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

• 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

• LOVD disease #05567 (SPGF19, OMIM:617592)
• MalaCards: Spermatogenic Failure 19
• MGI: OMIM:617592
• DrugMap disease DIS2ZB4B
• GlyCosmos DOID:0070170
• Tang et al. 2017, PubMed 28552195
• Coutton/Auguste et al., Nat Commun
• Sha et al. 2018, PubMed 29277146
• Sha et al. 2019, Andrologia
• PubMed 41549427
• PubMed search: CFAP43 MMAF

Reference Validation

Checked with linkml-reference-validator 0.3.0.

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.

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.