Aug 2026· Medicina· Vol 62· 0 citations· 37 references
Medicine
TL;DR
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.
Abstract
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.
The co-occurrence of variants in AKAP4 and RNF220 may suggest an oligogenic etiology of NOA and contribute to the phenotypic variability associated with AKAP4 variants.
Razieh Ebrahimi Askari, A. Malcher, Fateme Sefid et al.· International Journal of Mol...· 0 citations
This work collected cases of HTX investigated by trio-based whole-exome (WES) and whole-genome sequencing (WGS) and performed detailed clinical and molecular characterization in seven children and fetuses from France and Vietnam and revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations.
Thi Bich Tuyen Ho, Alicia Coudert, Thi Thuy Hang Do et al.· Clinical Genetics· 0 citations
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.
Ling-Yi Li, F. Wan, K. Feng et al.· Frontiers in Cell and Develo...· 0 citations
It is demonstrated that even in the absence of functional experiments, comprehensive family analysis can provide crucial clues for variant of uncertain significance (VUS) interpretation.
Xiulan Hao, Yan-Chou Ye, Man Liu et al.· Frontiers in Genetics· 0 citations
A Chinese patient presenting with classic hallmarks of MGORS7 alongside atypical clinical features, including hearing and visual impairments is reported, suggesting that growth hormone therapy may be beneficial for growth retardation in patients with MGORS7.
Ying Zhao, Yi-Yang Fu, Shu-Ying Zhang et al.· Frontiers in Genetics· 0 citations
Background/Objectives: Müllerian duct anomalies (MDAs) are congenital structural abnormalities of the female reproductive tract with heterogeneous and incompletely defined genetic contributions. PAX8 is a developmental transcription factor implicated in thyroid and urogenital development. This study assessed the functional consequences of a rare PAX8 variant identified by whole-exome sequencing (WES) in an MDA cohort, without presuming a causal relationship. Methods: WES was performed in 150 patients with MDAs. The PAX8 c.791T>C (p.Leu264Pro) variant was evaluated using computational predictions, cellular assays, and RNA sequencing in a 293FT transient-overexpression model. Results: The heterozygous p.Leu264Pro variant was identified in one patient with a complex septate uterine, cervical, and vaginal anomaly and was absent from 120 controls. Parental samples were unavailable. No statistically significant difference in construct-derived PAX8 mRNA abundance was detected between PAX8-WT and PAX8-L264P, and both proteins showed predominantly nuclear localization. In the direct PAX8-WT-versus-L264P RNA-seq comparison, 76 transcripts had nominal p values below 0.05, but none remained significant after Benjamini–Hochberg correction, and no gene met the prespecified differential-expression criteria. AK5, RCBTB2, and IFT88 were identified as candidate PAX8-responsive genes in this experimental system. Conclusions: No major functional difference was detected between PAX8-WT and L264P under the tested conditions; however, these findings do not establish functional equivalence or exclude smaller, tissue-specific, or developmental-stage-specific effects. The p.Leu264Pro variant remains a variant of uncertain significance with respect to MDAs, and the functional results were not used as benign evidence under ACMG/AMP criterion BS3.
Lin He, Liang-Zhe Li, Yuxiao Li et al.· Genes· 0 citations
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