OBJECTIVE: To analyze the clinical characteristics of patients with 11q23 rearrangement acute lymphoblastic leukemia (ALL) with non-KMT2A::AFF1 fusion genes. METHODS: The clinical data of 10 patients with KMT2A fusion gene positive and partner gene non-AFF1 ALL admitted to Henan Cancer Hospital from December 2016 to December 2024 were retrospectively summarized. The immunophenotype, molecular genetic characteristics, clinical manifestations and disease prognosis of these patients were analyzed. This research has been approved by the Medical Ethics Committee of Henan Cancer Hospital (Ethics No.: 2019342). RESULTS: Among the 10 patients, the fusion genes were KMT2A::MLLT1 in 7 cases, KMT2A::MLLT4, KMT2A::MLLT3 and KMT2A::MLLT10 in 1 case each. The European Group for the Immunological Classification of Leukemias (EGIL) classification included 6 cases of T-ALL, 2 cases of pro-B-ALL, 1 case of Common-B-ALL and 1 case of pre-B-ALL. 4 cases of B-ALL all expressed CD19, cCD79a, CD38 and HLA-DR, and some expressed CD34 and CD22, without expression or weak expression of CD10, without expression of CD20. One case was accompanied by myeloid marker CD15 expression. 6 cases of T-ALL all expressed CD34, CD7, most expressed CD38, and some expressed CD3, CD5, CD2, CD4 and CD8, and 1 case expressed CD4 and CD8 together. Chromosomal abnormalities were detected in 3 cases, 5 cases were positive for WT1 fusion gene, and 6 cases had gene alterations. 9 patients achieved the first complete remission (CR1) during chemotherapy, and 1 patient relapsed within 6 months after CR1. At the last follow up, 1 patient (the fusion gene was KMT2A::MLLT4) remained unrelieved. There were 2 cases of KMT2A rearrangement (KMT2A-r) persistent positive (+/+) and 8 cases of KMT2A-r negative (+/-). The overall survival (OS) rate and leukemia-free survival (LFS) rate of patients with KMT2A-r persistent positive were significantly lower than those of patients with negative change, and the differences were statistically significant (P values were all < 0.05). Among the 3 patients who received chemotherapy+allogeneic hematopoietic stem cell transplantation (allo-HSCT), no relapse was observed until the follow up day. The OS rate and LFS rate of patients with KMT2A::MLLT1 and chemotherapy+allo-HSCT were higher than those of non-KMT2A::MLLT1 and single chemotherapy patients, and the differences were not statistically significant (P values were all ≥ 0.05). There was no significant difference in OS rate and LFS rate between T-ALL and B-ALL patients (P values were all ≥ 0.05). The median LFS time of the 10 patients was 32 (0 ~ 100) months, and the median OS time was 36 (1 ~ 101) months. CONCLUSION The 11q23 rearrangement ALL with non-KMT2A::AFF1 transcript is mainly KMT2A::MLLT1, T-ALL is more common, and the rate of chromosomal karyotype detection is relatively low. Persistent positive KMT2A-r is unfavorable for patient survival, and allo-HSCT during the CR1 period may improve patient survival.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Female ; Male ; Myeloid-Lymphoid Leukemia Protein/genetics* ; Histone-Lysine N-Methyltransferase/genetics* ; Adult ; Adolescent ; Chromosomes, Human, Pair 11/genetics* ; Child ; Transcriptional Elongation Factors/genetics* ; Gene Rearrangement ; Oncogene Proteins, Fusion/genetics* ; Retrospective Studies ; Young Adult ; Middle Aged ; Prognosis ; Child, Preschool ; DNA-Binding Proteins/genetics*

Objective Zinc finger protein 335 (Zfp335) plays a crucial role in the early development of thymic T cells and the differentiation of peripheral T cell subpopulations. The objective of this study is to investigate the role and underlying mechanisms of Zfp335 in the regulation of regulatory T cell (Treg) within tumor immunity. Methods The Zfp335 gene was specifically knocked out in Treg using tamoxifen (Zfp335^fl/fl FOXP3^creERT2), and the MC38 tumor model was established. On the 7th day after tumor inoculation, tumor size was observed and measured. Tumor size was monitored and recorded daily starting from day 7 post-inoculation. On day 12, tumors were harvested, and the proportions of CD4⁺ T cells, CD8⁺ T cells, and Treg were analyzed by flow cytometry. Additionally, the mitochondrial function of effector regulatory T cell (eTreg) was assessed. Results From day 10 post-tumor inoculation, tumor volume in the Zfp335^CKO group was significantly reduced compared to that of the wild-type (WT) group. Furthermore, the infiltration of CD4⁺ and CD8⁺ T cells, along with their respective effector cells, was significantly higher in the Zfp335^CKO group than in the WT group. The proportions of CD4⁺ and CD8⁺ T cells producing interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) were also significantly increased in the Zfp335^CKO group compared to that of the WT group. In addition, the percentage of CD8⁺ T cells secreting granzyme B (GzmB) was significantly higher in the Zfp335^CKO group than that in the WT group. In contrast, the proportion of Treg and inducible T cell co-stimulator (ICOS)⁺ Treg in the Zfp335^CKO group was significantly lower than that in the WT group. Finally, the expression level of Mitotracker Deep Red in eTreg from the Zfp335^CKO group was significantly reduced compared to that in the WT group. Conclusion During tumorigenesis, the specific deletion of Zfp335 impairs Treg activation, which is related to decreased mitochondrial function in eTreg. In Zfp335^CKO mice. Tumors exhibit increased infiltration of effector T cells, accompanied by elevated levels of cytotoxic cytokines, ultimately enhancing resistance to tumor progression.
Animals ; T-Lymphocytes, Regulatory/metabolism* ; Mice ; CD8-Positive T-Lymphocytes/immunology* ; Neoplasms/genetics* ; Cell Line, Tumor ; Mice, Inbred C57BL ; Mice, Knockout ; DNA-Binding Proteins/genetics* ; Female

OBJECTIVE: To explore the genetic etiology of a child with Renpenning syndrome (RS), and review the literature on the clinical characteristics and gene mutations of RS. METHODS: A child with RS (patient 1) who was diagnosed and treated in the Pediatric Intensive Care Unit of the Third Affiliated Hospital of Zhengzhou University in November 2023 was selected as the research object. The medical history, family history, physical examination, cerebrospinal fluid examination, echocardiography, brain magnetic resonance imaging (MRI), brain magnetic resonance angiography, cardiac coronary CT angiography and intelligence quotient (IQ) score of child 1 were retrospectively collected. Peripheral venous blood samples were collected from patient 1, his parents, sister and brother, respectively. Genomic DNA was extracted from the child and his family members, and Trios-whole exome sequencing (Trios-WES) was performed. Sanger sequencing was used to verify the pedigree. Bioinformatics softwares (Mutation Taster, REVEL, SIFT, PolyPhen-2, GERP++, SWISS-MODEL) were applied. The pathogenicity of the detected variants was rated according to the American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines for the Classification of Genetic Variants (hereinafter referred to as the ACMG Guidelines). "PQBP1 gene" "Renpenning syndrome" "PQBP1 gene" "Renpenning syndrome" were used as keywords in Chinese and English, respectively. Case reports of patients with RS caused by PQBP1 gene variants were retrieved from Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed database. The clinical features and gene variants of RS caused by PQBP1 gene variants were summarized and analyzed. This study was reviewed by the Medical Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Approval No. 2024-334-01). RESULTS The patient 1, a 12-year-old boy, was admitted to the hospital due to fever and disturbance of consciousness. Cerebrospinal fluid test showed viral encephalitis caused by human herpesvirus 7 infection. The main clinical manifestations were unusual facies (microcephaly, long narrow face, microphthalmos, superior oblique palpebral fissure, hypertelorism of inner canthus, bulbous nasal columella) and mental retardation. Auxiliary examination showed than patient 1 had atrial septal defect, nodular heterotopia in the posterior horn of the left ventricle, angiodysplasia, and low IQ. The disease began in infancy, and there was no family history of related diseases. A hemizygous deletion, c.459_462del (p.Arg153SerfsTer41), was identified in exon 5 of the PQBP1 gene in patient 1, which was inherited from his mother by Sanger sequencing. The results of bioinformatics analysis showed that the mutation was harmful. This variant was rated as pathogenic (PVS1+PS4+PM2_Supporting+PP3) according to ACMG Guidelines. According to the literature search strategy set in this study, a total of 13 cases of RS were retrieved, involving 16 cases of RS patient caused by PQBP1 gene mutation (patients 2-17), including patient 1, a total of 17 cases of RS. Among the 17 patients, 16 male patients had hemizygous mutations in the X chromosome PQBP1 gene, and 1 female patient had heterozygous mutations, including 12 deletion frameshift nonsense mutations, 3 point missense mutations, and 2 duplication mutations. Except for two fetuses, all patients had special facial features and low IQ to varying degrees. Ten patients had abnormal development of one or more organs such as eyes, heart, brain, etc. CONCLUSION: The main clinical manifestations of RS are developmental delay, long narrow face, bulbous nose, microcephaly, and may be accompanied by heterotopia of gray matter of ventricle and congenital heart disease. The c.459_462del (p.Arg153SerfsTer41) variant of the PQBP1 gene is the genetic basis of patient 1 in this study.
Humans ; Male ; Mutation ; Pedigree ; Child ; DNA-Binding Proteins/genetics* ; Nuclear Proteins/genetics* ; Female ; Exome Sequencing

OBJECTIVE: To explore the clinical and genetic characteristics of fetuses with Kabuki syndrome (KS) and their genotype-phenotype correlation. METHODS: A retrospective analysis was carried out on the prenatal manifestations and results of genetic testing of six KS fetuses diagnosed by whole-exome sequencing (WES). The findings were compared with 28 prenatally diagnosed KS cases reported in the literature to summarize the prenatal features of KS. This study has been approved by the Ethics Committee of Maternal and Child Health Care Hospital of Hubei Province (Ethics No.: 2025-141-01). RESULTS: Prenatal ultrasound findings in KS fetuses showed high heterogeneity. The most common abnormalities were cardiac (23/35, 65.7%) and renal (20/35, 57.1%), which are often accompanied by amniotic fluid abnormalities (5/35, 14.3%), single umbilical artery (5/35, 14.3%), and fetal hydrops (4/35, 11.4%). Among the six fetuses from our center, all were identified by WES to harbor pathogenic variants of the KMT2D gene, and all of which were de novo. These included 3 frameshift variants, 2 nonsense variant, and 1 missense variant, among which 4 were unreported previously. CONCLUSION This study has expanded the mutational spectrum of the KMT2D gene. Prenatal ultrasound findings of KS lack specificity, though multi-system anomalies or specific soft markers may indicate KS. WES is an effective tool for the diagnosis, and KS should be included in the differential diagnosis list for prenatal cardiac and renal abnormalities.
Humans ; Hematologic Diseases/diagnostic imaging* ; Face/diagnostic imaging* ; Female ; Vestibular Diseases/diagnostic imaging* ; Abnormalities, Multiple/diagnostic imaging* ; Pregnancy ; Ultrasonography, Prenatal ; Adult ; Neoplasm Proteins/genetics* ; Retrospective Studies ; DNA-Binding Proteins/genetics* ; Male ; Exome Sequencing ; Fetus/diagnostic imaging* ; Genetic Association Studies ; Mutation

OBJECTIVE: To explore the clinical and genetic characteristics of a boy with X-linked familial Behcet-like autoinflammatory syndrome-2 (AIFBL2). METHODS: A boy who was admitted to Children's Hospital Affiliated to Zhengzhou University in December 2023 due to recurrent oral ulcers for 2 years, intermittent abdominal pain and fever for more than 1 year was selected as the study subject. Clinical data of the patient was collected. Whole exome sequencing (WES) was carried out, and candidate variant was verified by Sanger sequencing and bioinformatic analysis. A literature search was conducted in OMIM, PubMed, Wanfang Data Knowledge Service Platform, China Biomedical Literature Service System, and the VIP database using the keywords "ELF4 gene" "deficiency in ELF4, X-linked" "ELF4 deficiency" and "DEX" to identify recently published studies. This study was approved by the Medical Ethics Committee of the Children's Hospital Affiliated to Zhengzhou University (Ethics No.: 2023-H-K44). RESULTS: The patient, a 12-year-old male, presented with recurrent mouth ulcers, fever and abdominal pain. Lymphocyte subsets showed a significant decrease in NK cells. Abdominal CT showed thickening of local intestinal wall in the lower right abdomen. Colonoscopy revealed a solitary deep longitudinal ulcer in the ileocecal region. Genetic testing revealed a hemizygote missense variant c.687C>G, with his mother showing the same mutation at this locus. According to the guidelines of the American College of Medical Genetics and Genomics (ACMG), the variant was considered likely pathogenic (PP1+PP2+PM2_Supporting+PP3+PP4). Literature review has found 19 AIFBL2 patients including 1 patient from this study. Mouth ulcer, fever, rash and abdominal pain were the primary clinical manifestations, for which genetic testing is the main diagnostic method. CONCLUSION The hemizygote c.687C>G missense variant of the ELF4 gene probably underlay the AIFBL2 in this child, which has provided a basis for his clinical diagnosis and genetic counseling.
Humans ; Male ; Behcet Syndrome/genetics* ; Child ; DNA-Binding Proteins/genetics* ; Exome Sequencing ; Hereditary Autoinflammatory Diseases/genetics* ; Mutation

OBJECTIVE: To analyze the clinical phenotype and genetic basis of four children with CHARGE syndrome. METHODS: A retrospective analysis was conducted on four children diagnosed with CHARGE syndrome at Xiamen Children's Hospital from May 2019 to May 2025. Peripheral venous blood samples were collected from the children and their parents and subjected to trio-whole exome sequencing. Candidate variants were verified by Sanger sequencing. Online tools were used for the conservation analysis and protein structure prediction. This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2024-126). RESULTS: The four children have included two neonates, one infant and one child, with their age at the initial diagnosis ranging from 16 days after birth to 11 years old. Their initial manifestations were not typical of CHARGE syndrome. All children were found to harbor missense variants of the CHD7 gene, including c.3059T>C (p.L1020S), c.3302G>A (p.C1101Y), c.5879C>T (p.S1960F) and c.8093C>T (p.S2698L). Sanger sequencing confirmed that two were de novo variants, and two were inherited from their parents. In child 1, the leucine at position 1020 was highly conserved, and the p.L1020S variant did not alter the spatial structure and hydrogen bond connections of the CHD7 protein, though the shape of the binding cavity and the number and distribution of binding probe clusters have changed. In child 4, an unreported variant in the epilepsy gene SCN9A (c.2152T>C, p.Y718H) was detected, along with bilateral lower limb deformities. Literature review suggested that missense variants of the CHD7 gene were most common (32.1%) among the Chinese population, whilst nonsense variants had the highest lethality rate (41.2%) in neonates. CONCLUSION Variants of the CHD7 gene probably underlay the pathogenesis in the four children. Changes in the binding sites and binding cavity morphology play an important role in CHARGE syndrome. The types of genetic variants in CHARGE patients may vary between different regions and races.
Humans ; CHARGE Syndrome/genetics* ; Male ; Female ; Child ; Infant ; Infant, Newborn ; DNA Helicases/genetics* ; DNA-Binding Proteins/chemistry* ; Mutation, Missense ; Retrospective Studies ; Child, Preschool ; Exome Sequencing ; Phenotype

OBJECTIVE: To explore the clinical presentation and genetic etiology of a case with Xeroderma pigmentosum in conjunct with basal cell carcinoma and melanoma. METHODS: A male patient with Xeroderma pigmentosum treated at Xinxiang Central Hospital in October 2022 was selected as study subject. Whole exome sequencing (WES) was carried out. Candidate variants were verified by Sanger sequencing of his family members. This study was approved by the Ethics Committee of the hospital (Ethics No.: 2021-167). RESULTS: Magnetic resonance imaging showed that the patient has a solid soft tissue mass in the anterior and lower part of his right eyeball and a small nodule on the left nasal wing. Histopathological biopsy showed that the periocular tumor was basal cell carcinoma in conjunct with malignant melanoma, and the nasal wing tumor was basal cell carcinoma. WES and Sanger sequencing revealed that he has harbored compound heterozygous variants of the XPC gene, namely c.2391delT (p.F797Lfs*11) and IVS1+1G>A, which were inherited from his father and mother, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variants were rated as likely pathogenic (PVS1+PM2_Supporting+PM3) and pathogenic (PVS1+PM2_Supporting+PM3+PP5), respectively. The c.2391delT variant was unreported previously. Bioinformatic analysis suggests that it could significantly affect the tertiary structure of XPC protein. CONCLUSION The c.2391delT(p.F797Lfs*11) and IVS1+1G>A compound heterozygous variants probably underlay the pathogenesis in this patient. The detection of the novel variant has enriched the mutational spectrum of the XPC gene.
Humans ; Male ; Xeroderma Pigmentosum/genetics* ; Basal Cell Carcinoma/genetics* ; DNA-Binding Proteins/genetics* ; Melanoma/genetics* ; Mutation ; Skin Neoplasms/genetics* ; Middle Aged ; Exome Sequencing ; Pedigree

The patient is a male neonate born at term. He was admitted 16 minutes after birth due to stridor and inspiratory respiratory distress. Physical examination revealed a cleft palate, and a grade II systolic ejection murmur was audible at the left sternal border. Whole exome sequencing identified a heterozygous variant in the SON gene, c.5753-5756del (p.Val1918GlufsTer87), which was absent in either parent, indicating a de novo mutation. According to the guidelines of the American College of Medical Genetics and Genomics, this was classified as a "pathogenic variant" leading to a diagnosis of Zhu-Tokita-Takenouchi-Kim (ZTTK) syndrome. Upon admission, symptomatic supportive treatment was provided. Follow-up at the age of 8 months revealed persistent stridor; the infant could only consume small amounts of milk and was unable to sit steadily. This patient represents the youngest reported case to date, and his symptoms expand the clinical spectrum of the disease, providing valuable insights for clinical diagnosis and treatment.
Humans ; Infant, Newborn ; Male ; Minor Histocompatibility Antigens/genetics* ; DNA-Binding Proteins/genetics* ; Rare Diseases/genetics* ; Neurodevelopmental Disorders/genetics*

OBJECTIVE: To explore the correlation between single nucleotide polymorphisms (SNPs) of ARID5B gene and the risk of acute lymphoblastic leukemia (ALL) and minimal residual disease (MRD) in children of Hui and Han nationality in Ningxia. METHODS: In this case-control study, 54 ALL children and control group with matched age, sex and nationality were detected for the polymorphism of ARID5B gene using fluorescence resonance energy transfer technique, and the susceptibility of different ALL genotypes and their correlation with MRD were analyzed. RESULTS: There were no significant differences in genotype and allele frequency of rs10994982, rs7089424, rs10740055, rs7073837, rs4245595 and rs7090445 between the two groups (P >0.05). At the locus of rs10821936, the frequencies of T/T genotype and T allele in ALL group were significantly higher than those in the control group (both P < 0.05). The C/C genotype of ARID5B gene SNP rs10821936 was a risk factor for early MRD positive in ALL children ( P < 0.05). CONCLUSION ARID5B gene SNP rs10821936 is related to the development of childhood ALL and MRD.
Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics* ; Polymorphism, Single Nucleotide ; Case-Control Studies ; Neoplasm, Residual/genetics* ; DNA-Binding Proteins/genetics* ; Transcription Factors/genetics* ; Genotype ; Genetic Predisposition to Disease ; Gene Frequency ; Child ; Male ; Female ; Alleles ; Risk Factors ; Child, Preschool

BACKGROUND: Abnormalities of the switch/sucrose nonfermentable (SWI/SNF) chromatin-remodeling complex are closely related to various cancers, and ARID1B (AT-rich interaction domain 1B) is one of the core subunits of the SWI/SNF complex. Mutations or copy number deletions of the ARID1B gene are associated with impaired DNA damage response and altered chromatin accessibility. However, whether ARID1B deficiency affects the proliferation, migration and invasion abilities of non-small cell lung cancer (NSCLC) cells and its molecular mechanisms remain poorly understood. This study aims to reveal the regulatory role of ARID1B gene deletion on the malignant phenotype of NSCLC cells and its molecular mechanism. METHODS: Online databases were used to analyze the relationship between ARID1B and the prognosis of patients with lung cancer, and the expression levels of ARID1B in lung cancer tissues. The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat) technology was employed to construct stable ARID1B gene knockout (KO) cell lines. The plate colony formation assay was used to detect cell proliferation, and the Transwell cell migration and invasion assays were used to detect changes in cell migration ability. RNA-Seq was utilized for the expression and enrichment analysis of differentially expressed genes. Western blot (WB) was used to verify the knockout effect of the ARID1B gene and to detect the expression changes of epithelial-mesenchymal transition (EMT) markers and mitogen-activated protein kinases (MAPK) signaling pathway-related proteins. Nude mouse tumor models were constructed and the tumorigenic abilities of control and ARID1B-deficient cells were compared. RESULTS: Patients with low ARID1B expression have poor overall survival. ARID1B is differentially expressed in lung cancer and normal tissues, and its expression level being lower in cancer cells. ARID1B-deficient cells had significantly enhanced in vitro proliferation, migration and invasion abilities. In animal experiments, the tumor formation speed of ARID1B gene deficient cells was significantly accelerated. Enrichment analysis of RNA-Seq results revealed that the differentially expressed genes were mainly enriched in MAPK, phosphoinositide 3-kinase-protein kinase B (PI3K/Akt) and other signaling pathways. WB experiments demonstrated that the expressions of E-cadherin, N-cadherin and Vimentin changed in ARID1B gene deficient cells, and the expressions of MAPK and p-MAPK was increased. CONCLUSIONS The A549-ARID1B KO and PC9-ARID1B KO cell lines were successfully established. The ARID1B-deficient cell lines demonstrated high migration, invasion and proliferation potential at both in vitro and in vivo biological behavior levels and at the transcriptome sequencing level. The changes in the expression of EMT markers and the activation of the MAPK signaling pathway suggest possible metastasis mechanisms of ARID1B-deficient NSCLC.
Humans ; Cell Proliferation/genetics* ; Cell Movement/genetics* ; Lung Neoplasms/metabolism* ; Animals ; Carcinoma, Non-Small-Cell Lung/physiopathology* ; Transcription Factors/metabolism* ; Neoplasm Invasiveness ; Mice ; DNA-Binding Proteins/metabolism* ; Gene Deletion ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Mice, Nude ; Gene Expression Regulation, Neoplastic