Chromosome 22q11 Research Articles

Synaptic-dependent developmental dysconnectivity in 22q11.2 deletion syndrome.

Chromosome 22q11.2 deletion increases the risk of neuropsychiatric disorders like autism and schizophrenia. Disruption of large-scale functional connectivity in 22q11 deletion syndrome (22q11DS) has been widely reported, but the biological factors driving these changes remain unclear. We used a cross-species design to uncover the developmental trajectory and neural underpinnings of brain dysconnectivity in 22q11DS. In LgDel mice, a model for 22q11DS, we found age-specific patterns of brain dysconnectivity, with widespread fMRI hyperconnectivity in juvenile mice reconfiguring to hippocampal hypoconnectivity over puberty. These changes correlated with developmental alterations in dendritic spine density, and both were transiently normalized by GSK3β inhibition, suggesting a synaptic origin for this phenomenon. Notably, analogous pubertal hyperconnectivity-to-hypoconnectivity reconfiguration occurs in human 22q11DS, affecting cortical regions enriched for GSK3β-associated synaptic genes and autism-relevant transcripts. This dysconnectivity also predicts age-dependent social alterations in 22q11DS individuals. These results suggest that synaptic mechanisms underlie developmental brain dysconnectivity in 22q11DS.

Large-scale dependency and drug screens characterize the therapeutic vulnerabilities of Multiple Myeloma with 1q.

Large-scale dependency and drug screens characterize the therapeutic vulnerabilities of Multiple Myeloma with 1q.

Interstitial 1q Deletion Syndrome: A New Patient with Congenital Diaphragmatic Hernia and Multiple Midline Anomalies

Background: Interstitial deletions of chromosome 1q are rare, with about 30 cases reported in the literature. The phenotypical features of the affected subjects described so far include microcephaly, pre- and post-natal growth retardation, psychomotor delays, ear anomalies, brachydactyly, in addition to small hands and feet, and rarely a congenital diaphragmatic hernia (CDH). Case presentation: Here, we report on a neonate with CDH, dysmorphic features, and multiple midline anomalies including a cleft palate, in whom an array-comparative genomic hybridization (a-CGH) analysis allowed the identification of an interstitial deletion of the long arm of chromosome 1. Our patient underwent a surgical correction of CDH on the fourth day of life, while that of cleft palate has been planned to be performed at 12 months. Conclusions: The few subjects suffering such rearrangement reported to date, along with the clinical and genetic profile of the present newborn, show that 1q deletions should be considered within the context of the “interstitial 1q deletion syndrome”. Comparing our case with those described in previous studies, the involved genomic regions and the phenotypic traits are partially overlapping, although the clinical picture of the present patient is among the few ones including a congenital diaphragmatic hernia within the phenotypical spectrum. A more extensive comparative analysis of a larger number of patients with similar genetic profiles may allow for a more precise clinical and genomic characterization of this rare syndrome, and for genotype–phenotype correlations.

Identification of a new genetic locus associated with atrial fibrillation in the Taiwanese population by genome-wide and transcriptome-wide association studies.

Identification of a new genetic locus associated with atrial fibrillation in the Taiwanese population by genome-wide and transcriptome-wide association studies.

Pathological and molecular insights into intravenous leiomyomatosis: an integrative multi-omics study

Intravenous leiomyomatosis (IVL) is a histologically well differentiated smooth muscle tumor with aggressive behavior, capable of extending throughout the venous system. Understanding how IVL occurs and develops is really important for diagnosing and treating it. Unfortunately, because IVL is quite rare, there aren’t many comprehensive studies available. In our research, we carried out an extensive multi-omics study, gathering tissue samples from IVL cases, uterine fibroid, and normal myometrium. The single-cell RNA sequencing analysis revealed a notable difference in cell composition between IVL and uterine fibroid. Additionally, H&E staining demonstrated more frequent hydropic changes and hyalinization in IVL tissues, along with a reduced vascular density compared to both normal myometrium and uterine fibroid. In our proteomics analysis of eight paired samples of IVL and normal myometrium fresh frozen tissue, we identified proteins that were differentially expressed, mainly related to focal adhesions and regulation of the actin cytoskeleton. The most frequently involved chromosomes included deletions in 10q22.2, 10q24.32, 13q14, and 13q21-31. Correlation analyses highlighted chromosome 10q as the most frequent cytoband, with corresponding proteins involved in regulating focal adhesions and the cytoskeleton. Integrated analysis between pathological and clinical characteristics indicated that chromosome 10q deletion and vascular morphology in IVL could serve as important markers predicting aggressive behavior. Our study sheds light on the pathological and molecular changes linked to IVL, which could pave the way for new treatment approaches.

Chromosomal 3p loss and 8q gain drive vasculogenic mimicry via HIF-2α and VE-cadherin activation in uveal melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults and is where Vasculogenic Mimicry (VM) was first described. VM enables aggressive cancer cells to independently form blood networks, complicating treatment for patients exhibiting VM. Previous studies linked VE-Cadherin phosphorylation at Y658 to gene expression via Focal Adhesion Kinase (FAK), enhancing the Kaiso/β-catenin/TCF-4 complex associated with VE-Cadherin and thereby promoting VM. Recently, an allosteric HIF-2α inhibitor (Belzutifan) was FDA-approved for VHL-associated ccRCCs. In this research, we elucidate the primary causes of VM formation in UM patients with chromosome 3p loss and chromosome 8q gain, identifying VHL, BAP1, and FAK as important factors driving VM and worsening prognosis. These factors promote abnormal activation of HIF-2α and VE-Cadherin under basal hypoxic conditions, leading to VM formation. Cytoscan 750k experiments on the MUM 2B cell line reveal a loss of chromosome 3p, where the VHL, BAP1, and CTNNB1 genes are located, and a gain of chromosome 8q (FAK), whereas the MUM 2C cell line shows a gain of chromosome 3p. This provides an outstanding cross-sectional model from patient samples to established cell lines for VM studies. LC-MS experiments demonstrate that VE-Cad/ENG expression is related to FAK activity in UM cell lines. Finally, using a combination of Belzutifan (HIF-2α inhibitor) and FAK inhibitor (FAKi), we observed a significant reduction in UM xenografts. Our results lead us to propose combining Belzutifan and FAKi as a personalized treatment strategy for UM patients. This approach inhibits VM formation and counters the initial hypoxic conditions resulting from chromosome 3p loss and chromosome 8q gain in UM patients, instilling confidence in the potential of this treatment strategy.

Haploinsufficiency of miR-143 and miR-145 reveal targetable dependencies in resistant del(5q) myelodysplastic neoplasm.

Myelodysplastic neoplasms (MDS) are stem cell disorders characterized by ineffective hematopoiesis and risk of transformation to acute myeloid leukemia (AML). Chromosomal alterations are frequent in MDS, with interstitial deletion of chromosome 5q (del(5q)) being the most common. Lenalidomide is the current first-line treatment for del(5q) MDS and its efficacy relies on degradation of CK1α which is encoded by the CSNK1A1 gene located in the commonly deleted region (CDR) of chromosome 5q. However, lenalidomide-resistance is common, often secondary to loss-of-function mutations in TP53 or RUNX1. The CDR in del(5q) harbors several genes, including noncoding miRNAs, the loss of which contribute to disease phenotypes. miR-143 and miR-145 are located within the del(5q) CDR, but precise understanding of their role in human hematopoiesis and in the pathogenesis of del(5q) MDS is lacking. Here we provide evidence that deficiency of miR-143 and miR-145 plays a role in clonal expansion of del(5q) MDS. We show that insulin-like growth factor 1 receptor (IGF-1R) is a direct target of both miR-143 and miR-145. Our data demonstrate that IGF-1R inhibition reduces proliferation and viability of del(5q) cells in vitro and in vivo, and that lenalidomide-resistant del(5q) MDS cells depleted of either TP53 or RUNX1 are sensitive to IGF-1R inhibition. Resistant del(5q) MDS-L cells, as well as primary MDS marrow cells, are also sensitive to targeting of IGF-1R-related dependencies in del(5q) MDS, which include the Abl and MAPK signaling pathways. This work thus provides potential new therapeutic avenues for lenalidomide-resistant del(5q) MDS.

Oxidative Stress Causes Mitochondrial and Electrophysiologic Dysfunction to Promote Atrial Fibrillation in Pitx2+/- Mice.

The strongest genetic risk factors for atrial fibrillation (AF) are DNA variants on chromosome 4q25 near the transcription factor gene PITX2 (Pitx2:Paired-like homeodomain transcription factor 2). Mice deficient in Pitx2 (Pitx2+/-) have increased AF susceptibility, although the molecular mechanism(s) remains controversial. Pitx2 encodes a transcription factor that activates an antioxidant response to promote cardiac repair. Increased reactive oxygen species causing oxidation of polyunsaturated fatty acids generates reactive lipid dicarbonyl moieties that adduct to proteins and other macromolecules to promote cellular injury. We tested the hypothesis that oxidative stress, and specifically isolevuglandins, the most reactive lipid dicarbonyls identified, are increased in the setting of Pitx2 deficiency to promote proarrhythmic remodeling and AF. Pitx2+/- and Pitx2+/+ wild-type littermate control mice were treated orally with vehicle, the lipid dicarbonyl scavenger 2-hydroxybenzylamine, or an inactive control compound at weaning, until study at age 16 to 18 weeks. Pitx2+/- mice demonstrated increased P wave duration indicative of slowed atrial conduction, as well as increased inducible AF burden and sustained AF, compared with wild type, and these abnormalities were prevented by 2-hydroxybenzylamine. Both reactive oxygen species and isolevuglandin protein adducts were elevated in Pitx2+/- atria with reduced expression of reactive oxygen species-protective genes. High-resolution respirometry demonstrated impaired mitochondrial function in Pitx2+/- atria, with disruption of mitochondrial integrity and cell-cell junctions with connexin lateralization, as well as decreased mitochondrial biogenesis gene expression. Proarrhythmic ionic current remodeling in Pitx2+/- atrial myocytes included elevated resting membrane potential, abbreviated action potential duration, and reduced maximum phase 0 upstroke velocity compared with wild type. Most of these abnormalities were ameliorated or prevented by 2-hydroxybenzylamine. These results demonstrate a critical role for lipid dicarbonyl mediators of oxidative stress in the proarrhythmic remodeling and AF susceptibility that occurs with Pitx2 deficiency, implying the possibility of genotype-specific therapy to prevent AF.

Molecular evolution of metastatic meningioma: A case report.

Distant metastases in meningioma are rare, and the molecular drivers of meningioma spread are not well understood. We describe the case of a 63-year-old woman who was diagnosed with an intracranial meningioma in 2020 which was graded as an atypical meningioma with brain invasion. Local recurrence occurred 1 year later, and in 2023 bone metastases were resected from the thoracic wall and humerus. Molecular analyses from all tumor sites by next-generation sequencing and genome-wide methylation profiling revealed several molecular alterations (loss of 1chromosome 1p, 3p, 4q, 8p, 9p, 10p, 14q, 18q, 22q) already present in the first tumor which remained surprisingly stable during progression and metastasis. However, distant metastasis was exclusively associated with gain of chromosome 1q and 17q. All samples harbored a homozygous CDKN2A deletion. This case expands the knowledge about molecular alterations associated with bone metastases of aggressive meningiomas.

Use of integrated multi-omics profiling in renal cell carcinoma to identify molecular subtypes and associated clinical outcomes and therapeutic vulnerabilities.

588 Background: Although histologically defined subtypes exist, renal cell carcinoma (RCC) is a heterogenous disease, resulting in various treatment outcomes and prognosis. Here, we conducted comprehensive profiling of RCC with histopathologic, proteomic, phosphoproteomic, genomic, and transcriptomic analyses on tumor and paired adjacent normal tissues from 113 patients. Methods: Tumor and matched normal tissues were subjected to proteomic and phosphoproteomic analysis (N=113), whole exome sequencing (N=74), and whole transcriptomic sequencing (N=70). Results: RCC tumors are molecularly distinct from corresponding normal tissues, revealing the loss of tissue identity and de-differentiation. Various hallmarks of cancer were differentially observed at the individual patient level, highlighting the intertumoral heterogeneity of RCC. Proteomic subtyping classifies RCC tumors into four subtypes (C1-4) with distinct phosphoproteomic, genomic, and transcriptomic characteristics with prognostic and predictive implications. Among these subtypes, C1-3 were almost composed of clear cell RCC (ccRCC; 96.8%), whereas C4 was composed of non-clear cell RCC (nccRCC) or other types of cancer (100.0%). Among each subtype, C1 (N=37) exhibits the strongest angiogenesis signaling pathway activation with favorable prognosis after surgical resection. C2 (N=39) was characterized with enrichment in DNA repair pathways along with genetic alteration in BAP1 (24.0%). C3 (N=19) was characterized by chromosome 7q amplification and associated with enrichment in inflammatory response with dismal prognosis along with therapeutic resistance to tyrosine kinase inhibitors and/or immunotherapy. C4 (N=18) was exclusively enriched with nccRCC with active mitochondrial and oxidation phosphorylation. VHL had significant trans -acting effects on various protein and phosphoprotein substrates, whereas PBRM1 and SETD2 had differential cis - and trans -acting profiles. Based on the in silico and in vitro exploration, we also identified CDK5, located on chromosome 7q and highly upregulated in C3 subtype, as a valuable target which can be modulated by small molecule inhibitors. Conclusions: This study reports a large-scale multi-omics-based approach of RCC, providing insights into biologic underpinning and evidence for rational treatment selection as well as linking the multiomics-derived phenotypes to clinical outcomes of RCC.

Genomic analysis of the SMN1 gene region in patients with clinically diagnosed spinal muscular atrophy: a retrospective observational study

BackgroundSpinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease. Most patients with SMA have a mutation in the survival motor neuron 1 (SMN1) gene on chromosome 5q. With current genetic testing, SMN1 copy number is determined; a diagnosis is reached when the copy number is zero. When the SMN1 copy number is 1, exons and intron/exon boundaries of the allele are examined for single-nucleotide variants (SNVs). Genetically undiagnosed cases of SMA exist when 2 copies of SMN1 exist or when a SNV is in the deep intron. Furthermore, SMN1 is highly homologous to SMN2; therefore, it is expected that many SNVs have not been elucidated.MethodsThis retrospective observational study conducted in Japan used pre-collected DNA samples from patients with clinically diagnosed SMA. Enrollment period was January 28, 2020 to September 30, 2021. SNV analysis of SMN1 (exon 1–8 and intron 1–7) was conducted by long-range polymerase chain reaction and next-generation sequencing.ResultsFrom 336 DNA samples collected from patients, 62 patient samples were included in the SNV analysis. Two patients have been genetically diagnosed (a heterozygous variant in intron 6 with 1 copy of SMN1; a homozygous missense mutation in exon 3 with 2 copies of SMN1). Three SNVs in intron 6, c.834+1506A>G (n = 9), c.834+1751G>A (n = 2), and c.835-367C>A (n = 5) were identified; all were numerically, and c.834+1506A>G and c.835-367C>A were significantly, more frequent in patients with 0 copies versus those with ≥ 1 copy of exon 7 in SMN1. We confirmed 3 hybrid SMN gene types in 5 patients that contained SMN2 gene sequence (aaTgg) flanked by upstream “t” and downstream “G” SMN1 sequence.ConclusionsIn this study of patients with clinically diagnosed SMA, 2 cases with genetic SMN types were identified that would not have been identified through current genetic testing, which examines SMN1 deletions only. Furthermore, for 1 patient with a homozygous SMN1 missense mutation, SMA was not suspected by the current copy number screening method. This study demonstrated the importance of performing full-length sequencing for clinically diagnosed SMA to complement current screening methods.Trial registration: University Hospital Medical Information Network Clinical Trials Registry (Number: UMIN000040095).

Loss of 18q Alters TGFβ Signalling Affecting Anteroposterior Neuroectodermal Fate in Human Embryonic Stem Cells.

Chromosomal abnormalities acquired during cell culture can compromise the differentiation potential of human pluripotent stem cells (hPSCs). In this work, we identified a diminished differentiation capacity to retinal progenitor cells in human embryonic stem cells (hESCs) with complex karyotypes that had in common the loss of part of chromosome 18q. Time-course gene-expression analysis during spontaneous differentiation and single-cell RNA sequencing found that these variant cell lines poorly specified into anterior neuroectoderm, and, when progressing through differentiation, they yielded poorly pigmented cells, with proliferating and pluripotent cell populations. The variant cell lines showed dysregulation of TGFβ signalling during differentiation, and chemical modulation of the TGFβ pathways showed that the basis of the improper specification was due to imbalances in the anteroposterior neuroectodermal fate commitment.

Neurodevelopmental delay, musculoskeletal disorders and dysmorphia associated with a novel pathogenic interstitial deletion of chromosome 10q21.1q21.3

BackgroundPrevious reports of distal deletions in chromosome 10q in patients have described distinct facial features combined with other neurodevelopmental abnormalities, including intellectual disability. However, the association of interstitial deletions in...

Loss of LDOC1 by chromatin compaction in mesenchymal tumor cells is required for PFA1 ependymoma growth.

Posterior fossa molecular subtype A (PFA) ependymoma occurs in young children and is the deadliest subtype of pediatric ependymoma. High-risk subtypes with chromosome 1q+ and/or 6q- exhibit significantly poorer outcome compared to wild-type PFA. However, 50% of wild-type PFA patients relapse and there is a high risk of gaining chromosome 1q at recurrence. We previously found constitutively active NF-κB, through loss of LDOC1, led to chronic IL-6 secretion and an overall immunosuppressive tumor microenvironment in the higher risk wild-type PFA ependymoma subset (PFA1). In this study, we delineate the mechanistic consequences of LDOC1 loss in PFA1, using our PFA ependymoma in vitro and in vivo models under normoxia and hypoxia conditions. We noted chromatin compaction by H3K27me3 at the LDOC1 loci results in loss of LDOC1 gene expression. Restoration of LDOC1 was sufficient to reduce proliferation, NF-κB signaling and significant decrease in IL-6 secretion. Furthermore, tumors implanted with LDOC1- transduced cells in vivo were out competed by non-transduced cells, suggesting loss of LDOC1 is required for PFA tumor growth. These findings shed further light on the biology of PFA1 ependymoma and the role LDOC1 loss has on the tumor and immunobiology of high risk pediatric ependymoma.

The Clinical Impact of Somatic Copy Number Variations in Patients With Stage IV Wilms Tumor Enrolled in the SIOP 2001 Trial and Study.

Recent research elucidated the prognostic significance of molecular biology in Wilms tumor (WT) by linking somatic genomic variants (such as gain of chromosome 1q) to unfavorable patient outcomes. This analysis describes the clinical impact of copy number variations (CNV) in tumor samples of WT patients with stage IV disease. Tumor samples of 55 WT patients with stage IV disease from the United Kingdom, France, and Germany enrolled in the SIOP 2001 study and treated with preoperative chemotherapy (pCHT) were examined for their CNVs of chromosome 1q and other regions of interest using multiplex ligation-dependent probe amplification (MLPA). The identified CNV were analyzed regarding their prognostic impact. Chromosome 1q gain (1q+) and TP53 loss occurred in 38.2% and 16.4% of tumors and were associated with older patient age at diagnosis (median [months]: 65 and 64 vs. 49 each, p = 0.03 and 0.02, respectively) and poorer 5-year event-free survival (40.0% and 11.1% vs. 67.7% and 82.6%, p = 0.04 and <0.01, respectively) compared to their specific control group of tumors without the respective CNV. In patients with pulmonary-only metastasis, 1q+ was an adverse prognostic marker irrespective of remission status after pCHT with or without metastasectomy. A simultaneous MYCN gain occurred more frequently in tumors with 1q+ than in tumors without 1q+ (p = 0.03). TP53 loss was linked to high-risk histology and inferior 5-year overall survival (p<0.001). We confirm the prognostic relevance of 1q+ and TP53 loss in stage IV WTs and emphasize their potential utility for future treatment stratification.

Unraveling Hematological Anomalies in DiGeorge Syndrome: A Retrospective Study of Thrombocytopenia and Mean Platelet Volume.

DiGeorge syndrome, arising from chromosome 22q11.2 deletion including the TBX1 gene, is known for its multifaceted developmental anomalies affecting the heart, immune system, and facial morphology. Despite extensive clinical characterization, hematological manifestations, particularly thrombocytopenia, remain underexplored. There is growing evidence of a potential association between DiGeorge syndrome and Bernard-Soulier syndrome, a rare platelet disorder characterized by defects in the GPIb-IX-V complex. This connection may be linked to the genetic location of the GPIBB gene, which encodes the GPIbβ subunit of the complex, on chromosome 22, where microdeletions are a hallmark of DiGeorge syndrome. This study investigates the hematological profile of pediatric DiGeorge syndrome patients followed up in Al Qassimi Women's and Children's Hospital, Sharjah, focusing on platelet counts, mean platelet volume, and potential genetic links to GPIBB mutations on chromosome 22q11.2. The aim is to deepen understanding of thrombocytopenia in DiGeorge syndrome and its implications for clinical management. A retrospective analysis of medical records identified eight pediatric DiGeorge syndrome patients diagnosed through fluorescent in situ hybridization (FISH) and microarray scanning, excluding cases with incomplete records or unrelated comorbidities. Uniform assessment of platelet parameters was conducted across all subjects. DiGeorge syndrome patients had a mean age of 5.1 years, with four males and four females. The mean number of complete blood counts (CBCs) per patient was 14.25 (range: 6-42). The mean platelet count was 194,295/µL and the mean mean platelet volume (MPV) was 10.8 fL. Thrombocytopenia and large platelets showed notable variability. Four patients had large platelets on 100% of their CBCs, while the lowest was 57%. Two patients had thrombocytopenia in >80% of CBCs, while the rest showed lower rates. One patient presented with immune bicytopenia that responded to immunosuppressive therapy. The findings underscore distinct hematological characteristics in DiGeorge syndrome. These insights into platelet abnormalities shed light on potential mechanisms underlying thrombocytopenia in DiGeorge syndrome. Specifically, the observed higher MPV and occasional presence of giant platelets suggest altered platelet production or function, possibly due to haploinsufficiency of gene within the 22q11.2 region, including GPIBB. The study's findings align with previous reports linking DiGeorge syndrome to thrombocytopenia and Bernard-Soulier syndrome features. This study provides insights into hematological manifestations of DiGeorge syndrome, highlighting the role of GPIb-IX-V complex deficiencies. Further research is warranted to elucidate genetic interactions and optimize management strategies for thrombocytopenia in DiGeorge syndrome patients. Future investigations comparing proximal versus distal 22q11.2 deletions and their clinical implications could enhance our understanding.

Hearing Loss in Children with 22q11.2 Deletion Syndrome.

Hearing loss is considered common in children with 22q11.2 deletion syndrome (22q11.2DS), with a few prior studies reporting a 32%-78% prevalence; mild-moderate conductive hearing loss has been reported most commonly. Overall, however, there remains a paucity of data regarding the frequency, type, age, and progression of hearing loss in children with 22q11.2DS. Retrospective chart review was completed, and data combined for two large 22q centers. Inclusion criteria were children with 22q11.2DS and a documented audiogram. Data extracted included a laboratory-confirmed chromosome 22q11.2 deletion; co-morbidities; results of all audiograms and radiologic temporal bone imaging; and otologic surgical procedures. One thousand seven hundred sixty-nine charts were reviewed; 775 met inclusion criteria. Of these, 563 (73%) children had at least one abnormal audiogram demonstrating hearing loss. A total of 2,536 audiograms were reviewed; 74% of these showed abnormal hearing in at least one ear. Most of the hearing loss was conductive (right ear 76%; left ear 69%) and mild severity. For the children with SNHL, 90% of all follow-up audiograms were stable without progression. Hearing loss was identified across all pediatric age ranges. Ear tube placement occurred in 39% of children. This study confirms the high incidence of hearing loss for children with 22q11.2DS at some point in their childhood. In our cohort, hearing loss occurred in 73% of children and was most often conductive and mild in severity. The results highlight the importance of otolaryngology and audiology involvement in managing children with 22q11.2DS for timely diagnosis and treatment of hearing loss. 4 Laryngoscope, 135:929-934, 2025.

Ataxia telangiectasia in a Bahraini child treated with intensive physiotherapy: A case report

Ataxia telangiectasia (AT) is a rare neurodegenerative condition with a prevalence of 1 in 40,000 to 1 in 300,000 worldwide. It involves a genetic mutation of chromosome 11q.26. The condition is inherited in an autosomal recessive manner causing atrophy of the cerebellum due to loss of Purkinje fibres. AT presents early in childhood and the clinical features depend on the type of mutation. The study is a case report of a rare genetic disorder of a 9-year-old female who came to the physiotherapy clinic with a diagnosis of AT. The patient was presented with progressively worsening gait problems with frequent falls, with complete dependence on assistance and impaired balance and coordination. The treatment program was 12 months divided into an intense physiotherapy program for two months followed by 10 months of two times per week of physiotherapy sessions. The program was divided into four elements which are: (1) Lifestyle changes, (2) Strengthening exercises, (3) Coordination exercises, and (4) Balance training exercises. The result showed a positive outcome in increasing the patient’s independence, increased muscle strength, reduced ataxia symptoms intensity, and the patient can carry out complex activities with the help of accessory orthosis devices.

Pan-cancer analysis and single-cell analysis identifies the CENPN as a biomarker for survival prognosis and immunotherapy

BackgroundCentromere protein N (CENPN), located on chromosome 16q23.2, encodes vital nucleosome-associated complexes that are essential for dynamic assembly processes. CENPN plays a pivotal role in regulating cell proliferation and cell cycle progression by influencing mitotic events. Despite its potential importance, the precise functional role and regulatory mechanisms of CENPN in diverse malignancies remain largely unexplored. This study aimed to elucidate the role of CENPN in human cancers and evaluate its prognostic significance.MethodsInvestigate the role of CENPN in various malignancies, we leveraged data from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We employed a comprehensive suite of web platforms and software tools for data analysis, including R, Cytoscape, an integrated repository portal for tumor-immune system interactions (TISIDB), CBio Cancer Genomics Portal (cBioPortal), Search Tool for the Retrieval of Interaction Gene/Proteins (STRING), Gene Set Cancer Analysis (GSCALite), and a cancer single-cell state atlas (CancerSEA).ResultsThe findings demonstrated that CENPN expression was elevated in the majority of cancer types and differentially expressed across molecular and immune subtypes. Functional enrichment analysis in multiple tumors also identified possible pathways of CENPN involvement in tumorigenesis. Its expression positively correlated with Th2 and Tcm cells in most cancers. It is also correlated with genetic markers of immunomodulators in various cancers.ConclusionsOverall, CENPN expression is closely related to cancers and has the potential to act as a cancer biomarker.

Somatic copy number deletion of chromosome 22q in papillary thyroid carcinoma.

Deletion of the long q arm of chromosome 22 (22qDEL) is the most frequently identified recurrent somatic copy number alteration observed in papillary thyroid carcinoma (PTC). Since its role in PTC is not fully understood, we conducted a pooled analysis of genomic characteristics and clinical correlates in 1094 primary tumors from four published PTC genomic studies. The majority of PTC cases with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC cases with 22qDEL had losses in 22q12 and 13, which together constitute 70% of the q arm. Our analysis confirmed that 22qDEL occurs more frequently with RAS point mutations (50.4%), particularly HRAS (70.3%), compared with other PTC drivers (9.3%), supporting the conclusion that 22qDEL is unlikely to be a solitary driver of PTC but possibly an important co-factor in carcinogenesis, particularly in PTCs with RAS driver mutations. Differential RNA expression analyses revealed downregulation of most genes located on chromosome 22 in cases with 22qDEL compared to those without 22qDEL. Many differentially expressed genes are drawn from immune response and regulation pathways. These findings highlight the value of further investigations into the contributions of 22qDEL events to PTC, perhaps mediated through immune perturbations.