Some men are told their sperm both move poorly and look abnormal, yet every routine test — hormones, scans, infection screening — comes back normal. Recent research is explaining why. A study published in Human Reproduction reports that loss-of-function variants in four genes, CFAP57, SEPTIN4, SPEM2 and CFAP46, cause asthenoteratozoospermia. For these men, the problem is written into the instructions for building a sperm cell.
Genetic male infertility evaluation with Dr. Arun Muthuvel in Chennai
Dr. Arun Muthuvel is an MCh-qualified reproductive medicine and surgery specialist in Chennai. When sperm defects are severe and unexplained, he considers a genetic cause early, so couples avoid months of supplements that cannot help and move to the treatment that can.
What Is Asthenoteratozoospermia?
The term combines two findings on a semen analysis: asthenozoospermia (reduced motility) and teratozoospermia (abnormal shape). In its most severe form, called multiple morphological abnormalities of the sperm flagella (MMAF), most sperm have tails that are short, bent, coiled, absent or irregular in width, and very few sperm swim.
A sperm tail is a precisely engineered motor. Hundreds of proteins must be assembled in the right place and order. If a single essential protein is missing, the motor fails — and no amount of lifestyle change can rebuild it.
What “Loss-of-Function” Means
A loss-of-function variant is a change in the DNA that stops a gene from producing a working protein. These conditions are usually autosomal recessive: a man is affected only when both of his copies of the gene — one from each parent — are faulty. Parents who carry one copy are healthy and usually unaware. This is why such variants are found more often when parents are related by blood, which remains common in parts of South India.
The Four Genes and What They Do
| Gene | Role in the sperm | What goes wrong |
|---|---|---|
| CFAP57 | A cilia and flagella protein needed to assemble the dynein “motor arms” of the tail | Malformed tails (MMAF) and very poor motility |
| SEPTIN4 | Forms the annulus, a ring that separates the midpiece from the rest of the tail | Thin, disorganised midpiece and immotile sperm |
| SPEM2 | Helps mature sperm shed excess cytoplasm and be released from the testis (spermiation) | Abnormally shaped sperm with retained cytoplasm and reduced motility |
| CFAP46 | Part of the central apparatus at the core of the tail | Defective tail assembly and abnormal head remodelling |
The new study builds on earlier work. CFAP57 variants were previously shown to cause MMAF in consanguineous families, with mouse studies confirming that loss of the gene disrupts the tail’s inner dynein arms. SEPTIN4 variants were linked to thin-midpiece sperm in 2022, and SPEM2 was recently shown to be essential for normal sperm release. Identifying CFAP46 as a cause of both tail and head defects adds another piece to the picture.
Why a Genetic Diagnosis Matters
- It ends the search. A confirmed genetic cause explains the infertility and stops repeated, unhelpful treatments.
- It sets realistic expectations. Antioxidants, hormone tablets and varicocele surgery cannot correct a structural gene defect.
- It guides ICSI counselling. Fertilisation and pregnancy rates after ICSI differ between genes, so knowing the gene helps predict what to expect.
- It informs the family. Brothers may share the same variants, and future children can be counselled about carrier status.
Who Should Be Tested?
Genetic testing, usually whole-exome sequencing or a targeted male infertility gene panel, is worth discussing if:
- Repeated semen analyses show severe asthenoteratozoospermia or MMAF
- Parents are related by blood (consanguineous marriage)
- A brother or male relative has similar infertility
- No other cause is found after a full evaluation
- There are frequent sinus or chest infections, which can point to a wider cilia disorder
Treatment: How Couples Can Still Conceive
The key treatment is IVF with ICSI. Because a single sperm is injected directly into the egg, the sperm does not need to swim. When ejaculated sperm are immotile, the laboratory uses vitality tests such as the hypo-osmotic swelling test to pick living sperm. If ejaculated sperm are unsuitable, sperm can sometimes be retrieved directly from the testis with TESA or TESE.
The female partner’s fertility, age and egg quality matter just as much. Where both partners carry variants in the same gene, preimplantation genetic testing (PGT) can be discussed.
Frequently Asked Questions
Can a genetic sperm defect be fixed with supplements or lifestyle changes?
No. When a gene needed to build the sperm tail is not working, antioxidants, diet and lifestyle changes cannot rebuild that structure. They remain good for general health, but treatment usually relies on ICSI.
Can men with these gene variants become fathers?
Often, yes. ICSI injects a single sperm directly into the egg, so the sperm does not need to swim. Results vary between genes and between couples, which is why a genetic diagnosis helps with counselling.
Will my children inherit the condition?
These conditions are usually inherited in an autosomal recessive pattern. Children of an affected man will normally carry one copy but are unlikely to be affected unless the mother also carries a variant in the same gene. Genetic counselling clarifies the risk for each family.
Who should consider genetic testing for sperm defects?
Men with severe asthenoteratozoospermia or MMAF, especially when parents are related by blood, a brother has similar infertility, or no other cause is found.
The Bottom Line
Loss-of-function variants in CFAP57, SEPTIN4, SPEM2 and CFAP46 are now recognised causes of sperm that swim poorly and look abnormal. A genetic diagnosis explains the problem, spares couples ineffective treatment and points directly to ICSI. Dr. Arun Muthuvel offers complete male infertility evaluation in Chennai, including genetic assessment and ICSI planning.
This article provides general medical information and does not replace individual diagnosis or treatment advice. Outcomes vary with age, diagnosis, test results and clinical circumstances.