Novel mutations in ZMYND15 expand the phenotypic spectrum to acephalic spermatozoa: abnormal sperm head-tail connection mediated by SUN5.

A novel frameshift variant in TTC29 associated with total asthenozoospermia and male infertility

Background Severe sperm motility defects are an important cause of male infertility and are frequently associated with sperm flagellar abnormalities. TTC29 encodes an evolutionarily conserved axonemal protein implicated in sperm flagellar assembly and motility, yet the pathogenic mechanisms of TTC29 variants remain incompletely understood. Methods A Chinese man with total asthenozoospermia was investigated using whole-exome sequencing, Sanger sequencing, transmission electron microscopy, sperm immunofluorescence, and heterologous expression analysis in HEK293 T cells. The clinical outcome following intracytoplasmic sperm injection (ICSI) was also evaluated. Results Whole-exome sequencing identified a novel TTC29 frameshift variant (NM_031956.4:c.121dupA; p. Ile41Asnfs*21), which was confirmed by Sanger sequencing. Transmission electron microscopy revealed severe ultrastructural abnormalities involving both the midpiece and principal piece, with disruption of the canonical 9 + 2 axonemal architecture and marked abnormalities of peri-axonemal structures. In representative immunofluorescence images, TTC29 signal was readily detected along the sperm flagellum in the fertile control, whereas a visibly weaker signal was observed in spermatozoa from the proband. Heterologous expression analysis showed little or no detectable production of the expected TTC29 protein product from the mutant construct. Although fertilization was achieved following two ICSI cycles, no clinical pregnancy was obtained. Conclusion We identified a novel TTC29 frameshift variant associated with total asthenozoospermia and male infertility. Genetic, ultrastructural, and heterologous expression evidence supports a deleterious effect of the identified TTC29 variant, thereby expanding the mutational spectrum of TTC29-related infertility and providing further insight into the molecular basis of severe sperm motility disorders.

A CCNA1 Missense Variant Associated With Chromatid Non-Disjunction in Abnormal-Headed Sperm and Male Infertility.

BACKGROUND Macrozoospermia is a rare form of teratozoospermia characterized by tetraploids, large-headed spermatozoa with multiple flagella, usually caused by bi-allelic AURKC mutations. The etiology of atypical phenotypes with a lower proportion of large headed spermatozoa and single flagella however often remains unresolved. OBJECTIVE To investigate the genetic cause of severe sperm-head abnormalities with moderate macrozoospermia without multiflagellated spermatozoa in a patient with repeated ICSI failure. An infertile male with three failed ICSI attempts underwent semen analysis, revealing complete teratozoospermia, including 25% macrocephalic spermatozoa. METHODS Multi-probe FISH targeting chromosomes 13, 18, 21, X, Y assessed chromosomal segregation. Whole-exome sequencing (WES) was performed to identify a candidate variant associated with meiotic abnormalities. RESULTS FISH analysis revealed a high proportion of spermatozoa with n (23) chromosomes and 2c DNA content, consistent with sister chromatid non-disjunction during meiosis II. WES identified a homozygous missense variation in CCNA1, coding for a protein described to be essential for meiotic progression and chromatin remodeling in male germ cells. DISCUSSION The variant affects a highly conserved residue within a functional domain and is predicted to be deleterious. This study establishes the first clinical association between CCNA1 mutations and chromatid non-disjunction in human spermatogenesis. It highlights the limitations of current morphology-based diagnostic thresholds and supports cytogenetic and genomic assessment for severe teratozoospermia (especially head abnormalities) and ART failure. CONCLUSION Expanding genetic screening panels to include CCNA1 may improve diagnostic precision and clinical management in atypical macrozoospermia cases.

A Homozygous NUP210L Variant Is Associated With Severe Defects in Human Spermiogenesis.

The findings support a role for NUP210L in human spermiogenesis that is not fully recapitulated in murine models and provide human-based evidence that nucleoporin dysfunction contributes to male infertility.

Biallelic FSIP2 variants are associated with sperm defective chromatin condensation beyond MMAF and acrosomal abnormalities.

A Novel Homozygous Mutation in ARL2BP Causes Multiple Morphological Abnormalities of the Flagella and Primary Ciliary Dyskinesia

Findings confirm ARL2BP as a causative gene for both PCD and MMAF, expanding the genotypic and phenotypic spectrum of ciliopathies and recommending long‐term ophthalmological follow‐up to detect delayed‐onset retinal degeneration.

A Novel Hemizygous CDX4 Missense Variant Identified in a Taiwanese Man with Severe Teratozoospermia

A rare hemizygous X-linked candidate variant associated with severe teratozoospermia in a single patient is identified and confirmed by Sanger sequencing, and the possible involvement of Caudal-Type Homeobox 4 (CDX4) in sperm morphogenesis is investigated.