Loss-of-function variants in CFAP57, SEPTIN4, SPEM2, and CFAP46 cause asthenoteratozoospermia.

CFAP46

Homozygous loss-of-function variants in CFAP46, CFAP57, SEPTIN4 and SPEM2; deficiency of CFAP46, a central apparatus protein, disrupts the flagellar axoneme

This study used genome or exome sequencing in 13 consanguineous families with primary male infertility and asthenoteratozoospermia. Homozygous loss-of-function variants in CFAP46, CFAP57, SEPTIN4 and SPEM2 segregated with infertility. For CFAP46, three CRISPR/Cas9 mouse models (null allele, FLAG-tagged knock-in and a humanised patient-specific nonsense allele) showed infertility of deficient males, with reduced sperm count and motility and severe axonemal disruption; the protein forms an in vivo complex with CFAP54, CFAP74 and CFAP221. In families without a monogenic cause, a burden analysis across 345 spermiogenesis genes found more rare deleterious variants in affected men than in fertile controls, an association the authors consider in need of functional validation.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

None of the four genes is entirely new to human disease: CFAP57, SEPTIN4 and SPEM2 have already been reported in male infertility, and CFAP46 in primary ciliary dyskinesia (PMID 39362668); the main contribution is the functional demonstration of the role of CFAP46 in spermiogenesis. These genes are already captured by the exome: the point is to interpret them in a male infertility work-up, bearing in mind the link between CFAP46 and ciliary dyskinesia. The oligogenic hypothesis based on rare-variant burden remains exploratory.

Analysis by Dr Thibaut Benquey