. Infertility-related psychosocial burden is plausible but not documented for this disease.
  • Extra-genital features. CFAP43 and CFAP44 are conserved axonemal proteins, and respiratory manifestations have been proposed. A 2025 paper is titled "CFAP43 mutations and familial male infertility with respiratory manifestations" (PMID:41341611; title only, content not read). Most reported cases are non-syndromic.
  • Female carriers/heterozygotes. Unaffected. The mouse knockout females are fertile. [verified]

4. Genetic/molecular information

  • Gene: CFAP43 (HGNC symbol CFAP43; look up the CURIE in HGNC and write it in lowercase hgnc: form per repository convention. I did not retrieve it, so do not copy one from here).
  • Variant types. Compound heterozygous splice-site, frameshift, nonsense and missense variants. Examples:
  • Novel compound heterozygous variants c.1859_1860+8delinsGT and c.3071A>G (PMID:41549427). [verified]
  • Splice acceptor-site deletion in a patient (PMID:29277146). [verified]
  • Biallelic loss-of-function variants in Pakistani families (PMID:34100391; title only).
  • Functional consequence. Loss of function. [verified at the level of titles and summaries]
  • Classification. ClinGen/DrugMap: definitive. Check for a CGGV record with just check-gene-validity. [verified for "definitive" via DrugMap]
  • Origin. Germline.
  • Population frequency. Not retrieved; query gnomAD directly.
  • Epigenetics and chromosomal abnormalities. None reported.

5. Environmental information

None established for the causal mechanism. There is no known infectious agent. No gene–environment data were located.

6. Mechanism / pathophysiology

Causal chain (the middle steps are partly inferred):

  1. Biallelic loss-of-function variants in CFAP43 reduce or abolish CFAP43 protein. [verified]
  2. CFAP43 is a conserved axonemal-associated protein. It is required for flagellogenesis in Trypanosoma and mouse; the evidence comes from Trypanosoma and knockout work. [verified]
  3. In elongating spermatids, loss of CFAP43 disrupts axoneme assembly and flagellar elongation. In mice, CFAP43 is also implicated in intra-manchette transport, which affects sperm head shaping and flagellum formation (PMID:33046149; title only). This step is demonstrated in model organisms, not directly in human testis.
  4. The result is MMAF sperm with absent, short, coiled or bent flagella. [verified]
  5. These sperm are immotile (asthenozoospermia), so natural fertilization fails: male infertility. [inferred from phenotype]
  6. Because the defect is confined to the late gamete's motility apparatus, sperm DNA and oocyte activation are largely preserved, so ICSI can bypass it (see §12). [inferred; supported by clinical outcomes]

Where this branches. CFAP43 is also expressed in motile cilia, so a respiratory arm is possible. The evidence is thin (see §3).

  • Suggested ontology terms (look up each in a live source before binding; do not write from memory):
  • GO: sperm flagellum assembly, cilium assembly or axoneme assembly, spermatid differentiation, sperm axoneme assembly.
  • CL: spermatid (and elongated spermatid).
  • GO CC: sperm flagellum, axoneme.
  • Omics, single-cell and screens. None located.

7. Anatomical structures affected

  • Organ: testis (seminiferous epithelium); sperm flagellum.
  • Cell: spermatid / spermatozoon (CL).
  • Subcellular: axoneme and sperm flagellum (GO CC); manchette in the mouse.
  • Secondary: possibly the respiratory tract (unconfirmed). Disease is bilateral. UBERON terms need lookup.

8. Temporal development

Congenital genetic defect that manifests at spermatogenesis (post-pubertal) and is diagnosed in adults presenting with infertility. It does not progress and is lifelong. There is no remission. The critical window is reproductive age, when ICSI is available. [background]

9. Inheritance and population

  • Inheritance: autosomal recessive (HP:0000007). [verified]
  • Prevalence. Not found. MMAF overall is rare. CFAP43 accounted for 10 of 78 patients (about 13%) in the Auguste/Coutton cohort, and combined DNAH1/CFAP43/CFAP44 about 28% in that cohort. These numbers are cohort-selected, not population rates. [verified via search summary]
  • Populations. Reported in Han Chinese (Tang 2017) and Pakistani families (PMID:34100391), and in a European/North African cohort (Coutton). Consanguinity is relevant in homozygous families [background].
  • Sex. Males only are affected; females are unaffected carriers. [verified in mouse; background in human]
  • Founder variants, penetrance and carrier frequency: not retrieved.

10. Diagnostics

  • Semen analysis: severe asthenozoospermia with a high proportion of MMAF-morphology sperm; sperm count is typically near-normal. [background]
  • Microscopy: light microscopy and transmission electron microscopy show disorganized axoneme and fibrous sheath. [background]
  • Genetic testing: exome sequencing or an MMAF/male-infertility gene panel including CFAP43, CFAP44, DNAH1, CFAP47 and others. Single-gene CFAP43 testing is a reasonable follow-up. [background]
  • Differential: other MMAF genes (DNAH1, CFAP44, CFAP69, WDR66 and others), primary ciliary dyskinesia (PCD), and acquired causes of asthenozoospermia.
  • A LOINC code for semen analysis is available, but I did not look up one. Per repository rules, use just loinc-seed-cache and do not type a code or label from memory.

11. Outcome / prognosis

  • No increased mortality is expected. [background]
  • Fertility prognosis with ICSI is good (see §12).
  • Sperm head defects in MMAF may affect embryo development; the mouse study is PMID:40070084 (title only).

12. Treatment

  • No curative or disease-modifying treatment exists.
  • ICSI (intracytoplasmic sperm injection) is the established route. Suggested NCIT term: look up Intracytoplasmic Sperm Injection or the closest assisted-reproduction term in a live source, rather than writing a code from memory.
  • Sha et al. 2019, Andrologia: retrospective cohort of six patients with CFAP44 or CFAP43 mutations versus DNAH1 patients and controls. The authors found no statistically significant differences in transferable embryo, implantation, clinical pregnancy or miscarriage rates, and concluded that MMAF patients with these mutations have a good ICSI prognosis. [verified via search summary; small cohort]
  • A newer report (PMID:41549427) describes compound heterozygous CFAP43 variants with ICSI resulting in a live birth. [verified]
  • Fertility outcomes after ICSI are also described in PMID:36960497 (title only).
  • Pharmacotherapy and PGx. Hormonal or antioxidant therapies are not established for genetic MMAF. [background]
  • Gene therapy, cell therapy and clinical trials. None identified; I did not search ClinicalTrials.gov.
  • Oocyte activation: not usually needed for this class of defect, but I have no source.

13. Prevention

  • Genetic counseling: AR recurrence risk is 25% per pregnancy for carrier couples. Brothers of an affected man have a 25% chance of being affected. [background]
  • Prenatal or preimplantation genetic testing is possible once the familial variants are known. Carrier screening for CFAP43 is not routine. [background]
  • No primary prevention exists. Daughters of affected men are obligate carriers.

14. Other species / natural disease

  • Orthologs exist in mouse and in Trypanosoma brucei. Gene IDs (NCBI Gene) and NCBITaxon CURIEs should be looked up rather than written from memory.
  • No naturally occurring animal disease identified. I did not check OMIA.

15. Model organisms

  • Mouse: CRISPR/Cas9 Cfap43 knockout (and Cfap44). Male mice display MMAF; females are fertile. This recapitulates the human phenotype well. [verified, PMID:28552195]
  • Trypanosoma brucei RNAi/knockout shows flagellar defects and supports evolutionary conservation of the flagellar function. [verified via search summary]
  • Additional mouse work on manchette transport and sperm head shaping (PMID:33046149, title only).
  • Limitations. Mouse and trypanosome data do not show whether human spermatogenesis proceeds identically. Respiratory and motile-cilia phenotypes are not clearly modeled.
  • Resources to check: MGI, IMPC, Alliance of Genome Resources.

Suggested direct quotes (from search-result excerpts; verify against cached abstracts)

  • Tang 2017, PMID:28552195: compound-heterozygous mutations in CFAP43 in three subjects and a homozygous frameshift mutation in CFAP44 in one subject. The recessive mutations were parentally inherited from heterozygous carriers and absent in 984 individuals from three Han Chinese control populations. These two lines are paraphrases from the search summary, not exact quotes. Pull exact text with just fetch-reference PMID:28552195.

Gaps and recommended next steps

  1. Fetch PMID:28552195 and the Coutton/Auguste paper through just fetch-reference, and take exact snippets from those caches.
  2. Look up the HGNC, GO, CL, UBERON, HPO and NCIT identifiers with the dismech-terms workflow.
  3. Check ClinGen for a CFAP43 gene-validity record.
  4. Run just check-genereviews for a chapter that might serve as a baseline. I did not look for one.
  5. Review population frequency, founder variants, respiratory involvement and clinical trials, none of which I covered.

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 0
Quoted claims not found in source 1
References weighed for topical relevance 9
On topic 8
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

  • PMID:41341611: "CFAP43 mutations and familial male infertility with respiratory manifestations"
  • closest text in source: "Additionally, they highlight the potential expansion of the CFAP43 gene's phenotypic spectrum to include respiratory manifestations"

Term Validation

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

Outcome Count
Terms checked 10
Resolved 9
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 6
Terms named correctly 2
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:0012864 (1 mention) - the report calls it "verify"; HP calls it Abnormal sperm morphology
  • HP:0012207 (1 mention) - the report calls it "verify"; HP calls it Reduced sperm motility

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:

  • MONDO:0004983 (1 mention) - the report calls it "Parent class: spermatogenic failure"; MONDO calls it spermatogenic failure

Prefixes with no resolver

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