Chromosome 22q11 Research Articles

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.

Development of a TaqMan-based dosage analysis PCR assay for the molecular diagnosis of 22q11.2 deletion syndrome.

A 1.5 to 3 Mb microdeletion of chromosome 22q11.2 with loss of multiple genes including histone cell cycle regulator (HIRA) causes 22q11.2 deletion syndrome (22q11.2 DS), a common disorder with variable manifestations including congenital malformations affecting the heart, palate and kidneys in association with neurodevelopmental, psychiatric, endocrine and autoimmune abnormalities. The aim of this study was to develop a TaqMan based dosage analysis PCR (TaqMan qPCR) for use as a rapid, cost-effective test for clinically suspected patients fulfilling previously described criteria for molecular diagnosis of 22q11.2 DS in a lower middle-income country where the cost of testing limits its use in routine clinical practice. Nineteen patients were recruited with informed consent following ethical approval from the Ethics Review Committee (ERC), Lady Ridgway hospital, Colombo. Dosage analysis of extracted DNA was performed using a TaqMan qPCR assay by amplifying regions within the target (HIRA) and control [Testin LIM domain protein (TES)] genes of a suspected patient (P) and unaffected person (N). For detection of a deletion, the normalized values (HIRA / TES dosage) of a patient were compared with normalized values of an unaffected person. A ratio of P:N of 0.5 confirmed presence of a deletion while a ratio of 1.0 refuted this. Seven of 19 (37%) cases were confirmed to have a HIRA deletion, confirming the diagnosis of 22q11.2 DS, with these results being in complete agreement with those of fluorescence in-situ hybridization (FISH), (performed in 9/19 (47.3%) of recruited cases) and whole exome sequencing (WES) (all 19 samples tested). This TaqMan qPCR assay was able to reliably distinguish HIRA deleted cases from the non-deleted ones. The assay was both less expensive and faster compared to commercially available alternatives in our setting, including FISH and multiple ligation-dependent probe amplification (MLPA).

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.

Cholangioblastic Cholangiocarcinoma (NIPBL::NACC1 cholangiocarcinoma): Expanded Morphologic Spectrum and Further Genetic Characterization.

The cholangioblastic variant of intrahepatic cholangiocarcinoma is a distinctive neoplasm that typically affects young women without underlying liver disease. Morphologically, it demonstrates solid, trabecular, and tubulocystic architecture, biphasic small cell-large cell cytology, and immunoreactivity for inhibin, neuroendocrine markers, and biliary but not hepatocellular markers. In 2021, our group identified a characteristic NIPBL::NACC1 gene fusion in cholangioblastic cholangiocarcinoma, and since then ~20 genetically confirmed cases have been reported in the literature. We report 2 additional cases, both of which caused diagnostic challenges. The first was previously published as a "biliary adenofibroma with malignant features" which we now show recurred as a high-grade adenocarcinoma. Re-review of the original lesion demonstrated the morphologic and immunohistochemical features of highly cystic cholangioblastic cholangiocarcinoma, whereas the high-grade recurrence lacked many of these features. In addition to the characteristic NIPBL::NACC1 gene fusion, the recurrence demonstrated loss of the RB1 and PTEN genes which were found in the highly cystic, bland areas of the original tumor, suggesting that the recurrence was derived from this bland component. The second case was originally misclassified as metastatic well-differentiated neuroendocrine neoplasm and only focally demonstrated the characteristic biphasic small cell-large cell cytology. In addition, a review of 7 cholangioblastic cholangiocarcinomas in our files demonstrates that loss of chromosome 13q14.2 (where the RB1 gene resides) and loss of chromosome 6q15-q16.3 are recurrent secondary changes in these neoplasms. Expression profiling demonstrated alterations in the transforming growth factor receptor beta superfamily, and overexpression of MYC which was validated by immunohistochemistry. Our findings expand the morphologic and genetic spectrum of this neoplasm and provide insight into secondary genetic changes associated with progression.

Blood DNA virome associates with autoimmune diseases and COVID-19

Aberrant immune responses to viral pathogens contribute to pathogenesis, but our understanding of pathological immune responses caused by viruses within the human virome, especially at a population scale, remains limited. We analyzed whole-genome sequencing datasets of 6,321 Japanese individuals, including patients with autoimmune diseases (psoriasis vulgaris, rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), pulmonary alveolar proteinosis (PAP) or multiple sclerosis) and coronavirus disease 2019 (COVID-19), or healthy controls. We systematically quantified two constituents of the blood DNA virome, endogenous HHV-6 (eHHV-6) and anellovirus. Participants with eHHV-6B had higher risks of SLE and PAP; the former was validated in All of Us. eHHV-6B-positivity and high SLE disease activity index scores had strong correlations. Genome-wide association study and long-read sequencing mapped the integration of the HHV-6B genome to a locus on chromosome 22q. Epitope mapping and single-cell RNA sequencing revealed distinctive immune induction by eHHV-6B in patients with SLE. In addition, high anellovirus load correlated strongly with SLE, RA and COVID-19 status. Our analyses unveil relationships between the human virome and autoimmune and infectious diseases.

InVivo CRISPR Activation Screening Reveals Chromosome 1q Genes VPS72, GBA1, and MRPL9 Drive Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) frequently undergoes regional chromosomal amplification, resulting in elevated gene expression levels. We aimed to elucidate the role of these poorly understood genetic changes by using CRISPR activation (CRISPRa) screening in mouse livers to identify which genes within these amplified loci are cancer driver genes. We used data from The Cancer Genome Atlas to identify that frequently copy number-amplified and up-regulated genes all reside on human chromosomes 1q and 8q. We generated CRISPRa screening transposons that contain oncogenic Myc to drive tumor formation. We conducted CRISPRa screens invivo in the liver to identify tumor driver genes. We extensively validated the findings in separate mice and performed RNA sequencing analysis to explore mechanisms driving tumorigenesis. We targeted genes that frequently undergo amplification in human HCC using an invivo CRISPRa screening system in mice, which induced extensive liver tumorigenesis. Human chromosome 1q genes Zbtb7b, Vps72, Gba1, and Mrpl9 emerged as drivers of liver tumorigenesis. In human HCC there is a trend in correlation between levels of MRPL9, VPS72, or GBA1 and poor survival. In validation assays, activation of Vps72, Gba1, or Mrpl9 resulted in extensive liver tumorigenesis and decreased survival in mice. RNA sequencing revealed different mechanisms driving HCC, with Mrpl9 activation altering genes functionally related to mitochondrial function, Vps72 levels altering phospholipid metabolism, and Gba1 activation enhancing endosomal-lysosomal activity, all leading to promotion of cellular proliferation. Analysis of human tumor tissues with high levels of MRPL9, VPS72, or GBA1 revealed congruent results, indicating conserved mechanisms driving HCC. This study reveals chromosome 1q genes Vps72, Gba1, and Mrpl9 as drivers of HCC. Future efforts to prevent or treat HCC can focus on these new driver genes.

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 (SCNA) 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 with 22qDEL exhibited arm-level loss of heterozygosity (86%); nearly all PTC 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 PTC with RAS driver mutations. Differential RNA expression analyses revealed downregulation of most genes located on chromosome 22 in those 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.

GENETIC ANALYSIS OF BMP-4 GENE IN BADDI GOAT BREED OF DISTRICT KHAIRPUR MIR'S SINDH PAKISTAN

Bone morphogentic protein 4 is a protein that found in goat, cattle, and human are encoded by BMP4 gene. the candidate gene is found on chromosome 10q in goats. BMP4 gene is the subfamily of the superfamily named as transforming growth factor beta. it is an evolutionary conserved member of BMPs family. BMP4 is a protein coding gene that concern with connective and soft tissues of the body structure . it play main role in goats, cattle, human and other animal's bodies for maintaining the body activities such as cell proliferation, differentiation, apoptosis and migration. Present study was aimed to investigate the mutational variations found with same area of indigenous goat breed. The Genomic DNA was extracted from blood samples of Baddi goat breed. The samples were transported and stored at 4 degree for further processing of DNA extraction. The targeted region of BMP4 gene that was amplified by the specific set of primers. The amplified products were sequenced by the ABI Genetic Anayzer 3500 and sequencing data was analyzed by Bio Edit v 7.2 and blasting was performed on ensemble.org. Result revealed that about 4 missense mutations found the breed with help of PCR, gel electrophoresis and DNA sequencing. The missense mutation was identified by the replacement of genetic codon from original codon such as first missense mutation found in replacement of Serine by Threonine at 157Bp, second and third from Glycine to isolecucine at 159 Bp and 173 Bp respectively. while fourth mutational variation occured from Arginine to Serine at 177 Bp. However, the percentage of mutation in Baddi breed was greater than 1% it means there was polymorphism has been found with replacement of original amino acids with variate amino acids that play a significant role in improvement of goat characteristic such as body, muscles, milk and meat quantities. Obtained result revealed a great heterogeneity in genetic makeup of Baddi breed and hence could be used in genetic marker which assisted the selection of Baddi breed than other breeds.

MicroRNA Profile of High-Grade B-Cell Lymphoma with 11q Aberration.

High-grade B-cell lymphoma with 11q aberration (HGBCL-11q) is a rare germi-nal centre lymphoma characterised by a typical gain/loss pattern on chromo-some 11q but without MYC translocation. It shares some features with Burkitt lymphoma (BL), HGBCLs and germinal centre-derived diffuse large B-cell lym-phoma, not otherwise specified (GCB-DLBCL-NOS). Since microRNA expression in HGBCL-11q remains unknown, we aimed to identify and compare the mi-croRNA expression profiles in HGBCL-11q, BL and in GCB-DLBCL-NOS. Next-generation sequencing (NGS)-based microRNA profiling of HGBCL-11q (n = 6), BL (n = 8), and GCB-DLBCL-NOS without (n = 3) and with MYC rearrange-ment (MYC-R) (n = 7) was performed. We identified sets of 39, 64, and 49 mi-croRNAs differentiating HGBCL-11q from BL, and from GCB-DLBCL-NOS without MYC-R, respectively. The expression levels of miR-223-3p, miR-193b-3p, miR-29b-3p, and miR-146a-5p consistently differentiated HGBCL-11q from both BL, GCB-DLBCL-NOS without MYC-R. In addition, HGBCL-11q presented greater heterogeneity in microRNA expression than BL. The expression profile of MYC-regulated microRNAs differed in HGBCL-11q and in BL, while also clearly distinguishing HGBCL-11q and BL from GCB-DLBCL-NOS. The microRNA pro-file of HGBCL-11q differs from those of BL and GCB-DLBCL-NOS, exhibiting greater heterogeneity compared to BL. The microRNA profile further supports that HGBCL-11q is a distinct subtype of B-cell lymphoma.

CRKL Gene Deletion in Familial Zinner (OSVIRA) and OHVIRA Syndromes.

We present the first description of a family in which 2 siblings show alternative expression of CRKL gene deletion as the phenotypes of Zinner (OSVIRA, obstructed seminal vesicle and ipsilateral renal agenesis) and OHVIRA (obstructed hemivagina with an ipsilateral renal anomaly) syndromes. The male infant with Zinner syndrome and his sister aged 5years with OHVIRA syndrome both have a paternally inherited 703-kb deletion at chromosome 22q11.21 that includes CRKL. This observation supports Acien's hypothesis that the upper vagina has an embryological dual origin and furthermore substantiates the theory that Zinner (OSVIRA) is the male equivalent of OHVIRA in females.

Swedish Genome-Wide Haplotype Association Analysis Suggests Breast Cancer Loci with Varying Risk-Modifying Effects.

Background: To find support for risk-modifying genes in breast cancer, a haplotype GWAS in sporadic breast cancer cases was undertaken. The results were compared with the results from previous analyses in familial cases and all cases from the same Swedish cohort. Methods: In total, 2550 women with sporadic invasive breast cancer and 5021 healthy controls were included in a sliding-window haplotype GWAS using PLINK 1.07. Results: The analysis of sporadic cases confirmed the loci on chromosomes 10q26.13, 11q13.3, and 16q12.1 and suggested one novel locus on chromosome 12p11.21 (OR = 1.42 p = 4.55 × 10-8). A comparison between these loci and the same loci in the analyses of familial cases and all breast cancer cases was undertaken. Conclusions: Haplotype GWAS in sporadic cases of Swedish breast cancer cases supported known risk loci and suggested another risk locus. The loci identified in the analysis of sporadic and all breast cancer cases were suggested to act as modifiers of the risk of breast cancer. Haplotype analysis identified other loci with higher odds ratios than single-variant analysis. Further studies are needed to find out how to best include the findings in breast cancer prevention.

Retrospective longitudinal study on the long-term impact of COVID-19 infection on polysomnographic evaluation in patients with Prader-Willi syndrome

BackgroundTo evaluate the impact of coronavirus disease 2019 (COVID-19) on polysomnographic evaluation in patients with Prader-Willi syndrome (PWS).Patients and methodsA retrospective cohort study of two consecutive overnight polysomnograms (PSG) in 92 PWS patients (mean age 9.1, range 3.1–22 years). 57/92 participants (35 female) had a COVID-19 infection between the two consecutive examinations. 35 patients (21 female) had no infection (control group). Distribution of genetics was as follows: 13/57 (22.8%) deletion, 19/57 (33.3%) uniparental disomy, 2/57 (3,5%) imprinting defect, 3/57 (5.3%) non-deletion, 20/57 (35.1%) diagnosed by analyses of the methylation pattern of chromosome 15q11-13. Mean time interval between COVID-19 infection and post-COVID-19 evaluation was 96.2 days.ResultsCourse of COVID-19 infection was asymptomatic 8/82 (9.8%), mild 63/82 (76.8%), medium 11/84 (13.4%). The five most frequently experienced symptoms in PWS patients were fever (56.1%); headache (45.1%); cold (42.7%); cough (31.7%) and body aches (21.95%). PWS patients who had COVID-19 infection had significantly lower mean oxygen saturation (SpO2) measured by pulse oximetry (post 94.8% vs. pre 95.7%, p = 0.001), lower detected lowermost SpO2 (post 86.2 vs. pre 87.3%, p = 0.003), and higher occurrence of hypopnoea (post 13.9 vs. pre 10.7, p = 0.001). Time in optimal SpO2 (95–100%) decreased significantly (post 54.3% vs. pre 73.8%, p = 0.001), whereas an increase was observed in time in suboptimal SpO2 (90–95%) (post 45.5% vs. 25.8%, p = 0.001) and in time in poor SpO2 (< 90%) (post 0.7% vs. pre 0.2%, p = 0.030). Body-Mass-Index (BMI)-SDS for PWS showed no differences between the groups at any time. BMI-SDS-differences showed no influence on differences in SpO2 evaluations. In the genetic subgroup with deletion there was a statistically significant effect on an increased number of OSA (p = 0.027). The genetic subgroup with uniparental disomy (UPD) was associated with a reduced risk of higher HF (p = 0.035) and less hypopnea (p = 0.011).ConclusionPWS patients predominantly experienced only mild to medium symptoms during COVID-19 infection without necessity of hospitalisation. However, on average three months after infection, differences in PSG evaluations were still apparent, manifesting in lower SpO2 and more frequent hypopnea. A long-lasting impairment of the pulmonary system due to the COVID-19 infection might be responsible.

Classification and Prognostic Stratification Based on Genomic Features in Myelodysplastic and Myeloproliferative Neoplasm- and Their Overlapping Conditions.

Background/Objectives: Myeloid neoplasms encompass a diverse group of disorders. In this study, we aimed to analyze the clinical and genomic data of patients with myeloproliferative neoplasm (MPN), myelodysplastic neoplasm (MDS), and their overlapping conditions, such as MDS/MPN and aplastic anemia (AA), to help redefine the disease classification. Methods: Clinico-genomic data of 1585 patients diagnosed with MPN (n = 715), MDS (n = 698), MDS/MPN (n = 78), and AA (n = 94) were collected. Patterns of 53 recurrent genomic abnormalities were compartmentalized into 10 groups using a Dirichlet process (DP). Results: These genomic groups were correlated with specific genomic features, survival outcomes, and disease subtypes. Groups DP1 and DP5, characterized by JAK2 and CALR mutations, respectively, showed very favorable prognoses among the patients with MPN. Groups DP2, DP7, and DP9 demonstrated very adverse prognoses across the disease subtypes. DP2 included patients with MDS harboring TP53 mutations and complex karyotypes; DP9 comprised patients with acute myeloid leukemia-related mutations, including NPM1; and DP7 included patients with SETBP1 mutations. Groups DP10 and DP8, linked to SF3B1 and DDX41 mutations or chromosome 1q derivatives, presented a favorable risk profile. Improved survival was observed with transplantation in groups DP2, DP7, and DP9. Conclusions: These findings highlight the role of genomic classifications in guiding personalized treatment strategies, ultimately enhancing the understanding and management of myeloid neoplasms.

Chromosome 1 Alterations in Multiple Myeloma: Considerations for Precision Therapy.

Multiple myeloma (MM) is an incurable blood malignancy characterized by the clonal expansion of plasma cells and the secretion of monoclonal immunoglobulins. High-risk MM, defined by specific cytogenetic abnormalities, poses significant therapeutic challenges and is associated with inferior survival outcomes compared to standard-risk disease. Although molecularly targeted therapies have shown efficacy in other hematologic malignancies, currently venetoclax is the only targeted therapy approved for MM (t(11;14)). However, chromosome 1q gains, amplifications, and 1p deletions are frequently observed in MM, and have been linked to drug resistance and poor patient prognosis. Accordingly, this review focuses on emerging MM precision therapies capable of targeting dysregulated genes within these regions. It addresses gene therapies, small molecule inhibitors and monoclonal antibodies currently under investigation to antagonize oncogenic drivers including MCL-1, BCL9, F11R, and CKS1B, all of which are implicated in cell survival, proliferation or drug resistance. In conclusion, the link between chromosome 1 abnormalities and high-risk disease in MM patients offers a compelling rationale to identify and explore therapeutic targeting of chromosome 1 gene products as a novel precision medicine approach for a poorly served patient population.

Genetic complexity in myelodysplastic syndromes: Insights from a case with complex karyotype and renal manifestations

Myelodysplastic syndrome (MDS) is a heterogeneous disorder with a significant risk of progression to acute myeloid leukemia. We present a case initially suspected of acute leukemia, subjected to comprehensive cytogenetic, immunophenotypic, and molecular evaluations. Cytogenetic analysis revealed a complex karyotype including translocation t (1;3) (q42;q21), near-tetraploidy, and deletions on chromosomes 5q and 20q. Fluorescence in situ hybridization confirmed the 5q and 20q deletions, along with trisomy 8. Immunophenotyping identified 7.5% abnormal myeloid blasts. Next-generation sequencing detected pathogenic TP53 mutations: c.569 (p.Pro190LeufsTer57) and c.464C&gt;A (p.Thr155Asn). In addition, renal imaging showed mildly raised echotexture. This case underscores the value of integrated multimodal analysis for precise diagnosis and management of MDS, offering insights into its complex genetic landscape.

Patient identified with interrupted aortic arch and 22q11.2 deletion syndrome in late pregnancy: a case report

Interrupted aortic arch (IAA) is an uncommon congenital heart malformation that can be fatal with no surgical intervention. Most patients have IAA discovered as newborns because of cardiac symptoms, and atypical adult patients are relatively rare. We report a case of atypical adult IAA in a woman in her 20s. Her first pregnancy and childbirth did not show any obvious abnormalities. Although this patient did not have any major clinical manifestations, she developed tachycardia during her second pregnancy and was diagnosed with IAA by echocardiography. The etiology of IAA was chromosome 22q11.2 deletion syndrome based on the results of whole-exome sequencing. After interdisciplinary diagnosis and treatment to reduce the pulmonary artery pressure and cardiac burden, the patient and her newborn had a favorable prognosis. This case highlights the importance of not overlooking cardiovascular concerns in patients who develop symptoms in pregnancy. Echocardiography can detect IAA, and genetic testing may assist in an etiological diagnosis, which improves the maternal and fetal prognosis.

Aortopathy in repaired tetralogy of Fallot and David procedure.

Tetralogy of Fallot (TOF) is a condition that often leads to long-term enlargement of the aortic root in after surgery. The aortic dilation is believed to be caused by histological abnormalities of the aortic media and the hemodynamic characteristics of increased aortic flow, compared to pulmonary flow. Severe cyanosis, severe right ventricular outflow tract (RVOT) obstruction, older age at repair, a larger aortic size at the time of repair, and a history of an aortopulmonary shunt parameters related to long-standing volume overload of the aortic root were the reported risk factors. Right aortic arch, male sex, and the association of chromosome 22q11 deletion were also reported to be risk factors. The enlargement of the aortic root can cause aortic regurgitation (AR), leading to left ventricular dysfunction and an increased risk of aortic dissection, necessitating surgical intervention. The outcomes of aortic valve repair for AR have improved, leading to an increasing trend of choosing this approach, particularly in younger patients who would otherwise require mechanical valve replacement, thereby avoiding the need for anticoagulation therapy. The indications and timing of prophylactic aortic root replacement in adult patients with congenital heart disease have not been described, and the current consensus recommends surgical intervention for an ascending aorta with a diameter of ≥55 mm. In this review article, we focus on valve-sparing root replacement (VSRR) in TOF.

A self-reported Brazilian registry of 5q-spinal muscular atrophy: data on natural history, genetic characteristics, and multidisciplinary care.

Spinal muscular atrophy linked to chromosome 5q (SMA-5q) is a neurodegenerative disorder caused by mutations in the SMN1 gene. To describe the key demographic, clinical and genetic characteristics, as well as natural history data of patients with SMA-5q. Up to January 2022, 706 patients with confirmed genetic diagnosis of SMA-5q, or their parents, completed a self-reported questionnaire on natural history, genetic characteristics, drug treatments, and multidisciplinary care. Most patients had type 1 SMA-5q (42%); with 33% having type 2, and 23% type 3. There were 667 patients (94.4%) with a homozygous SMN1-exon 7 deletion. Of the total, 131 (18.6%) patients had a previous family history of the disease, and the familial recurrence rate was higher in type 3 (25.6%). Type 1 patients had a mean age of 3 months at the onset of symptoms and a delay of more than 3 months until genetic diagnosis. The median survival of patients with type 1 without invasive ventilation was 27 months. Before 2018, the median age of use of invasive ventilation was 16 months and, after, most patients (71%) were not submitted to invasive ventilation. About 50% of patients with type 3 lost their walking ability by 37 years of age. Further, 384 (54.4%) patients had access to disease-modifying therapy, and 62.3% of type 1 patients were in treatment, compared with only 47.2% of type 2 and 31.9% of type 3 patients. There is still a substantial diagnostic delay, especially in those patients with types 2 and 3 SMA-5q. However, the present study demonstrated prolonged survival, especially in type 1 patients.

Loss of chromosome cytoband 13q14.2 orchestrates breast cancer pathogenesis and drug response

Breast cancer (BCa) is a major global health challenge. The BCa genome often carries extensive somatic copy number alterations (CNAs), including gains/amplifications and losses/deletions. These CNAs significantly affect tumor development, drug response and patient survival. However, how individual CNAs contribute is mostly elusive. We identified loss of chromosome 13q14.2 as a key CNA in BCa, occurring in up to 63% of patients, depending on the subtype, and correlating with poor survival. Through multi-omics and in vitro analyses, we uncover a paradoxical role of 13q14.2 loss, promoting both cell cycle and pro-apoptotic pathways in cancer cells, while also associating with increased NK cell and macrophage populations in the tumor microenvironment. Notably, 13q14.2 loss increases BCa susceptibility to BCL2 inhibitors, both in vitro and in patient-derived xenografts. Thus, 13q14.2 loss could serve as a biomarker for BCa prognosis and treatment, potentially improving outcomes for BCa patients.Graphical abstract

Abstract B021: Aneuploidy-associated cohesin RAD21 gains promote immune evasion in prostate cancers

Abstract Aneuploidy, characterized by imbalanced chromosome numbers, is a hallmark of cancer and is strongly correlated with lethal progression in prostate cancer. Our recent work identified that gains of chromosome 8q, the most frequently gained chromosome in aneuploidy prostate cancers, drive cancer progression, partially through the cohesin RAD21 gene located on the chr8q24 region. We demonstrated that increased RAD21 expression accelerates lethal progression and oncogenesis in both prostate cancer and Ewing sarcoma by alleviating oncogenic stress during early-stage oncogenesis in both cell line and organoid models. Therefore, we hypothesize that elevated RAD21 levels could enable cancer cells to evade immune surveillance by mitigating oncogenic stress and DNA damage. In this study, we developed isogenic prostate and breast cancer cell culture models with varying levels of RAD21. Using a natural killer (NK) cell co-culture assay, we observed that cells with elevated RAD21 expression were significantly less susceptible to NK-mediated cytotoxicity and exhibited increased survivorship when co-cultured with NK cells. These findings align with publicly available data showing that tumors with high RAD21 levels have reduced NK cell infiltration in prostate cancer. Our results suggest that increased RAD21 expression, commonly associated with chr8q gains, facilitates immune evasion in cancer cells, thereby promoting early-stage oncogenesis. Understanding the role of RAD21 in immune evasion could reveal novel therapeutic strategies targeting immune surveillance mechanisms in prostate cancer. Citation Format: Elise G. DeArment, Ruoxi W. Wang, Kate Lu, Xiaofeng A. Su, Andrew Elliott, Nicholas A. Zorko, Justin H. Hwang, Xiaofeng A. Su. Aneuploidy-associated cohesin RAD21 gains promote immune evasion in prostate cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B021.