Genomic analysis of 13 families identified variants in CFAP57, SEPTIN4, SPEM2 and CFAP46.
Mouse experiments supported a role in disrupted sperm formation, expanding research into genetic diagnosis of unexplained male infertility.
Why can pregnancy remain difficult even when sperm numbers are sufficient? Sperm that cannot move properly, or have abnormal heads and tails, may struggle to reach and fertilize an egg.
Research suggests that some of these abnormalities can arise from specific gene variants, rather than lifestyle or environmental factors alone.
An international study published in Human Reproduction on October 21, 2026 analyzed the genomes of 13 families affected by male infertility and identified four genes involved in abnormal sperm motility and morphology: CFAP57, SEPTIN4, SPEM2 and CFAP46.
The findings offer clues to the genetic basis of asthenoteratozoospermia, the combination of reduced sperm motility and abnormal shape, and to processes that standard semen analysis cannot fully explain.
Short, bent sperm tails and genetic variants
A sperm consists of a head, midpiece and tail. The head contains genetic information, the midpiece supplies energy for movement, and the tail provides propulsion.
Abnormal formation of any of these parts can reduce movement and affect the possibility of fertilization.
The researchers performed genome or exome analysis in 13 families affected by male infertility, comparing infertile men with relatives whose fertility had been established.
Loss-of-function variants in CFAP57, SEPTIN4, SPEM2 and CFAP46 were identified in five families. These variants were associated with structural tail defects and abnormal development of the head and midpiece.
Men with CFAP57 variants had sperm with short, bent or coiled tails. SEPTIN4 variants involved a protein function needed to maintain tail structure, while SPEM2 variants were implicated in formation of the acrosome and nucleus in the sperm head.
This indicates that abnormal motility and morphology can be connected to genetic defects arising during sperm formation, rather than being merely descriptive semen-test findings.
CFAP46 function tested in mice
CFAP46 was a particular focus. The researchers found evidence that it plays an important role in forming normal sperm head and tail structures.
Sperm from men with CFAP46 variants showed pronounced abnormalities: enlarged neck regions, short or bent tails, and problems with the acrosome, which is important for fertilization.
To test whether loss of CFAP46 function could produce these defects, the researchers used gene editing in mice.
Male mice lacking CFAP46 function had markedly reduced sperm counts and motility. Severe abnormalities developed in the internal tail ultrastructure, and the animals lost their fertility.
These findings support a role for CFAP46 across the formation of the sperm head and tail, beyond simply regulating movement.
Could multiple variants act together?
The researchers also examined families whose infertility could not readily be explained by one gene.
They screened rare variants across 345 genes known to be associated with sperm formation. In families without an established cause, infertile men carried more rare, potentially damaging variants than fertile relatives.
Such variants were found across 4–16 genes per family among infertile men.
This raises the possibility that male infertility does not always arise from a single genetic abnormality. Variants across several genes may act together to influence sperm formation and motility.
The authors cautioned that these combined genetic effects are not yet established and require analysis in more patients and functional validation.
What this may mean for unexplained male infertility
The study opens possibilities for understanding the cause of male infertility and informing discussions about care.
Semen analysis currently measures sperm number, motility and the proportion of normal forms. It cannot, on its own, establish why sperm developed abnormally or which genetic defects were involved.
Genetic analysis may help identify a cause in some men with severely reduced motility or recurrent morphological abnormalities.
An identified genetic cause can help clinicians explain the background to infertility and discuss genetic counseling and whether assisted reproduction is appropriate.
This study does not establish that IVF or ICSI will necessarily succeed in patients with these variants. The limited number of families and the reliance on mouse experiments for part of the evidence mean further validation is needed for clinical application.
Nevertheless, it broadens investigation beyond sperm numbers and movement toward precise genetic mechanisms operating during sperm formation.
Poor motility and abnormal shape are visible outcomes; their underlying causes may begin at the level of genes involved in producing sperm.
Source: This article is based on “Loss-of-function variants in CFAP57, SEPTIN4, SPEM2, and CFAP46 cause asthenoteratozoospermia,” by Shoaib Nawaz and an international team, published October 21, 2026 in Human Reproduction. The researchers analyzed 13 families affected by male infertility and used gene-edited mice to investigate CFAP46 function. DOI: 10.1093/humrep/deag154.
Image disclosure: The image was created using generative AI (ChatGPT, OpenAI); any people depicted are fictional, not real individuals.
For background on ovarian reserve, semen analysis and when additional investigations may be considered, see our guide to the first fertility clinic visit.
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