Aug 2026· Italian Journal of Pediatrics· Vol 52· 0 citations· 116 references
Medicine
TL;DR
The findings support a multilayered pathogenic model in which genetic variants collectively disrupt the core developmental pathways involved in posterior axis formation, vasculogenesis, and organogenesis and identify potential targets for future research and clinical applications.
Abstract
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.
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
Hemophagocytic lymphohistiocytosis (HLH) is a severe immunological disorder characterized by dysregulated immune activation. Pathogenic variants in HLH-causative genes serve as diagnostic criteria and guide treatment decisions. However, known genes do not fully explain the molecular basis of many cases, and the polygenic contribution to HLH susceptibility remains poorly characterized. Here, we retrospectively analyzed whole-exome sequencing data from 1241 patients with clinically diagnosed or suspected HLH to characterize the HLH genetic landscape. Rare variant association analysis identified two candidate susceptibility genes,
IKBKG
and
DDX3X
. Functional experiments showed that
IKBKG
knockdown impaired NK cell cytotoxicity and degranulation, supporting a contributory role of
IKBKG
in HLH-related immune dysfunction. Exploratory common variant analysis identified potential susceptibility loci, and an integrated model incorporating rare variant burden and polygenic risk score achieved an AUC of 0.71 in this cohort. These findings expand understanding of HLH genetic architecture and support contributions from both rare and common variants.
The role of the PI3K/AKT pathway in the PIK3CA-related overgrowth is clarified, with one pediatric patient carrying a novel mosaic de novo in-frame deletion mutation in the PIK3CA gene identified.
Jing-Heng Wu, Shan-Lin Chen, Yun-Hao Xue et al.· Yi chuan = Hereditas· 0 citations
Objective: The objective of this study was to detect genetic factors associated with dermatochalasis using a genome-wide association study (GWAS) across three large cohorts. Design: GWAS meta-analysis Participants: A total of 13,200 dermatochalasis cases and 962,513 controls were included. Methods: A GWAS meta-analysis of dermatochalasis combining data from the FinnGen, the Estonian Biobank and the UK Biobank was conducted. We also performed colocalization analyses, a phenome-wide association study and age-at-onset analysis, and assessed genetic correlations with various diseases and traits. Main outcome measures: Identification of genetic variants associated with dermatochalasis. Results: We identified 18 loci associated with dermatochalasis at genome-wide significance, 16 of which were novel. Most of these loci had genes involved in skin biology and cutaneous diseases, such as the genes encoding elastin (ELN) and Latent TGF-{beta} binding protein 1 (LTBP1). Phenome-wide association study revealed previous associations with morphology-related traits, while genetic correlation analysis highlighted multiple genetic correlations, especially with smoking and pain. Conclusions: We detected 18 genetic loci associated with dermatochalasis, characterized these loci in detail and demonstrated their relevance in skin biology and related processes. These findings give novel information on the genetic background of dermatochalasis and provide a solid basis for further research.
K. Rajueni, F. Koskimaki, V. Salo et al.· medRxiv· 0 citations
Abstract Background Non-obstructive azoospermia (NOA) is a severe form of male infertility characterized by impaired spermatogenesis. Although chromosomal abnormalities and Y-chromosome microdeletions are known causes, many cases remain idiopathic, suggesting that other genetic factors may be involved. RAD54 like (RAD54L) is a key component of the homologous recombination pathway required for DNA double-strand break repair and meiotic progression. Objective To identify the potential genetic cause of NOA using whole-genome sequencing (WGS) in affected individuals from consanguineous families. Materials and Methods For performing this experimental study, 10 NOA men who were referred to Infertility Center of the Yazd Reproductive Sciences Institute, Yazd, Iran underwent clinical, hormonal, and genetic evaluations. Genomic DNA was extracted from peripheral blood and was subjected to WGS. Variants were filtered and prioritized based on allele frequency, predicted pathogenicity, inheritance pattern, and gene expression data. In silico splicing analyses were performed using SpliceAI and Human Splicing Finder. Results WGS identified an ultrarare homozygous splice-site variant, c.1375+1G > T, in the RAD54L gene. The variant affects a canonical donor splice site and is predicted to cause loss of normal splicing, likely resulting in exon 12 skipping, frameshift, and premature termination codon formation. RAD54L shows the highest expression in testicular tissue and plays a critical role in homologous recombination and meiotic DNA repair. The patient exhibited hormonal findings consistent with primary testicular failure. Conclusion This study proposes RAD54L as a potential novel candidate gene linked to NOA and underscores the efficacy of WGS in identifying rare genetic etiologies of idiopathic male infertility. Further functional and clinical studies are needed to validate this association.
Razieh Ebrahimi Askari, A. Malcher, Sara Sadeghzadeh et al.· International Journal of Rep...· 0 citations
A male infant with a severe FINCA-like phenotype is reported, including early-onset hemolytic anemia, pulmonary involvement, neurodevelopmental impairment, growth failure, recurrent infections, and fatal progression at 8.5 months.
A. Rozhkova, Anton A. Esibov, Aleksandra Borkovskaia et al.· International Journal of Mol...· 0 citations
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