Jul 2026· Journal of Applied Genetics· 0 citations· 39 references
Medicine
TL;DR
Rare candidate variants in SSX1, CPNE1, and SPTBN5 that may potentially be associated with the molecular basis of oligoasthenoteratozoospermia are identified and support the application of WGS in unresolved male infertility.
Abstract
Reduced sperm count, impaired motility, and abnormal morphology are characteristics of oligoasthenoteratozoospermia (OAT). Genetic factors play an important role in spermatogenic failure, but the molecular basis of OAT is still not fully understood. Whole-genome sequencing (WGS) was performed in 17 infertile men with normal karyotypes and no Y-chromosome microdeletions, including 10 patients with azoospermia and 7 with OAT. Among the OAT group, three patients carrying prioritized rare variants with potential relevance to spermatogenesis were selected for detailed analysis and presentation in the current study. Variants were called using DeepVariant, and they were annotated by Ensembl Variant Effect Predictor (VEP). Variants were prioritized based on low allele frequency (< 1% in gnomAD), predicted functional impact, relevance to spermatogenesis, and consistency with a recessive inheritance model. Candidate variants were validated by Sanger sequencing and inspection of BAM files. Structural protein modeling and characterization of mutation-induced changes in molecular interactions were also performed using SWISS-MODEL and AlphaFold. We identified a hemizygous splice donor variant (c.*4 + 1G > T) in SSX1 and a missense variant (c.1190 A > G) in CPNE1 in one patient with OAT. SSX1 is a testis-expressed gene, while CPNE1 encodes a calcium-dependent phospholipid-binding protein. In another patient, a stop-gained variant (c.790 C > T) in SPTBN5 was identified, which encodes a spectrin beta chain protein. This study identifies rare candidate variants in SSX1, CPNE1, and SPTBN5 that may potentially be associated with the molecular basis of OAT. These findings provide preliminary evidence supporting further investigation of these genes in OAT and support the application of WGS in unresolved male infertility.
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
A previously unreported splice-site mutation in TACR3 that likely causes familial infertility by disrupting the neurokinin B/NK3R signaling pathway is identified and extended the mutational landscape of TACR3 and highlight its essential contribution to male reproductive endocrinology.
Mohammadreza Saberiyan, S. Kalantar, R. Mirfakhraie et al.· Reproductive Sciences· 0 citations
Sirenomelia is a rare and lethal congenital malformation representing the most severe form of caudal dysgenesis, with a stillbirth rate of up to 53%. The genetic basis of sirenomelia remains poorly understood. Consequently, in this study, we aimed to comprehensively characterize genomic variants and explore potential pathogenic mechanisms in sirenomelia. Whole-genome resequencing was performed on peripheral blood mononuclear cells from one patient with sirenomelia and one matched healthy newborn. Variants were identified and prioritized using the gnomAD and ClinVar population databases. single nucleotide polymorphisms (SNP)/InDel and structural variants were further analyzed using multidimensional functional enrichment approaches. A total of 116 candidate genes harboring rare and potentially deleterious SNP/InDel variants were identified, including BMP5 and BMP6. Structural variant analysis revealed 549 sirenomelia-specific variants involving genes such as TWSG1 and Retinoic acid receptor beta (RARB). Functional enrichment revealed that these genes were predominantly involved in key developmental pathways, including BMP, WNT and TGF-β signaling. Integrated analysis indicated convergent disruption of signaling networks regulating posterior axis development, particularly those associated with kidney formation, cloacal partitioning, and limb patterning. These findings support a multilayered pathogenic model in which genetic variants collectively disrupt the core developmental pathways involved in posterior axis formation, vasculogenesis, and organogenesis. Our findings provide a genomic framework for understanding the molecular basis of sirenomelia and identify potential targets for future research and clinical applications.
Zefeng Zhu, Wanting Hao, Ziyu Wan et al.· Italian Journal of Pediatric...· 0 citations
Findings identify LRGUK as a novel gene involved in male infertility, essential for spermatid morphogenesis and flagellum assembly, essential for spermatid morphogenesis and flagellum assembly.
Wiâme Mokkedem, Zeinab Wehbe, A. Barbotin et al.· Clinical Genetics· 0 citations
BACKGROUND
Classical Ehlers-Danlos syndrome (cEDS), caused by pathogenic variants in COL5A2, is characterized by skin hyperextensibility, joint hypermobility and atrophic scarring. This study aimed to identify and validate the pathogenicity of an unreported COL5A2 intronic variant in a Chinese family with cEDS.
METHODS
Trio-based whole exome sequencing (Trio-WES) was performed to screen for pathogenic variants, and the candidate variant was confirmed by Sanger sequencing. Minigene assays were then conducted to evaluate the functional consequences of key variants.
RESULTS
A de novo COL5A2 (NM_000393.3) c.2499 + 4_2499 + 5insTAA variant was identified. Minigene assays demonstrated that this variant induced exon 37 skipping, resulting in an in-frame deletion. Based on ACMG guidelines, the variant was classified as pathogenic and considered the likely underlying etiology of cEDS in this family.
CONCLUSION
These findings expand the variant spectrum of COL5A2, improving molecular diagnosis of cEDS.
