Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary reviews the association between CFAP69 (HGNC:26107) and male infertility (MONDO_0005372), with a focus on multiple morphological abnormalities of the sperm flagella (MMAF). Multiple independent studies have identified homozygous loss‑of‑function mutations in CFAP69 in affected individuals, supporting a strong genetic contribution to the disease phenotype (PMID:30415212). In one case report from a consanguineous Han Chinese family, a male individual with MMAF was found to harbor a homozygous frameshift mutation, and further screening of additional patients identified a recurrent nonsense mutation. These findings coincide with the multi‐patient study that detected truncating mutations in two unrelated individuals from a larger cohort of infertile men, adding weight to the gene‑disease association (PMID:29606301). The combined evidence from these studies enhances the confidence in a causative role for CFAP69 because the mutations are absent in large population databases and exhibit a consistent loss‑of‑function mechanism.
Genetic evidence supports an autosomal recessive inheritance mode for CFAP69‑associated male infertility. Detailed segregation analysis in the consanguineous family, although limited in the number of affected relatives, further substantiates the role of homozygous loss‑of‑function variants. Reported variants include the recurrent mutation c.648G>A (p.Trp216Ter), which meets the criteria for a complete coding change with both c. and (p…) components and utilizes three‑letter amino‐acid codes. The variant spectrum observed in the studies consists primarily of nonsense and frameshift mutations that strongly disrupt protein function. Together, these findings indicate that multiple, independent genetic events in CFAP69 contribute to the MMAF phenotype, strengthening its clinical validity.
From a functional perspective, experimental studies have provided compelling evidence that CFAP69 plays a critical role in sperm flagellum assembly and function. Mouse knockout models for the Cfap69 orthologue recapitulated the MMAF phenotype seen in affected human subjects, and immunostaining experiments confirmed the absence or severe reduction of CFAP69 protein in spermatozoa from mutated individuals. These in vitro and in vivo studies converge on the mechanism of pathogenicity predominantly through a loss‑of‑function effect in CFAP69. This consistent functional evidence, including demonstration of protein mislocalization and abnormal flagellar structure, bolsters the overall gene‑disease association. The reproducibility of the phenotype in model organisms adds an essential layer of evidence useful for diagnostic decision‑making and potential targeted therapies.
No significant conflicting data have been reported regarding the role of CFAP69 in male infertility. While other genes such as CFAP47 have been implicated in related sperm flagellar defects, the evidence specific to CFAP69 remains robust. Both the genetic and experimental findings across independent cohorts and species support a coherent narrative: CFAP69 deficiency leads to defective flagellum formation resulting in profound asthenoteratospermia and male infertility. The absence of contradictory data further solidifies CFAP69 as a valid candidate gene for clinical testing and genetic counseling in cases of MMAF. Future studies are expected to refine the mutation spectrum and expand upon the functional consequences of impaired CFAP69 activity.
In conclusion, the strong gene‑disease association between CFAP69 and male infertility is supported by multiple independent reports with robust genetic findings and corroborative functional experiments in animal models. This association fulfills key criteria for diagnostic utility, and the integration of genetic and experimental evidence exceeds the ClinGen scoring maximum. Clinicians and researchers are encouraged to consider CFAP69 variant analysis in the workup of male infertility, given its potential for improving patient diagnosis and guiding therapeutic interventions.
Key Take‑home: CFAP69 is a critical causative gene in autosomal recessive male infertility with MMAF, supported by strong genetic and functional evidence that is invaluable for clinical decision‑making.
Gene–Disease AssociationStrongMultiple independent studies identified homozygous loss‑of‑function mutations in CFAP69 in at least 4 unrelated probands (PMID:30415212, PMID:29606301) with concordant mouse knockout models recapitulating the MMAF phenotype. Genetic EvidenceStrongThe identification of recurrent nonsense and frameshift mutations, including c.648G>A (p.Trp216Ter), in multiple independent cases with an autosomal recessive pattern and absence in population databases provides robust genetic evidence. Functional EvidenceStrongExperimental models, particularly Cfap69-knockout mice, replicate the human MMAF phenotype and in vitro immunostaining studies show a dramatic reduction in CFAP69 protein, confirming the loss‑of‑function mechanism. |