Management of Paediatric Cancers Associated With Bloom SyndromePacaud, Camille; Nazon, Charlotte; Pages, Mélanie; Rouger, Jérémie; Berthet, Pascale; Winter, Sarah; Thebault, Éric; Faure-Conter, Cécile; Berger, Claire; Paillard, Catherine; Macrae, Finlay
doi: 10.1155/humu/7065233pmid: 40641635
Bloom syndrome (BS) is a rare genetic disorder associated with an elevated risk of cancer. In a national multicentre study, nine paediatric patients with BS and cancer were analysed. Median age at cancer diagnosis was 12 years. Four of the nine patients were diagnosed with BS prior to cancer detection. Six presented with solid tumours, whilst three had haematological malignancies. Six received polychemotherapy, often with dose reductions. Complications included prolonged aplasia, sepsis and early treatment discontinuation. Two patients received radiotherapy. Four relapsed, and four died, including one toxic death. However, five achieved remission, highlighting the possibility of curative treatment despite significant toxicities.
Likely Pathogenic/Pathogenic Variants in the Spliceosome Complex Genes SNRNP200, SF3B1, SF3B2, and SF3B4 Implicated in Nonsyndromic Orofacial CleftRanji, Peyman; Pairet, Eleonore; Helaers, Raphael; Brouillard, Pascal; Bayet, Bénédicte; Gerdom, Alexander; Revencu, Nicole; Vikkula, Miikka; De Baere, Elfride
doi: 10.1155/humu/2991452pmid: 41427026
The genetic basis of nonsyndromic orofacial cleft (NsOFC) remains elusive, although associations have been identified with various genetic loci. NsOFC has a less pronounced genetic background than syndromic orofacial cleft (SyOFC), albeit Mendelian inheritance has been identified. Our hypothesis was that genes related to spliceosome function may contribute to NsOFC pathophysiology, as they do for some syndromic cases. Exome sequencing was conducted on 224 unrelated NsOFC probands. We performed filtering and analyses of predicted pathogenicity of rare variants using Highlander. We focused on 26 genes encoding spliceosome proteins. Subsequently, bioinformatic tools, such as AlphaFold, and PyMol, were applied to generate three‐dimensional structures to interpret the effects of the identified variants on protein structure and interaction domains. We found six likely damaging variants: three heterozygous missense variants in small nuclear ribonucleoprotein U5 200 kDa subunit (SNRNP200) in three multiplex NsOFC families, and two missense and one splice site variant in splicing factor 3b subunit 1 (SF3B1), 4 (SF3B4), and 2 (SF3B2) in two posterior CP families and a complete CP patient, respectively. These results suggest that variants in the spliceosome complex genes, observed in 2.7% of NsOFC cases in our cohort, may contribute to disease susceptibility as potential risk factors.
Functional Analysis of Complex Structural and Splice‐Altering Variants in the ARSB Gene Towards the Personalized Antisense‐Based Therapy for Mucopolysaccharidosis Type VI PatientsBychkov, Igor; Filatova, Alexandra; Baydakova, Galina; Sikora, Nataliya; Garifullina, Emiliya; Bykova, Anna; Tabakov, Vyacheslav; Skretnev, Alexandr; Skoblov, Mikhail; Zakharova, Ekaterina; Chen, Jian-Min
doi: 10.1155/humu/2250030pmid: 40677925
Mucopolysaccharidosis Type VI (MPS VI) is a lysosomal storage disorder associated with biallelic pathogenic variants in the ARSB gene. Herein, we present three patients with biochemical and clinical pictures of MPS VI, for whom routine molecular genetic analysis using Sanger sequencing of ARSB failed to identify one or both causative variants. RNA analysis of patients’ samples revealed alterations of the wild‐type ARSB mRNA isoform in all cases, and one case required further analysis using whole genome sequencing. As a result, we identified one complex structural variant, which is a 52‐kb insertion of the LHFPL2 gene fragment in the ARSB Intron 4, derived from nonallelic homologous recombination and leading to premature transcription termination, a recurrent deep intronic variant leading to pseudoexon activation and an intragenic deletion altering the integrity and splicing of the ARSB Exon 2.
Deciphering the Mutational Background in Citrin Deficiency Through a Nationwide Study in Japan and Literature ReviewKido, Jun; Sugawara, Keishin; Tavoulari, Sotiria; Makris, Georgios; Rüfenacht, Véronique; Nakamura, Kimitoshi; Kunji, Edmund R. S.; Häberle, Johannes; Patrinos, George P.
doi: 10.1155/humu/9326326pmid: 40309478
Citrin deficiency (CD) is an autosomal recessive disorder caused by the absence or dysfunction of the mitochondrial transporter citrin, resulting from mutations in SLC25A13. The disease presents with age‐dependent clinical manifestations: neonatal intrahepatic cholestasis caused by CD (NICCD), failure to thrive and dyslipidemia by CD (FTTDCD), and an adult‐onset form (formerly called Type II citrullinemia, CTLN2, recently renamed to “adolescent and adult citrin deficiency,” AACD). We performed this study to compile known genotypes found in CD patients and investigate their impact on the clinical course. Through a nationwide survey in Japan as well as a literature review, we collected information regarding 68 genetic variants of a total of 345 patients with CD (285 NICCD, 19 post‐NICCD, and 41 AACD). In this cohort, the pathogenic variants, arising from nonsense, insertion/deletion, and splice site mutations, are expected to have severe functional or biogenesis defects. Of 82 alleles in patients with AACD, the two most common variants, c.852_855del and c.1177+1G>A, accounted for 25 alleles (30.5%) and 15 alleles (18.3%), respectively. The c.852_855del variant, even when present as part of compound heterozygosity, often presented with hyperammonemia (≥ 180 μmol/L), cognitive impairment, short stature (< ‐2SD), liver cirrhosis, and pancreatitis, with some patients requiring liver transplantation. In conclusion, certain SLC25A13 genotypes are particularly frequent, especially those that result in severely truncated citrin proteins with often a significant impact on the clinical outcome of the patient. The most prevalent variant is c.852_855del, which was found in 42% (128/304) of NICCD/post‐NICCD cases and 49% (20/41) of AACD patients.
A Cell‐Based Functional Assay Calibrated for Analysis of MSH6 and MSH2 Mismatch Repair Gene VariantsSzabo, Elizabeth; Blackburn, Emily; Amodeo, Olivia N.; Nadeau, Samantha; Radecki, Alexander A.; Grady, James P.; Rath, Abhijit; Heinen, Christopher D.; Macrae, Finlay
doi: 10.1155/humu/3923193pmid: 40948606
Variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes can confound the diagnosis and treatment of suspected Lynch syndrome (LS) patients. To aid the reclassification of VUS, we developed the in cellulo analysis of MMR variants (inCAMA) and used known control variants to calibrate this assay such that results can be readily applied as functional evidence by expert classification panels. We used CRISPR gene engineering to introduce known pathogenic and benign variants into the MSH6 or MSH2 loci in human embryonic stem cells and assessed their effects on cellular MMR repair and damage response functions. Our functional assay successfully discerned known pathogenic and benign variants. Using these results and performing a linear regression analysis with available odds of pathogenicity scores for the known calibration variants, we created equations that can generate a functional odds of pathogenicity score for any future MSH6 or MSH2 variant tested. In summary, inCAMA represents a new, calibrated assay for testing the function of virtually any MSH6 or MSH2 variant. The conversion of assay results directly into odds of pathogenicity scores makes it possible to use any PS3 or BS3 evidence strength level toward the reclassification of VUS.
Prognostic Value of Ubiquitination‐Related Genes in Ovarian Cancer and Their Correlation With Tumor ImmunityZhao, Shu; Lin, Xiaojing; Huang, Yuying; Kang, Zhongmin; Luo, Huali; Zhang, Qizhu; Li, Qinshan; Li, Mengxing; Ren, Minghua
doi: 10.1155/humu/8369299pmid: 40697329
Numerous studies have emphasized the importance of the ubiquitin–proteasome system (UPS) in the malignant progression of ovarian cancer (OC). However, whether ubiquitination‐related genes (UbRGs) can be used to predict the prognosis of OC remains to be revealed. Patients with OC were divided into two clusters based on the expression of UbRGs, and prognosis was compared between the two clusters. A prognostic model was established based on UbRGs, and its predictive efficiency was validated using Kaplan–Meier (K–M) curves, receiver operating characteristic (ROC) curves, and a nomogram. Immune infiltration and gene mutation analyses were used to examine the effects of UbRGs on the prognosis of OC. The prognostic model served as a valid and independent predictor of OC prognosis. Immune infiltration revealed that the unique immune microenvironment of OC was regulated by UbRGs. Gene mutation analysis indicates that UbRGs likely influence OC malignant behavior by modulating gene mutation patterns. In addition, Ube2j1 was found to play an important role in regulating the malignant progression of OC. Furthermore, the mechanism by which Ube2j1 modulates the OC phenotype and reshapes its immune microenvironment via the JAK2/STAT3/PD‐L1 pathway was elucidated, providing novel insights into the potential for ubiquitination‐based immunotherapy in OC. This study provides novel insights into precision immunotherapy based on UbRGs in OC. The UbRGs‐based prognostic model may help to provide novel insights for the application of ubiquitination‐based immunotherapy in OC.
Glucokinase Regulatory Protein (GCKR) Links Metabolic Reprogramming With Immune Exclusion: Insights From a Pan‐Cancer Analysis and Gastric Cancer ValidationFan, Shaohua; He, Youfu; Chen, Zhen; Yuan, Chiting; Chen, Jiangjie; Xu, Chenhao; Huang, Weixing; Yao, Can; Hong, Dun; Zhang, Liwei; Ren, Minghua
doi: 10.1155/humu/4240223pmid: 41235343
Glucokinase regulatory protein (GCKR) is a metabolic regulator implicated in glucose homeostasis, but its genetic and functional roles in cancer remain poorly understood. Through integrated pan‐cancer multiomics and experimental analyses, we mapped the expression and mutational landscape of GCKR with a focus on gastric cancer. GCKR expression was downregulated in most tumors but upregulated in subsets such as kidney renal papillary carcinoma (KIRP) and lung adenocarcinoma (LUAD). Genomic profiling revealed recurrent alterations, with the highest mutation frequencies observed in sarcoma (SARC) and uterine corpus endometrial carcinoma (UCEC), and missense mutations representing the predominant variant type, particularly in breast cancer (BRCA). Functionally, reduced GCKR expression in gastric cancer was associated with an immune‐cold phenotype characterized by diminished cytotoxic T cell infiltration, impaired antigen presentation, and metabolic reprogramming. Spatial transcriptomics and single‐cell analyses highlighted compartment‐specific heterogeneity and links with cancer‐associated fibroblasts and macrophages. Clinically, low GCKR expression predicted poorer survival and reduced immunotherapy benefit, while higher expression indicated selective sensitivity to MEK inhibitors including refametinib and PD0325901. These findings define GCKR as both a mutation‐ and expression‐driven biomarker that connects metabolic regulation with immune remodeling, offering translational value for prognosis and precision therapy in gastric cancer.