Aug 2026· International Journal of Molecular Sciences· Vol 27· 0 citations· 22 references
Medicine
TL;DR
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.
Abstract
More than 70% of non-obstructive azoospermia (NOA) cases remain idiopathic, and the underlying genetic causes need to be investigated. In this study, we aimed to identify genes and variants associated with the etiology of NOA. Two NOA patients from consanguineous families, with normal karyotypes and no Y-chromosome microdeletions, were selected for whole-genome sequencing (WGS). Candidate variants were validated by Sanger sequencing. Structural protein modeling and assessment of mutation-induced changes in molecular interactions were performed using SWISS-MODEL and AlphaFold. We identified a candidate homozygous missense variant (c.899C>T, p.(Ser300Phe); rs375931805) in SOX30 in one patient; this transcription factor is highly expressed in the testis. In the second patient, a homozygous missense variant (c.1472C>T, p.(Thr491Met); rs746902232) in RNF220 and a hemizygous missense variant (c.2354A>G, p.(Gln785Arg) in the X-linked AKAP4 gene were simultaneously detected. Previous studies have shown that SOX30 knockout in mice leads to meiosis I arrest and impaired spermiogenesis. AKAP4 is exclusively expressed in the testis, and missense variants have been reported in different forms of 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.
Nephronophthisis (NPHP), an autosomal recessive kidney disorder characterized by chronic tubulointerstitial nephritis, is the most prevalent monogenic cause of end-stage renal disease (ESRD). Previous studies have identified variants in more than 20 genes, designated NPHP1 to NPHP20, and in additional loci as the genetic causes of NPHP. Here, a Chinese patient who presented with NPHP and proteinuria was enrolled. By employing whole exome sequencing and Sanger sequencing, we identified a rare compound heterozygous mutation in the NPHP4 gene (c.2611C > T/p.R871X and c.2768G > A/p.R923H) in the patient. Sanger sequencing further confirmed that the p.R871X variant was inherited from the father and that the p.R923H variant originated from the mother. Both variants were predicted to be deleterious by bioinformatic software. In accordance with the American College of Medical Genetics and Genomics guideline, the p.R871X variant was classified as pathogenic, and the p.R923H variant was classified as likely pathogenic. So far, neither of these mutations has been reported in patients with NPHP. Our findings contribute to the precise diagnosis of the patient and further underscore the utility of genetic testing in the accurate diagnosis of NPHP.
Wang Li, Gao-Hui Cao, Nannan Li et al.· Frontiers in Pediatrics· 0 citations
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.
C. Au, Ya-Yun Wang, T. Lai et al.· Medicina· 0 citations
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.
Sara Sadeghzadeh, A. Malcher, Razieh Ebrahimi Askari et al.· Journal of Applied Genetics· 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
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, Yiyang Fu, Shuying Zhang et al.· Frontiers in Genetics· 0 citations
Heterotaxy (HTX) is a rare condition characterized by complex congenital heart defects and a wide spectrum of extracardiac abnormalities that significantly impact survival. While molecular diagnosis is essential for clinical management, next-generation sequencing (NGS) currently identifies disease-causing variants in only 20%-30% of HTX cases. To address this diagnostic gap, we 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. In parallel, we conducted a systematic review of 108 published cases to refine genotype-phenotype correlations. We identified seven variants in four key genes: DNAH9, PKD1L1, MMP21, and GDF1. The findings revealed significant phenotypic heterogeneity while highlighting strong genotype-phenotype correlations, such as the association of MMP21 and GDF1 variants with severe conotruncal malformations. Two unreported variants were identified, further expanding the mutational spectrum of laterality defects. By integrating fetopathological data with advanced genomic analyses, we further delineate the phenotypic spectrum of these conditions. Ultimately, this work underscores the high diagnostic value of NGS in prenatal and neonatal cardiology, enabling earlier diagnosis and more personalized clinical management.
Thi Bich Tuyen Ho, Alicia Coudert, Thi Thuy Hang Do et al.· Clinical Genetics· 0 citations
