Biallelic Truncating Variant in LRGUK Is Associated With Severe Multiple Morphological Abnormalities of the Sperm Flagella and Sperm Nuclear Defects in Humans.

A novel homozygous frameshift mutation in CFAP65 is associated with multiple morphological abnormalities of sperm flagella in a consanguineous Pakistani family

A novel domain-specific CFAP65 mutation associated with MMAF and male infertility in a consanguineous Pakistani family is identified, thereby expanding the known genetic mutational landscape of MMAF.

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

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.

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

Acephalic spermatozoa syndrome (ASS) is a rare cause of male infertility characterized by sperm tails lacking heads. Although zinc finger MYND-type containing 15 (ZMYND15) mutations are linked to male infertility, their role in ASS is unknown. In this study, whole-exome sequencing identified novel homozygous truncating mutations, c.292C>T (p.Arg98Ter) and c.337G>T (p.Glu113Ter), in ZMYND15 from two infertile patients. These mutations caused protein truncation and impaired function, leading to extremely low sperm counts, poor motility, and numerous acephalic spermatozoa. Electron microscopy and sperm immunofluorescence revealed abnormal sperm neck structures, missing mitochondrial sheaths, failure of acrosome formation, and a lack of central microtubules. Experiments showed reduced mutant protein expression and high rates of degradation. Coimmunoprecipitation experiments indicated a direct interaction between ZMYND15 and Sad1 and UNC84 domain containing 5 (SUN5), crucial for forming the sperm head-tail connection. One patient achieved a live birth via intracytoplasmic sperm injection (ICSI), whereas the other had an early miscarriage. This study links ZMYND15 mutations directly to ASS, highlighting its role in spermatogenesis and offering insights for clinical diagnosis and treatment.

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

Background and Objectives: Male factors account for approximately 30–50% of subfertile couples. Teratozoospermia is one of the major causes of male infertility; however, the genetic factors underlying many cases remain incompletely understood. This study aimed to identify potential genetic variants associated with teratozoospermia and to investigate the possible involvement of Caudal-Type Homeobox 4 (CDX4) in sperm morphogenesis. Materials and Methods: Whole-exome sequencing was performed in 44 individuals with teratozoospermia. A rare CDX4 variant (NM_005193.2, c.103G>T; NP_005184.1, Gly35Cys) was identified and confirmed by Sanger sequencing. Because CDX4 is located on the X chromosome, this variant was interpreted as hemizygous in the male patient. Sperm morphology, CDX4 localization, public GEO transcriptomic data (GSE6969), and CDX4 expression during murine spermiogenesis were analyzed. Results: The CDX4 p.Gly35Cys variant is located within the Caudal-like transactivation domain, a conserved region involved in transcriptional regulation. Spermatozoa from the patient carrying this variant exhibited severe morphological abnormalities, predominantly involving sperm-head defects, together with aberrant CDX4 localization along the midpiece and tail, in contrast to the neck- and annulus-enriched distribution observed in control spermatozoa. Reanalysis of the GEO dataset showed increased CDX4 transcript levels in teratozoospermic samples compared with normozoospermic controls. During murine spermiogenesis, CDX4 was detected in the nuclei of spermatogonia and spermatocytes and subsequently localized to the sperm head and neck/tail regions during sperm morphogenesis. Conclusions: CDX4 c.103G>T (p.Gly35Cys) is a rare hemizygous X-linked candidate variant associated with severe teratozoospermia in a single patient. Further cohort-based, segregation, and functional studies are required to clarify its role in sperm morphogenesis.