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Pathogenic variants in the cohesin genes, NIPBL and SMC1A, both cause Cornelia de Lange syndrome (CdLS), a rare genetic disorder associated with developmental delay and intellectual disability. This study aimed to compare sleep behaviors across individuals with CdLS caused by a variant in NIPBL or SMC1A, and identify relationships between sleep and behavior functioning. A total of 31 caregivers of individuals with a variant in NIPBL (N = 22) or SMC1A (N = 9) completed questionnaires regarding their child's sleep behaviors, behavior regulation, attention, and autistic features (repetitive behaviors and social communication difficulties) as part of the Coordination of Rare Diseases (CoRDS) registry. Findings showed a trend of increased behavior regulation difficulties and repetitive behaviors in the NIPBL compared to the SMC1A participants. Both groups presented with a similar degree of attention, social communication, and sleep challenges. In the whole sample, sleep disturbance was strongly correlated with more behavior regulation difficulties, a relationship that was more robust in the NIPBL sample. In brief, study results support our prior observations of greater behavior difficulties among those with a variant in NIPBL as compared to SMC1A. Preliminary findings point to unique associations between sleep and behavior regulation in the NIPBL group, suggesting sleep interventions may yield differential effects on behavior management across variants. [ABSTRACT FROM AUTHOR]

Background: The STAG1 gene encodes a component of the cohesin complex, involved in chromosome segregation and DNA repair. Variants in genes of the cohesin complex determine clinical conditions characterized by facial dysmorphisms, upper limb anomalies, intellectual disability, and other neurological deficits. However, to date, the STAG1-related clinical phenotype has been poorly investigated (around 20 cases reported). Methods and Results: We report, for the first time, two twins affected by a syndromic neurodevelopmental disorder associated with a de novo variant in the STAG1 gene. Although both the twins showed a neurodevelopmental delay, one of them showed a more severe phenotype with greater behavioral problems, speech defects and limb apraxia. CGH array showed a 15q13.3 microduplication, inherited from an unaffected mother. Conclusions: We found different degrees of behavioral, speech and cognitive impairment in two twins affected by a neurodevelopmental disorder associated with a STAG1 variant. These findings highlight the variability of the STAG1-associated phenotype or a probable role of associated variants (like the discovered 15q13.3 microduplication) in modulating the clinical features. [ABSTRACT FROM AUTHOR]

Cornelia de Lange Syndrome (CdLS) is a rare, dominantly inherited multisystem developmental disorder characterized by highly variable manifestations of growth and developmental delays, upper limb involvement, hypertrichosis, cardiac, gastrointestinal, craniofacial, and other systemic features. Pathogenic variants in genes encoding cohesin complex structural subunits and regulatory proteins (NIPBL, SMC1A, SMC3, HDAC8, and RAD21) are the major pathogenic contributors to CdLS. Heterozygous or hemizygous variants in the genes encoding these five proteins have been found to be contributory to CdLS, with variants in NIPBL accounting for the majority (>60%) of cases, and the only gene identified to date that results in the severe or classic form of CdLS when mutated. Pathogenic variants in cohesin genes other than NIPBL tend to result in a less severe phenotype. Causative variants in additional genes, such as ANKRD11, EP300, AFF4, TAF1, and BRD4, can cause a CdLS-like phenotype. The common role that these genes, and others, play as critical regulators of developmental transcriptional control has led to the conditions they cause being referred to as disorders of transcriptional regulation (or DTRs). Here, we report the results of a comprehensive molecular analysis in a cohort of 716 probands with typical and atypical CdLS in order to delineate the genetic contribution of causative variants in cohesin complex genes as well as novel candidate genes, genotype-phenotype correlations, and the utility of genome sequencing in understanding the mutational landscape in this population.

Introduction: Hepatocellular carcinoma (HCC) as the malignant cancers with high morbidity. The EMT of HCC has closely linked to the metastasis and recurrence. Moreover, tumor-associated macrophages (TAMs) can interact with HCC cells in the immune microenvironment; the M2 polarization of TAMs enhance the HCC cells EMT. The mechanism between HCC cells and TAMs is still unclear and our study was aimed to uncover it. Methods: We performed RT-qPCR and western to detach the RNA and protein expression. The relationship among has_circ_0000092, U2AF2, SMC1A and IL24 were revealed through mechanism experiments. Rescue assays were implemented to determine how circ_0000092 modulates M2 polarization of TAMs. Results: As detected by RT-qPCR, has_circ_0000092 was with high expression in HCC cells and could recruit U2AF2 to promote transcription of SMC1A. Moreover, circ_0000092 could control macrophage M2 polarization via promoting IL24 expression in HCC cells. Conclusion: To conclude, hsa_circ_0000092 can up-regulates IL24 by SMC1A to induce macrophages M2 polarization.

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with multisystemic involvement. The clinical presentation is highly variable, but the classic phenotype, characterized by distinctive craniofacial features, pre- and postnatal growth retardation, extremity reduction defects, hirsutism and intellectual disability can be distinguished from the nonclassic phenotype, which is generally milder and more difficult to diagnose. In addition, the clinical features overlap with those of other neurodevelopmental disorders, so the use of consensus clinical criteria and artificial intelligence tools may be helpful in confirming the diagnosis.Pathogenic variants in NIPBL, which encodes a protein related to the cohesin complex, have been identified in more than 60% of patients, and pathogenic variants in other genes related to this complex in another 15%: SMC1A, SMC3, RAD21, and HDAC8. Technical advances in large-scale sequencing have allowed the description of additional genes (BRD4, ANKRD11, MAU2), but the lack of molecular diagnosis in 15% of individuals and the substantial clinical heterogeneity of the syndrome suggest that other genes and mechanisms may be involved.Although there is no curative treatment, there are symptomatic/palliative treatments that paediatricians should be aware of. The main medical complication in classic SCdL is gastro-esophageal reflux (GER), which should be treated early. Resumen: El síndrome de Cornelia de Lange (SCdL) es un raro trastorno congénito del desarrollo de afectación multisistémica. Las manifestaciones clínicas son muy variables, pero se distingue entre un fenotipo clásico, caracterizado por unos rasgos craneofaciales distintivos, retraso del crecimiento pre y postnatal, defectos por reducción de las extremidades, hirsutismo y discapacidad intelectual y un fenotipo no clásico, generalmente más leve y más difícil de diagnosticar. Además, las características clínicas se superponen con las de otros desordenes del neurodesarrollo, por lo que la utilización de criterios clínicos consensuados y herramientas de inteligencia artificial pueden ser útiles para confirmar el diagnóstico.En más del 60% de los pacientes se han identificado variantes patogénicas en el gen NIPBL, que codifica una proteína relacionada con el complejo de la cohesina, y en otro 15% en 4 genes también asociados a este complejo: SMC1A, SMC3, RAD21 y HDAC8. Los progresos técnicos en las técnicas de secuenciación masiva han permitido describir otros genes relacionados (BRD4, ANKRD11 y MAU2), pero la ausencia de diagnóstico molecular en el 15% de los casos y la gran heterogeneidad clínica del síndrome, sugiere la existencia de otros genes y mecanismos relacionados.Aunque no haya un tratamiento curativo, sí hay tratamientos sintomáticos/paliativos que deben ser conocidos por el pediatra. La principal complicación médica en el SCdL clásico es el reflujo gastroesofágico (RGE), que debe ser tratado de forma precoz y contundente, ya que es una de las causas más frecuentes de fallecimiento en estos pacientes.

Abstract Background Cornelia de Lange (CdLS) is a rare genetic disorder that affects most body systems. Variants in multiple genes including NIPBL and SMC1A, can cause the syndrome. To date, literature on genotype–phenotype associations in individuals with CdLS is extremely limited, although studies suggest some differences in clinical phenotype severity across variants. This study aimed to examine and compare neurobehavioral differences and developmental variability across CdLS genes, specifically NIPBL and SMC1A, and identify genotype–phenotype correlations. Participants and methods This patient-reported outcomes study included accessing data from the Coordination of Rare Diseases registry at Sanford. Parents of a total of 26 children/adults with CdLS and a known variant in NIPBL (Mean age = 20.46 years, SD = 11.21) and 12 with a known variant in SMC1A (Mean age = 11.08 years, SD = 9.04) completed a series of questionnaires regarding their child’s developmental history. This included attainment of common language and motor milestones, intervention history, and behavior functioning. Developmental history and reported behavior regulation difficulties were compared across variant groups. Results Overall, individuals with a pathogenic variant in NIPBL or SMC1A were similarly delayed across motor and language milestones with about 70% not using phrase speech and 30–50% not walking by 5 years of age. However, those with NIPBL variants showed more severity in behavioral phenotype, namely with more repetitive behaviors, tantrums, and withdrawn behaviors. In addition, these individuals were more likely than those with SMC1A variants to demonstrate self-injurious behaviors, and anxiety. Both groups yielded a similar proportion of participants who participated in speech and occupational therapy, however those with SMC1A variants were more likely to engage in physical therapy. Both clinical groups report low rate of communicative or assistive device use despite a large proportion of participants never mastering single word or sentence use. Conclusions Study results are consistent with recent investigations highlighting more severe behavioral phenotype, particularly autistic features, anxiety, and behavior regulation challenges, among those with NIPBL variants albeit comparable developmental milestones. Both groups endorsed very elevated attention problems. Findings highlight importance of early interventions, including behavioral health services.

Background: Cornelia de Lange (CdLS) is a rare genetic disorder that affects most body systems. Variants in multiple genes including NIPBL and SMC1A, can cause the syndrome. To date, literature on genotype–phenotype associations in individuals with CdLS is extremely limited, although studies suggest some differences in clinical phenotype severity across variants. This study aimed to examine and compare neurobehavioral differences and developmental variability across CdLS genes, specifically NIPBL and SMC1A, and identify genotype–phenotype correlations. Participants and methods: This patient-reported outcomes study included accessing data from the Coordination of Rare Diseases registry at Sanford. Parents of a total of 26 children/adults with CdLS and a known variant in NIPBL (Mean age = 20.46 years, SD = 11.21) and 12 with a known variant in SMC1A (Mean age = 11.08 years, SD = 9.04) completed a series of questionnaires regarding their child's developmental history. This included attainment of common language and motor milestones, intervention history, and behavior functioning. Developmental history and reported behavior regulation difficulties were compared across variant groups. Results: Overall, individuals with a pathogenic variant in NIPBL or SMC1A were similarly delayed across motor and language milestones with about 70% not using phrase speech and 30–50% not walking by 5 years of age. However, those with NIPBL variants showed more severity in behavioral phenotype, namely with more repetitive behaviors, tantrums, and withdrawn behaviors. In addition, these individuals were more likely than those with SMC1A variants to demonstrate self-injurious behaviors, and anxiety. Both groups yielded a similar proportion of participants who participated in speech and occupational therapy, however those with SMC1A variants were more likely to engage in physical therapy. Both clinical groups report low rate of communicative or assistive device use despite a large proportion of participants never mastering single word or sentence use. Conclusions: Study results are consistent with recent investigations highlighting more severe behavioral phenotype, particularly autistic features, anxiety, and behavior regulation challenges, among those with NIPBL variants albeit comparable developmental milestones. Both groups endorsed very elevated attention problems. Findings highlight importance of early interventions, including behavioral health services. [ABSTRACT FROM AUTHOR]

Objective: To explore the electroencephalogram (EEG) and clinical characteristics of childhood bathing epilepsy. Methods: We conducted a prospective summary of the clinical data from 10 children with bathing epilepsy who were admitted to Hunan Children's Hospital from April 2019 to November 2023 and analyzed their EEGs and clinical characteristics. Results: Our 10 patients included eight males and two females, with seizureonset ages ranging from 4 months and 20 days to 14 months. Nine cases showed normal intellectual development, and one case manifested delayed development. The Video-EEG (VEEG) findings showed that nine cases exhibited normal background with no interictal epileptic discharge. The seizures were characterized by lip cyanosis, tachycardia or bradycardia, weakness, paleness, and loss of consciousness. Ictal EEG revealed rhythmic fast waves, spike waves, spike-slow waves, or slow and sharp-wave activity over the temporal region (eight cases) or the occipital and temporal regions (one case), finally evolving into a delta rhythm that lasted for 57-201 s. These children exhibited no seizures after discontinuing bathing and were not administered antiseizure medication. The interictal EEG of one case reflected mild slow background and focal interictal epileptic discharge; and her semiology was eyes gazing to right, with clonic movements of the right face and lips, lip cyanosis, bradycardia, and impaired consciousness. Ictal EEG showed spike-wave and spike-slow-wave rhythms over the left central, parietal, and temporal regions; these then spread to the left hemisphere, lasting for approximately 104 s. This patient did not exhibit bathing seizures after stopping her bathing but later experienced frequent spontaneous and drug-resistant seizures. The interictal EEG background slowed down, while focal epileptic discharge increased. Her intellectual development was significantly delayed, and a novel pathogenic mutation in the SMC1A gene, c.298+2T>C, was detected. She was diagnosed with developmental and epileptic encephalopathy. Conclusion: A majority of children with bathing epilepsy in our study showed focal autonomic seizures accompanied by impaired consciousness. Stopping bathing could control the seizures and showed a good prognosis. A few infants manifested a poor prognosis, and we posit that bathing seizure rarely constitute the early manifestations of developmental and epileptic encephalopathy. VEEG findings and clinical features can also indicate the prognosis. [ABSTRACT FROM AUTHOR]

Abstract Background SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC. Methods At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo. Results We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes. Conclusions These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC.

Background: SMC1A is a subunit of the cohesin complex that participates in many DNA- and chromosome-related biological processes. Previous studies have established that SMC1A is involved in cancer development and in particular, is overexpressed in chromosomally unstable human colorectal cancer (CRC). This study aimed to investigate whether SMC1A could serve as a therapeutic target for CRC. Methods: At first, we studied the effects of either SMC1A overexpression or knockdown in vitro. Next, the outcome of SMC1A knocking down (alone or in combination with bevacizumab, a monoclonal antibody against vascular endothelial growth factor) was analyzed in vivo. Results: We found that SMC1A knockdown affects cell proliferation and reduces the ability to grow in anchorage-independent manner. Next, we demonstrated that the silencing of SMC1A and the combo treatment were effective in increasing overall survival in a xenograft mouse model. Functional analyses indicated that both treatments lead to atypical mitotic figures and gene expression dysregulation. Differentially expressed genes were implicated in several pathways including gene transcription regulation, cellular proliferation, and other transformation-associated processes. Conclusions: These results indicate that SMC1A silencing, in combination with bevacizumab, can represent a promising therapeutic strategy for human CRC. [ABSTRACT FROM AUTHOR]

Background: Upregulation of SMC1A (Structural maintenance of chromosomes 1A) is linked with many types of cancer and its oncogenic function, which has been associated with crucial cellular mechanisms (cell division, cell cycle checkpoints regulation and DNA repair). Recent studies have shown that SMC1A was involved in breast cancer, although the exact mechanisms of SMC1A remain to be determined. Methods: Using The Cancer Genome Atlas (TCGA) database, we examined SMC1A expression and its relation to other genes, including FOXM1 and STMN1. Short hairpin RNA was used to subsequently examine the biological roles of SMC1A in MDA‐MB‐231 and MDA‐MB‐468 cell lines. Bioinformatics were performed to identify the SMC1A‐related gene FOXM1. Results: Here, we used the TCGA database to show that SMC1A is overexpressed in breast cancer. Later investigations showed SMC1A's role in breast cancer cell survival, apoptosis and invasion. Using bioinformatics and western blot assays, we confirmed that FOXM1 acted as the downstream of SMC1A, and SMC1A knockdown significantly downregulated the FOXM1 expression via the AKT signal pathway. Interestingly, the inhibition effects induced by SMC1A downregulation could be reversed by FOXM1 overexpression. In the clinic, SMC1A expression is favorably linked with FOXM1 expression in breast cancer tumor tissues. Conclusions: Collectively, our results not only enhance our knowledge of SMC1A's molecular pathways in breast cancer, but also suggest a potential new therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract Background Liver cancer is a highly malignant disease and the third leading cause of cancer death worldwide. Abnormal activation of PI3K/Akt signaling is common in cancer, but whether phosphoinositide‐3‐kinase regulatory subunit 3 (PIK3R3) plays a role in liver cancer is largely unexplored. Methods We determined the expression of PIK3R3 in liver cancer by using TCGA data and our clinical samples and knocked it down by siRNA or overexpressing it by the lentivirus vector system. We also investigated the function of PIK3R3 by colony formation, 5‐Ethynyl‐2‐Deoxyuridine, flow cytometry assay, and subcutaneous xenograft model. The downstream of PIK3R3 was explored by RNA sequence and rescue assays. Results We found that PIK3R3 was significantly upregulated in liver cancer and correlated with prognosis. PIK3R3 promoted liver cancer growth in vitro and in vivo by controlling cell proliferation and cell cycle. RNA sequence revealed that hundreds of genes were dysregulated upon PIK3R3 knockdown in liver cancer cells. CDKN1C, a cyclin‐dependent kinase inhibitor, was significantly upregulated by PIK3R3 knockdown, and CDKN1C siRNA rescued the impaired tumor cell growth. SMC1A was partially responsible for PIK3R3 regulated function, and SMC1A overexpression rescued the impaired tumor cell growth in liver cancer cells. Immunoprecipitation demonstrated there is indirect interaction between PIK3R3 and CNKN1C or SMC1A. Importantly, we verified that PIK3R3‐activated Akt signaling determined the expression of CDKN1C and SMC1A, two downstream of PIK3R3 in liver cancer cells. Conclusion PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDNK1C and SMC1A. Targeting PIK3R3 could be a promising treatment strategy for liver cancer that deserves further investigation.

Abstract Background Our previous study suggested that SMC1 has significant functions in colorectal cancer (CRC). However, few reports have shown the effects of structural maintenance of chromosomes 1 (SMC1A) on the immune microenvironment and tumor stem cells. Methods The Cancer Genome Atlas (TCGA) database, CPTAC database, Human Protein Atlas (HPA) database, the Cancer Cell Line Encyclopedia (CCLE) and Tumor Immune Single‐cell Hub were used. Flow cytometry and immunohistochemical analysis were checked for immune infiltration on MC38 mice model. Human CRC tissues were tested with RT‐qPCR. Results The mRNA and protein levels of SMC1A were increased in colon adenocarcinoma (COAD) samples. SMC1A was associated with DNA activity. Interestingly, SMC1A was highly expressed in many types of immune cells at single‐cell levels. Moreover, the high expression of SMC1A was positively correlated with immune infiltration, and immunohistochemical analysis showed that SMC1A was positively associated with CD45 expression in MC38 mice model. Also, the percentage of IL4+CD4+ T cells (Th2) and FoxP3+CD4+ T cells (Tregs) was significantly higher in the SMC1A overexpression group than in control by flow cytometry assay in vivo. SMC1A expression could affect the proliferation of T cells in the mice model. The mutation and somatic cell copy number variation (SCNV) of SMC1A were also associated with immune cell infiltration. In addition to SMC1A in the “hot” T‐cell inflammatory microenvironment of colon cancer, SMC1A also positively correlates with the immune checkpoint genes CD274, CTLA4, and PDCD1 in colon adenocarcinoma (COAD) samples. Furthermore, we also found that SMC1A plays a positive correlation with the induction of cancer stem cells (CSCs). Our results also showed that miR‐23b‐3p binds SMC1A. Conclusion SMC1A may be a bidirectional target switch that simultaneously regulates the immune microenvironment and tumor stem cells. Moreover, SMC1A may be a biomarker for the prediction of immune checkpoint inhibitor (ICI) therapy.

Structural maintenance of chromosome 1A (SMC1A) is a crucial compound of the cohesin complex. It has been reported to regulate the epithelial-mesenchymal transition (EMT) process in multiple cancers. Objectives: The present study aims to further clarify the role of SMC1A in cervical cancer. Methods: We analyzed data from four datasets and confirmed that SMC1A showed high expression in cervical cancer samples and was related to poor prognosis of patients with cervical cancer. Cell proliferation of SiHa and C-33A with knockdown of SMC1A was assessed using CCK-8 and colony formation assay. The migration and invasion were estimated by wound healing assay and Transwell assay separately. The effect of SMC1A on the chemosensitivity of cisplatin and paclitaxel in cervical cancer cells was detected by flow cytometry assay. Results: Results of the immunohistochemistry (IHC) assay confirmed that the expression of SMC1A was increased in tumor tissues. The cell viability was remarkably suppressed in SiHa and C-33A by knocking down the expression of SMC1A. The increase of E-cadherin expression and decrease of N-cadherin and Snail expression verified that inhibition of SMC1A suppressed the EMT process of cervical cancer cells. Further, cell migration, and invasion were significantly repressed by the absence of SMC1A. Cisplatin and paclitaxel are effective chemotherapeutic agents used in the treatment of cervical cancer. Silencing of SMC1A remarkably promoted the apoptosis induced by cisplatin and paclitaxel, revealing that the chemotherapy resistance to cisplatin and paclitaxel in cervical cancer could reduce by knocking down SMC1A. Further, metastasis associated with colon cancer 1 (MACC1) was identified as the downstream factor of SMC1A. Its upregulation reversed the proliferation and the EMT process induced by SMC1A silencing. Conclusion: Therefore, our study concluded that SMC1A serves as a therapeutic molecular target to regulate the malignant phenotypes of cervical cancer. [ABSTRACT FROM AUTHOR]

Background: Liver cancer is a highly malignant disease and the third leading cause of cancer death worldwide. Abnormal activation of PI3K/Akt signaling is common in cancer, but whether phosphoinositide‐3‐kinase regulatory subunit 3 (PIK3R3) plays a role in liver cancer is largely unexplored. Methods: We determined the expression of PIK3R3 in liver cancer by using TCGA data and our clinical samples and knocked it down by siRNA or overexpressing it by the lentivirus vector system. We also investigated the function of PIK3R3 by colony formation, 5‐Ethynyl‐2‐Deoxyuridine, flow cytometry assay, and subcutaneous xenograft model. The downstream of PIK3R3 was explored by RNA sequence and rescue assays. Results: We found that PIK3R3 was significantly upregulated in liver cancer and correlated with prognosis. PIK3R3 promoted liver cancer growth in vitro and in vivo by controlling cell proliferation and cell cycle. RNA sequence revealed that hundreds of genes were dysregulated upon PIK3R3 knockdown in liver cancer cells. CDKN1C, a cyclin‐dependent kinase inhibitor, was significantly upregulated by PIK3R3 knockdown, and CDKN1C siRNA rescued the impaired tumor cell growth. SMC1A was partially responsible for PIK3R3 regulated function, and SMC1A overexpression rescued the impaired tumor cell growth in liver cancer cells. Immunoprecipitation demonstrated there is indirect interaction between PIK3R3 and CNKN1C or SMC1A. Importantly, we verified that PIK3R3‐activated Akt signaling determined the expression of CDKN1C and SMC1A, two downstream of PIK3R3 in liver cancer cells. Conclusion: PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDNK1C and SMC1A. Targeting PIK3R3 could be a promising treatment strategy for liver cancer that deserves further investigation. PIK3R3 is upregulated in liver cancer and activates Akt signaling to control cancer growth by regulation of CDNK1C and SMC1A.Targeting PIK3R3 could be a promising treatment strategy for liver cancer that deserves further investigation. [ABSTRACT FROM AUTHOR]

Background: Our previous study suggested that SMC1 has significant functions in colorectal cancer (CRC). However, few reports have shown the effects of structural maintenance of chromosomes 1 (SMC1A) on the immune microenvironment and tumor stem cells. Methods: The Cancer Genome Atlas (TCGA) database, CPTAC database, Human Protein Atlas (HPA) database, the Cancer Cell Line Encyclopedia (CCLE) and Tumor Immune Single‐cell Hub were used. Flow cytometry and immunohistochemical analysis were checked for immune infiltration on MC38 mice model. Human CRC tissues were tested with RT‐qPCR. Results: The mRNA and protein levels of SMC1A were increased in colon adenocarcinoma (COAD) samples. SMC1A was associated with DNA activity. Interestingly, SMC1A was highly expressed in many types of immune cells at single‐cell levels. Moreover, the high expression of SMC1A was positively correlated with immune infiltration, and immunohistochemical analysis showed that SMC1A was positively associated with CD45 expression in MC38 mice model. Also, the percentage of IL4+CD4+ T cells (Th2) and FoxP3+CD4+ T cells (Tregs) was significantly higher in the SMC1A overexpression group than in control by flow cytometry assay in vivo. SMC1A expression could affect the proliferation of T cells in the mice model. The mutation and somatic cell copy number variation (SCNV) of SMC1A were also associated with immune cell infiltration. In addition to SMC1A in the "hot" T‐cell inflammatory microenvironment of colon cancer, SMC1A also positively correlates with the immune checkpoint genes CD274, CTLA4, and PDCD1 in colon adenocarcinoma (COAD) samples. Furthermore, we also found that SMC1A plays a positive correlation with the induction of cancer stem cells (CSCs). Our results also showed that miR‐23b‐3p binds SMC1A. Conclusion: SMC1A may be a bidirectional target switch that simultaneously regulates the immune microenvironment and tumor stem cells. Moreover, SMC1A may be a biomarker for the prediction of immune checkpoint inhibitor (ICI) therapy. [ABSTRACT FROM AUTHOR]

The X-linked SMC1A gene encodes a core subunit of the cohesin complex that plays a pivotal role in genome organization and gene regulation. Pathogenic variants in SMC1A are often dominant-negative and cause Cornelia de Lange syndrome (CdLS) with growth retardation and typical facial features; however, rare SMC1A variants cause a developmental and epileptic encephalopathy (DEE) with intractable early-onset epilepsy that is absent in CdLS. Unlike the male-to-female ratio of 1:2 in those with CdLS associated with dominant-negative SMC1A variants, SMC1A-DEE loss-of-function (LOF) variants are found exclusively in females due to presumed lethality in males. It is unclear how different SMC1A variants cause CdLS or DEE. Here, we report on phenotypes and genotypes of three females with DEE and de novo SMC1A variants, including a novel splice-site variant. We also summarize 41 known SMC1A-DEE variants to characterize common and patient-specific features. Interestingly, compared to 33 LOFs detected throughout the gene, 7/8 non-LOFs are specifically located in the N/C-terminal ATPase head or the central hinge domain, both of which are predicted to affect cohesin assembly, thus mimicking LOFs. Along with the characterization of X-chromosome inactivation (XCI) and SMC1A transcription, these variants strongly suggest that a differential SMC1A dosage effect of SMC1A-DEE variants is closely associated with the manifestation of DEE phenotypes. [ABSTRACT FROM AUTHOR]

As a component of N6-methyladenosine (m6A) “writers,” KIAA1429 was reported to promote breast cancer proliferation and growth in m6A-independent manners. However, the related mechanism of KIAA1429 in breast cancer metastasis has not been reported. In the present study, we found KIAA1429 could significantly promote the migration and invasion of breast cancer cells. Then we demonstrated that knockdown of KIAA1429 could impede breast cancer metastasis in nude mice in vivo. The level of SNAIL expression and epithelial-mesenchymal transition (EMT) progress was positively related with KIAA1429. Furthermore, we confirmed that the suppression of cell migration, invasion, and EMT progress by knockdown of KIAA1429 could be reversed by the upregulation of SNAIL. However, structural maintenance of chromosomes 1A (SMC1A), not KIAA1429, bound with the SNAIL promoter region directly and promoted the transcription of SNAIL. Then we confirmed that KIAA1429 could bind to the motif in the 3′ UTR of SMC1A mRNA directly and enhance SMC1A mRNA stability. In conclusion, our study revealed a novel mechanism of the KIAA1429/SMC1A/SNAIL axis in the regulation of metastasis of breast cancer. Moreover, it first provided detailed investigation of how KIAA1429 regulated the targeted gene expression at posttranscriptional levels as an RNA binding protein unrelated to its m6A modification.

Developmental and epileptic encephalopathies (DEE) are conditions in which a mutated gene may cause abnormal functioning of the central nervous system, resulting in both encephalopathy and epileptogenesis. We present a case of a girl with a DEE characterized by a Rett-like phenotype in association with febrile and afebrile clusters of focal seizures. The girl presented typical development until the age of 18 months, followed by regression. The first febrile bilateral tonic-clonic seizure was observed at 30 months of age, and the following month seizures recurred in clusters of several episodes per day every 10 days. These seizures were characterized by behavioural arrest, emotional symptoms, head turning, and followed by bilateral tonic-clonic seizures. The administration of valproic acid and levetiracetam led to prolonged seizure control. However, from the age of 7 years, she had monthly recurrent clusters of focal seizures and non-convulsive status epilepticus which occurred at different ages. Brain and spinal cord MRI showed mild non-progressive hemispheric cerebellar atrophy. A next generation sequencing panel for epilepsy identified the de novo splicing mutation c.2973+1G>A of the SMC1A gene.

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (~13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk. [ABSTRACT FROM AUTHOR]

Pathogenic truncating variants in SMC1A , which is located on chromosome Xp11.2, are known to cause infantile-onset epilepsy and severe intellectual disability in girls. Several studies have reported a correlation between SMC1A truncations and seizure clustering; however, the associated electroencephalogram (EEG) patterns remain largely unknown. We investigated an 12-year-old girl who had developed epilepsy at the age of 4 months. The patient experienced unknown onset, tonic-clonic seizures that occurred in clusters several times a week. Her interictal EEG at the age of 2 years showed paroxysmal, generalized, high-amplitude slow waves, whereas epileptiform discharges were scarce. The patient's interictal EEG gradually deteriorated; at the age of 11 years, diffuse continuous spike-and-wave discharges were predominantly observed in the left temporal region and were particularly obvious in the awake state. Although the unknown onset, tonic seizures occurring weekly persisted under multiple antiepileptic medications, the patient did not experience seizure clustering since the age of 9 years. Whole-genome sequencing revealed a de novo known nonsense variant in SMC1A (c.2923C > T, p.R975*). Our patient presented with a mild abnormality in the interictal EEG during infancy and early childhood despite frequent seizure clustering. Notably, the patient's EEG findings gradually deteriorated over time, which was inconsistent with the amelioration of seizure clustering. [ABSTRACT FROM AUTHOR]

Ultimate advances in genetic technologies have permitted the detection of transmitted cases of congenital diseases due to parental gonadosomatic mosaicism. Regarding Cornelia de Lange syndrome (CdLS), up to date, only a few cases are known to follow this inheritance pattern. However, the high prevalence of somatic mosaicism recently reported in this syndrome (∼13%), together with the disparity observed in tissue distribution of the causal variant, suggests that its prevalence in this disorder could be underestimated. Here, we report a new case of parental gonadosomatic mosaicism in SMC1A gene that causes inherited CdLS, in which the mother of the patient carries the causative variant in very low allele frequencies in buccal swab and blood. While the affected child presents with typical CdLS phenotype, his mother does not show any clinical manifestations. As regards SMC1A, the difficulty of clinical identification of carrier females has been already recognized, as well as the gender differences observed in CdLS expressivity when the causal variant is found in this gene. Currently, the use of DNA deep-sequencing techniques is highly recommended when it comes to molecular diagnosis of patients, as well as in co-segregation studies. These enable us to uncover gonadosomatic mosaic events in asymptomatic or oligosymptomatic parents that had been overlooked so far, which might have great implications regarding genetic counseling for recurrence risk.

Adult stem and progenitor cells are critical for replenishing lost tissue due to injury or normal turnover. How these cells maintain self-renewal and sustain the tissue they populate are areas of active investigation. Here, we show that the cohesin complex, which has previously been implicated in regulating chromosome segregation and gene expression, is necessary to promote epidermal stem and progenitor cell self-renewal through cell-autonomous mechanisms. Cohesin binds to genomic sites associated with open chromatin, including DNase-I-hypersensitive sites, RNA polymerase II, and histone marks such as H3K27ac and H3K4me3. Reduced cohesin expression results in spontaneous epidermal differentiation due to loss of open chromatin structure and expression of key self-renewal genes. Our results demonstrate a prominent role for cohesin in modulating chromatin structure to allow for enforcement of a stem and progenitor cell gene expression program.

Cornelia de Lange syndrome (CdLS) is a spectrum disorder due to variants in genes of the cohesin protein complex. The following abstracts are from the Cornelia de Lange Syndrome Scientific and Educational Symposium held virtually in October 2020. Aspects of behavior, including autistic features, impulsivity, adaptive skills, executive function, and anxiety are described. Applied behavioral analysis is a promising approach for autism, and an N‐acetylcysteine trial is proposed. Children below 6 years with CdLS have an increased number of and further travel to medical providers, with insurance type comprising a significant barrier. Speech, language, and feeding abilities fall significantly below expectations for age in CdLS. Augmentative alternative communication can yield potential barriers as well as interesting benefits. Developmentally, studies in animal models further elucidate the mechanisms and roles of cohesin: link with mediator transcriptional complex; facilitation of enhancer‐promoter communication; regulation of gene expression; allocation of cells to germ layers; and repair of spontaneous DNA damage in placental cells. Genome and RNA sequencing can help identify the molecular cause in the 20% of individuals with suspected CdLS and negative testing. The phenotypes in individuals with variants in the SMC1A gene are distinct, and that with intractable seizures has been further evaluated. AMA CME credits provided by GBMC, Baltimore, MD. All studies approved by an ethics committee. [ABSTRACT FROM AUTHOR]

SMC1A variants are known to cause Cornelia de Lange Syndrome (CdLS) which encompasses a clinical spectrum of intellectual disability, dysmorphic features (long or thick eyebrows, a hypomorphic philtrum and small nose) and, in some cases, epilepsy. More recently, SMC1A truncating variants have been described as the cause of a neurodevelopmental disorder with early-childhood onset drug-resistant epilepsy with seizures that occur in clusters, similar to that seen in PCDH19-related epilepsy, but without the classical features of CdLS. Here, we report the case of a 28-year-old woman with a de novo heterozygous truncating variant in SMC1A who unusually presented with seizures at the late age of 12 years and had normal development into adulthood.

Introduction: Hepatocellular carcinoma (HCC) as the malignant cancers with high morbidity. The EMT of HCC has closely linked to the metastasis and recurrence. Moreover, tumor-associated macrophages (TAMs) can interact with HCC cells in the immune microenvironment; the M2 polarization of TAMs enhance the HCC cells EMT. The mechanism between HCC cells and TAMs is still unclear and our study was aimed to uncover it., Methods: We performed RT-qPCR and western to detach the RNA and protein expression. The relationship among has_circ_0000092, U2AF2, SMC1A and IL24 were revealed through mechanism experiments. Rescue assays were implemented to determine how circ_0000092 modulates M2 polarization of TAMs., Results: As detected by RT-qPCR, has_circ_0000092 was with high expression in HCC cells and could recruit U2AF2 to promote transcription of SMC1A. Moreover, circ_0000092 could control macrophage M2 polarization via promoting IL24 expression in HCC cells., Conclusion: To conclude, hsa_circ_0000092 can up-regulates IL24 by SMC1A to induce macrophages M2 polarization., Competing Interests: The authors declare that they have no conflict of interest., (© 2024 The Authors.)

Near-haploidization, that is, loss of one copy of most chromosomes, is a relatively rare phenomenon in most tumors, but is enriched among certain soft tissue sarcomas, including undifferentiated pleomorphic sarcoma (UPS). Presumably, near-haploidization can arise through many mechanisms. This study aimed to identify gene rearrangements that could cause near-haploidization. We here present two UPS in which near-haploidization was an early event, identified through single nucleotide polymorphism (SNP) array analysis. One of the cases was studied further using whole genome and transcriptome sequencing, as well as cytogenetic and molecular cytogenetic methods. Both tumors had chromosomal rearrangements in the form of copy number shifts/structural variants affecting the SMC1A gene. These findings suggest that cohesin defects could contribute to mitotic errors resulting in massive loss of chromosomes. SMC1A encodes one of the components of the cohesin multiprotein complex, which is critical for proper alignment of the sister chromatids during S-phase and separation to opposite spindle poles. Further studies should explore the role of cohesin defects in near-haploidization in other sarcomas and to clarify its role in tumor development., (© 2024 Wiley Periodicals LLC.)

Abstract Background Cancer cells are characterized by chromosomal instability (CIN) and it is thought that errors in pathways involved in faithful chromosome segregation play a pivotal role in the genesis of CIN. Cohesin forms a large protein ring that binds DNA strands by encircling them. In addition to this central role in chromosome segregation, cohesin is also needed for DNA repair, gene transcription regulation and chromatin architecture. Though mutations in both cohesin and cohesin-regulator genes have been identified in many human cancers, the contribution of cohesin to cancer development is still under debate. Methods Normal mucosa, early adenoma, and carcinoma samples deriving from 16 subjects affected by colorectal cancer (CRC) were analyzed by OncoScan for scoring both chromosome gains and losses (CNVs) and loss of heterozygosity (LOH). Then the expression of SMC1A was analyzed by immunochemistry in 66 subjects affected by CRC. The effects of SMC1A overexpression and mutated SMC1A were analyzed in vivo using immunocompromised mouse models. Finally, we measured global gene expression profiles in induced-tumors by RNA-seq. Results Here we showed that SMC1A cohesin core gene was present as extra-copies, mutated, and overexpressed in human colorectal carcinomas. We then demonstrated that cohesin overexpression led to the development of aggressive cancers in immunocompromised mice through gene expression dysregulation. Conclusion Collectively, these results support a role of defective cohesin in the development of human colorectal cancer.

Background & Objective: Nonsense mutations in SMC1A have been reported only in females with cluster seizures, all of whom have been described as drug-resistant epilepsy. Here, we aim to explore the use of ketogenic diet treatment. Methods: The clinical data of female patients with de novo nonsense mutations in SMC1A were collected and analyzed. The clinical data was recruited and analyzed. The peripheral blood of children and their parents was collected. The next generation sequencing was used to find suspected pathogenic mutations and all the confirmed mutations were verified by Sanger sequencing. Results: Three patients with heterozygous de novo mutations in SMC1A gene were reviewed. All patients were females, presenting with seizure onset at age between 2.5 to 11 months old. One patient had mild developmental delay. One had moderate developmental delay. Another had severe developmental retardation. None of the patients had a clinical diagnosis of Cornelia de Lange syndrome. All three patients had prominent clinical features of cluster seizures. All the nonsense mutations were predicted damaging SMC1A protein by PolyPhen-2 HVAR. All the patients were treated with multiple antiepileptic drugs but their seizures remained refractory. When initiated with ketogenic diet, they became seizure free within 3 to 4 weeks. Conclusion: SMC1A nonsense mutations can cause early onset epilepsy only in females with cluster seizures. These patients are characterized by drug-resistant epilepsy, but all our three patients have good effect on ketogenic diet add-on therapy. [ABSTRACT FROM AUTHOR]

Cornelia de Lange syndrome (CdLS) is a rare congenital developmental disorder with multisystemic involvement. The clinical presentation is highly variable, but the classic phenotype, characterized by distinctive craniofacial features, pre- and postnatal growth retardation, extremity reduction defects, hirsutism and intellectual disability can be distinguished from the nonclassic phenotype, which is generally milder and more difficult to diagnose. In addition, the clinical features overlap with those of other neurodevelopmental disorders, so the use of consensus clinical criteria and artificial intelligence tools may be helpful in confirming the diagnosis. Pathogenic variants in NIPBL, which encodes a protein related to the cohesin complex, have been identified in more than 60% of patients, and pathogenic variants in other genes related to this complex in another 15%: SMC1A, SMC3, RAD21, and HDAC8. Technical advances in large-scale sequencing have allowed the description of additional genes (BRD4, ANKRD11, MAU2), but the lack of molecular diagnosis in 15% of individuals and the substantial clinical heterogeneity of the syndrome suggest that other genes and mechanisms may be involved. Although there is no curative treatment, there are symptomatic/palliative treatments that paediatricians should be aware of. The main medical complication in classic SCdL is gastro-esophageal reflux (GER), which should be treated early., (Copyright © 2024 Asociación Española de Pediatría. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Due to extensive clinical and genetic heterogeneity of intellectual disability (ID) syndromes, the process of diagnosis is very challenging even for expert clinicians. Despite recent advancements in molecular diagnostics methodologies, a significant fraction of ID patients remains without a clinical diagnosis. Methods, results, and conclusions: Here, in a prospective study on a cohort of 21 families (trios) with a child presenting with ID of unknown etiology, we executed phenotype‐driven bioinformatic analysis method, PhenIX, utilizing targeted next‐generation sequencing (NGS) data and Human Phenotype Ontology (HPO)‐encoded phenotype data. This approach resulted in clinical diagnosis for eight individuals presenting with atypical manifestations of Rubinstein–Taybi syndrome 2 (MIM 613684), Spastic Paraplegia 50 (MIM 612936), Wiedemann–Steiner syndrome (MIM 605130), Cornelia de Lange syndrome 2 (MIM 300590), Cerebral creatine deficiency syndrome 1 (MIM 300352), Glass Syndrome (MIM 612313), Mental retardation, autosomal dominant 31 (MIM 616158), and Bosch–Boonstra–Schaaf optic atrophy syndrome (MIM 615722). [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is a common malignant tumor of the urinary system in males. LncRNA taurine-upregulated gene 1 (TUG1) has been verified to play a crucial role in progression and prognosis of PCa. However, the functional mechanism of TUG1 remains unclear with radiosensitivity of PCa. Methods: Quantitative real-time PCR (qRT-PCR) was conducted to measure the transcription levels of genes. 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay and flow cytometry analysis were employed to assess cell proliferation and apoptosis, respectively. Moreover, colony formation assay was used to measure colony survival. Western blot was performed to detect the relative proteins expression. The interaction among variables was predicted by online tool starbase, and then confirmed using the dual luciferase reporter assay. A xenograft mouse model was constructed to investigate the effect of TUG1 on tumor growth in vivo. Results: The levels of lncRNA TUG1 and SMC1A were remarkably increased, while miR-139-5p was downregulated in PCa. Patients with high expression of TUG1 showed a lower survival rate and poor prognosis. Knockdown of TUG1 inhibited PCa cell proliferation and colony survival fraction, and promoted apoptosis. Downregulation of miR-139-5p reversed the effects of TUG1 deletion on proliferation, apoptosis and colony survival fraction in PCa cells treated with 4 Gy of X-ray radiation. Moreover, TUG1 sponged miR-139-5p to regulate SMC1A expression. SMC1A deletion blocked the effects of TUG1 on the progression of PCa cells treated with 4 Gy of X-ray radiation. The tumor volume and weight were illustriously reduced with radiation and TUG1 silencing in xenograft model. Conclusion: Knockdown of lncRNA TUG1 enhanced radiosensitivity in PCa via the TUG1/miR-139-5p/SMC1A axis. It may become a promising target for PCa treatment. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) with NPM1 mutation is a disease driving genetic alteration with good prognosis. Although it has been suggested that NPM1 mutation induces chemosensitivity in leukemic cells, the underlying cause for the better survival of NPM1 mutated patients is still not clear. Mutant NPM1 AML has a unique microRNA and their target gene (mRNA) signature compared to wild-type NPM1. Dynamic regulation of miRNA‐mRNA has been reported to influence the prognostic outcome. In the present study, in silico expression data of miRNA and mRNA in AML patients was retrieved from genome data commons, and differentially expressed miRNA and mRNA among NPM1 mutated (n = 21) and NPM1 wild-type (n = 162) cases were identified to establish a dynamic association at the molecular level. In vitro experiments using high-throughput RNA sequencing were performed on human AML cells carrying NPM1 mutated and wild-type allele. The comparison of in vitro transcriptomics data with in silico miRNA‐mRNA expression network data revealed downregulation of SMC1A. On establishing miRNA‐mRNA interactive pairs, it has been observed that hsa-mir-215-5p (logFC: 0.957; p = 0.0189) is involved in the downregulation of SMC1A (logFC: ‐0.481; p = 0.0464) in NPM1 mutated AML. We demonstrated that transient expression of NPM1 mutation upregulates miR-215-5p, which results in downregulation of SMC1A. We have also shown using a rescue experiment that neutralizing miR-215-5p reverses the effect of NPM1 mutation on SMC1A. Using the leukemic blasts from AML patients, we observed higher expression of miR-215-5p and lower expression of SMC1A in NPM1 mutated patients compared to wild-type cases. The overall survival of AML patients was significantly inferior in SMC1A high expressers compared to low expressers (20.3% vs. 58.5%, p = 0.018). The data suggest that dynamic miR-215- SMC1A regulation is potentially modulated by NPM1 mutation, which might serve as an explanation for the better outcome in NPM1 mutated AML. [ABSTRACT FROM AUTHOR]

Adult stem and progenitor cells are critical for replenishing lost tissue due to injury or normal turnover. How these cells maintain self-renewal and sustain the tissue they populate are areas of active investigation. Here, we show that the cohesin complex, which has previously been implicated in regulating chromosome segregation and gene expression, is necessary to promote epidermal stem and progenitor cell self-renewal through cell-autonomous mechanisms. Cohesin binds to genomic sites associated with open chromatin, including DNase-I-hypersensitive sites, RNA polymerase II, and histone marks such as H3K27ac and H3K4me3. Reduced cohesin expression results in spontaneous epidermal differentiation due to loss of open chromatin structure and expression of key self-renewal genes. Our results demonstrate a prominent role for cohesin in modulating chromatin structure to allow for enforcement of a stem and progenitor cell gene expression program.

Objective: To explore the electroencephalogram (EEG) and clinical characteristics of childhood bathing epilepsy., Methods: We conducted a prospective summary of the clinical data from 10 children with bathing epilepsy who were admitted to Hunan Children's Hospital from April 2019 to November 2023 and analyzed their EEGs and clinical characteristics., Results: Our 10 patients included eight males and two females, with seizure-onset ages ranging from 4 months and 20 days to 14 months. Nine cases showed normal intellectual development, and one case manifested delayed development. The Video-EEG (VEEG) findings showed that nine cases exhibited normal background with no interictal epileptic discharge. The seizures were characterized by lip cyanosis, tachycardia or bradycardia, weakness, paleness, and loss of consciousness. Ictal EEG revealed rhythmic fast waves, spike waves, spike-slow waves, or slow and sharp-wave activity over the temporal region (eight cases) or the occipital and temporal regions (one case), finally evolving into a delta rhythm that lasted for 57-201 s. These children exhibited no seizures after discontinuing bathing and were not administered antiseizure medication. The interictal EEG of one case reflected mild slow background and focal interictal epileptic discharge; and her semiology was eyes gazing to right, with clonic movements of the right face and lips, lip cyanosis, bradycardia, and impaired consciousness. Ictal EEG showed spike-wave and spike-slow-wave rhythms over the left central, parietal, and temporal regions; these then spread to the left hemisphere, lasting for approximately 104 s. This patient did not exhibit bathing seizures after stopping her bathing but later experienced frequent spontaneous and drug-resistant seizures. The interictal EEG background slowed down, while focal epileptic discharge increased. Her intellectual development was significantly delayed, and a novel pathogenic mutation in the SMC1A gene, c.298+2T>C, was detected. She was diagnosed with developmental and epileptic encephalopathy., Conclusion: A majority of children with bathing epilepsy in our study showed focal autonomic seizures accompanied by impaired consciousness. Stopping bathing could control the seizures and showed a good prognosis. A few infants manifested a poor prognosis, and we posit that bathing seizure rarely constitute the early manifestations of developmental and epileptic encephalopathy. VEEG findings and clinical features can also indicate the prognosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kuang, Liao, Fang, Zhang, Wang, Yang and Wu.)

Ｏｂｊｅｃｔｉｖｅ 　Ｔｏ ｉｎｖｅｓｔｉｇａｔｅ ｔｈｅ ｅｆｆｅｃｔｓ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ｏｎ ｐｒｏｌｉｆｅｒａｔｉｏｎ， ｍｉｇｒａｔｉｏｎ ａｎｄ ａｐｏｐｔｏｓｉｓ ｏｎ ｈｕｍａｎ ａｃｕｔｅ ｍｙｅｌｏｉｄ ｌｅｕｋｅｍｉａ （ＡＭＬ） ｃｅｌｌｓ ｂｙ ｔａｒｇｅｔｉｎｇ ＳＭＣ１Ａ． Ｍｅｔｈｏｄｓ 　Ｍｉｃｒｏａｒｒａｙ ａｎａｌｙｓｉｓ ｗａｓ ｕｓｅｄ ｔｏ ｓｃｒｅｅｎ ｄｉｆｆｅｒｅｎｔｉａｌｌｙ ｅｘｐｒｅｓｓｅｄ ｍｉｃｒｏＲＮＡｓ ａｎｄ ｍＲＮＡｓ ｉｎ ｈｕｍａｎ ＡＭＬ ｃｅｌｌｓ． Ｒｅａｌ⁃ｔｉｍｅ ｆｌｕｏｒｅｓｃｅｎｃｅ ｑｕａｎｔｉｔａｔｉｖｅ ＰＣＲ （ＲＴ⁃ｑＲＣＲ） ｗａｓ ｕｓｅｄ ｔｏ ｄｅｔｅｃｔ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎｓ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ａｎｄ ＳＭＣＡ ｉｎ ｈｕｍａｎ ＡＭＬ ｃｅｌｌ ｌｉｎｅ Ｕ９３７． ＴａｒｇｅｔＳｃａｎ ｄａｔａｂａｓｅ ｗａｓ ｕｓｅｄ ｔｏ ａｎａｌｙｚｅ ｔｈｅ ｃｏｒｒｅｌａｔｉｏｎ ｂｅｔｗｅｅｎ ｍｉＲ⁃２３ａ⁃３ｐ ａｎｄ ＳＭＣ１Ａ． Ｄｏｕｂｌｅ ｌｕｃｉｆｅｒａｓｅ ｒｅｐｏｒｔｅｒ ｇｅｎｅ ｗａｓ ｕｓｅｄ ｔｏ ｄｅｔｅｃｔ ｔｈｅ ｉｎｔｅｒａｃｔｉｏｎ ｂｅｔｗｅｅｎ ｍｉＲ⁃２３ａ⁃３ｐ ａｎｄ ＳＭＣ１Ａ． Ｔｈｅ ｅｆｆｅｃｔ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ｅｘｐｒｅｓｓｉｏｎ ｏｎ ｔｈｅ ｐｒｏｌｉｆｅｒａｔｉｏｎ ｏｆ Ｕ９３７ ｃｅｌｌｓ ｗａｓ ｄｅｔｅｃｔｅｄ ｂｙ ｃｌｏｎａｌ ａｓｓａｙ． Ｔｈｅ ｍｉｇｒａｔｉｏｎ， ａｐｏｐｔｏｓｉｓ， ｃｅｌｌ ｃｙｃｌｅ ａｎｄ ｃａｓｐａｓｅ⁃３ ａｃｔｉｖｉｔｙ ｏｆ Ｕ９３７ ｃｅｌｌｓ ｒｅｇｕｌａｔｅｄ ｂｙ ｍｉＲ⁃２３ａ⁃３ｐ ｗｅｒｅ ｄｅｔｅｃｔｅｄ ｂｙ ｃｅｌｌ ｓｃｒａｔｃｈ ａｓｓａｙ ａｎｄ ｆｌｏｗ ｃｙｔｏｍｅｔｒｙ， ｒｅｓｐｅｃｔｉｖｅｌｙ． Ｗｅｓｔｅｒｎ ｂｌｏｔ ｗａｓ ｕｓｅｄ ｔｏ ｄｅｔｅｃｔ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎｓ ｏｆ Ｂａｘ ａｎｄ Ｂｃｌ⁃２ ｉｎ Ｕ９３７ ｃｅｌｌｓ． Ｒｅｓｕｌｔｓ　Ｃｏｍｐａｒｅｄ ｗｉｔｈ ｈｕｍａｎ ｎｏｒｍａｌ ｍｏｎｏｃｙｔｅ ＳＣ ｇｒｏｕｐ （１．００）， ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ｉｎ Ｕ９３７ ｃｅｌｌｓ ｗａｓ ｕｐ⁃ｒｅｇｕｌａｔｅｄ （２．５６±０．７８） （Ｐ＜０．０１）， ｗｈｉｌｅ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ｏｆ ＳＭＣ１Ａ ｗａｓ ｄｏｗｎ⁃ｒｅｇｕｌａｔｅｄ （０．４８±０．５６， Ｐ＜０．０１）． ｍｉＲ⁃２３ａ⁃３ｐ ｓｐｅｃｉｆｉｃａｌｌｙ ｂｏｎｄ ｔｏ ＳＭＣ１Ａ ３′ＵＴＲ ａｎｄ ｒｅｇｕｌａｔｅｄ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ａｃｔｉｖｉｔｙ ｏｆ ＳＭＣ１Ａ． Ｏｖｅｒｅｘｐｒｅｓｓｉｏｎ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ｐｒｏｍｏｔｅｄ ｔｈｅ ｐｒｏｌｉｆｅｒａｔｉｏｎ ａｎｄ ｍｉｇｒａｔｉｏｎ ｏｆ Ｕ９３７ ｃｅｌｌｓ ａｎｄ ｉｎｈｉｂｉｔｅｄ ｔｈｅ ａｐｏｐｔｏｓｉｓ ｏｆ Ｕ９３７ ｃｅｌｌｓ， ｗｈｉｌｅ ｕｐ⁃ｒｅｇｕｌａｔｉｏｎ ｏｆ ＳＭＣ１Ａ ｉｎｈｉｂｉｔｅｄ ｔｈｅ ｐｒｏｌｉｆｅｒａｔｉｏｎ ａｎｄ ｍｉｇｒａｔｉｏｎ ｏｆ Ｕ９３７ ｃｅｌｌｓ ａｎｄ ｐｒｏｍｏｔｅｄ ｔｈｅ ａｐｏｐｔｏｓｉｓ ｏｆ Ｕ９３７ ｃｅｌｌｓ． Ｔｈｅ ｐｅｒｃｅｎｔａｇｅｓ ｏｆ Ｇ０ ／ Ｇ１ ｐｈａｓｅ， Ｇ２ ／ Ｍ ｐｈａｓｅ ａｎｄ Ｓ ｐｈａｓｅ ｃｅｌｌｓ ｉｎ ｔｈｅ ｎｅｇａｔｉｖｅ ｃｏｎｔｒｏｌ ｇｒｏｕｐ ｗｅｒｅ （３７．４８± ０．２１）％， （１６．７８±０．１８）％ ａｎｄ （４５．７４±０．１５）％ ｒｅｓｐｅｃｔｉｖｅｌｙ， ａｎｄ ｔｈｏｓｅ ｉｎ ｔｈｅ ｍｉＲ⁃２３ａ⁃３ｐ ｍｉｍｉｃｓ ｇｒｏｕｐ ｗｅｒｅ （１９．９６±０．１１）％， （４１．６９±０．２４）％ ａｎｄ （３８．２４±０．３４）％， ｒｅｓｐｅｃｔｉｖｅｌｙ． Ｔｈｅ ｄｉｆｆｅｒｅｎｃｅ ｗａｓ ｓｔａｔｉｓｔｉｃａｌｌｙ ｓｉｇｎｉｆｉｃａｎｔ （ａｌｌ Ｐ＜０．０５）． Ｔｈｅ ｐｒｏｐｏｒｔｉｏｎｓ ｏｆ Ｇ０ ／ Ｇ１ ｐｈａｓｅ， Ｇ２ ／ Ｍ ｐｈａｓｅ ａｎｄ Ｓ ｐｈａｓｅ ｃｅｌｌｓ ｉｎ ｔｈｅ ｇｒｏｕｐ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ｍｉｍｉｃｓ＋ｐｃＤＮＡ３．１⁃ＳＭＣ１Ａ ｗｅｒｅ （３６．８８±０．２１）％， （３０．４４±０．３３）％ ａｎｄ （３２．８８±０．１６）％， ｒｅｓｐｅｃｔｉｖｅｌｙ， ｗｉｔｈｏｕｔ ｓｉｇｎｉｆｉｃａｎｔ ｄｉｆｆｅｒｅｎｃｅ ｗｈｅｎ ｃｏｍｐａｒｅｄ ｗｉｔｈ ｔｈｏｓｅ ｏｆ ｔｈｅ ｍｉＲ⁃２３ａ⁃３ｐ ｍｉｍｉｃｓ ｇｒｏｕｐ （Ｐ＞ ０．０５）． Ｔｈｅ ｒｅｌａｔｉｖｅ ｅｘｐｒｅｓｓｉｏｎ ｌｅｖｅｌｓ ｏｆ Ｂａｘ ａｎｄ Ｂｃｌ⁃２ ｐｒｏｔｅｉｎ ｉｎ ｔｈｅ ｎｅｇａｔｉｖｅ ｃｏｎｔｒｏｌ ｇｒｏｕｐ ｗｅｒｅ ０．５５±０．４５ ａｎｄ ０．３１±０．５４， ｒｅｓｐｅｃｔｉｖｅｌｙ． Ｏｖｅｒｅｘｐｒｅｓｓｉｏｎ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ｉｎｈｉｂｉｔｅｄ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ｏｆ Ｂａｘ ｐｒｏｔｅｉｎ ｉｎ Ｕ９３７ ｃｅｌｌｓ （０．２３±０．１３， Ｐ＜０．００１）， ｐｒｏｍｏｔｅｄ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ｏｆ Ｂｃｌ⁃２ ｐｒｏｔｅｉｎ （０．５０±０．２３， Ｐ＜０．０１）， ｗｈｉｌｅ ＳＭＣ１Ａ ｉｎｃｒｅａｓｅｄ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ｏｆ Ｂａｘ ｐｒｏｔｅｉｎ ｉｎ Ｕ９３７ ｃｅｌｌｓ （０．４０±０．１１， Ｐ＜０．０１）， ａｎｄ ｉｎｈｉｂｉｔｅｄ ｔｈｅ ｅｘｐｒｅｓｓｉｏｎ ｏｆ Ｂｃｌ⁃２ ｐｒｏｔｅｉｎ （０．３７±０．１５）． Ｉｎ ｔｈｅ ｎｅｇａｔｉｖｅ ｃｏｎｔｒｏｌ ｇｒｏｕｐ， ｃａｓｐａｓｅ⁃３ ａｃｔｉｖｉｔｙ ｗａｓ （２５．８２± ０．８９）％． Ｏｖｅｒｅｘｐｒｅｓｓｉｏｎ ｏｆ ｍｉＲ⁃２３ａ⁃３ｐ ｉｎｈｉｂｉｔｅｄ ｃａｓｐａｓｅ⁃３ ａｃｔｉｖｉｔｙ ｉｎ Ｕ９３７ ｃｅｌｌｓ （３．６４±０．５６）％， Ｐ＜０．０１， ｗｈｉｌｅ ｕｐ⁃ｒｅｇｕｌａｔｉｏｎ ｏｆ ＳＭＣ１Ａ ｐｒｏｍｏｔｅｄ ｃａｓｐａｓｅ⁃３ ａｃｔｉｖｉｔｙ ｉｎ Ｕ９３７ ｃｅｌｌｓ （１５． ２９ ± ０． ８５）％， Ｐ ＜ ０． ０１． Ｃｏｎｃｌｕｓｉｏｎ　ｍｉＲ⁃２３ａ⁃３ｐ ｃａｎ ｉｎｈｉｂｉｔ ｔｈｅ ｐｒｏｌｉｆｅｒａｔｉｏｎ ａｎｄ ｍｉｇｒａｔｉｏｎ ａｎｄ ｐｒｏｍｏｔｅ ａｐｏｐｔｏｓｉｓ ｏｆ ｈｕｍａｎ ＡＭＬ ｃｅｌｌｓ ｂｙ ｔａｒｇｅｔｉｎｇ ＳＭＣ１Ａ． [ABSTRACT FROM AUTHOR]

Chronic myelomonocytic leukemia (CMML) is a rare malignant neoplasm of the blood-forming cells in bone marrow characterized by persistent monocytosis. Although most patients with CMML show clonal genetic aberrations, there is no known cytogenetic or molecular genetic finding that is specific to CMML. We report a patient who had a clinical and morphological presentation consistent with CMML. The genetic work-up showed an ETV6-ABL1 fusion consequent to a 9;12 translocation, and a missense mutation in SMC1A (c.1757G>A, p.Arg586Gln). The SMC1A mutations are recurrent, albeit rare, in myeloid malignancies, without an established clinical significance in CMML. ETV6-ABL1 fusion is a rare but recurrent genetic aberration found in various hematologic malignancies involving both the lymphoid and myeloid lineage, but to the best of our knowledge, CMML is an exceptionally rare presentation of ETV6-ABL1 rearranged neoplasm. ETV6-ABL1 fusion is often formed through complex rearrangements, and usually cryptic by routine G-banded chromosome analysis. The diseases associated with this rearrangement generally have an aggressive course, hence detecting or excluding this rearrangement during diagnostic work-up is critical for treatment planning. [ABSTRACT FROM AUTHOR]

The aim of this study was to determine the function of the NEAT1/miR‐23a‐3p/SMC1A axis in cell proliferation and apoptosis in acute myeloid leukemia (AML). Microarray analysis was used to screen differentially expressed lncRNAs/miRNAs/mRNAs in primary AML cells. The expression of nuclear paraspeckle assembly transcript 1 (NEAT1), miR‐23a‐3p, and structural maintenance of chromosome 1 alpha (SMC1A) in primary AML cells and THP‐1 cells were measured by quantitative real‐time polymerase chain reaction (qRT‐PCR). A Cell Counting Kit‐8 (CCK‐8) assay was used to analyze proliferation. Cell cycle progression and apoptosis were examined by flow cytometry. RNA immunoprecipitation (RIP) and dual‐luciferase assays were performed to determine the correlation between miR‐23a‐3p and NEAT1 or SMC1A. The qRT‐PCR illustrated that NEAT1 and SMC1A expression was decreased but that miR‐23a‐3p expression was increased in primary AML cells and THP‐1 cells compared with that in normal cells. The RIP assay and dual‐luciferase assay revealed the targeting relationship between miR‐23a‐3p and NEAT1 or SMC1A. The CCK‐8 assay showed that the overexpression of NEAT1 and SMC1A or repression of miR‐23a‐3p inhibited cell proliferation. Flow cytometry showed that the upregulation of NEAT1 and SMC1A or repression of miR‐23a‐3p promoted apoptosis and affected the cell cycle. NEAT1 repressed the expression of miR‐23a‐3p, and therefore promoted SMC1A, which in turn suppressed myeloid leukemia cell proliferation and enhanced apoptosis. 1.This study illustrates the molecular interaction between nuclear paraspeckle assembly transcript 1 (NEAT1), miR‐23a, and structural maintenance of chromosome 1 alpha (SMC1A) in acute myeloid leukemia (AML). 2.Reduced expression of NEAT1 induced the tumorigenesis and progression of AML through the miR‐23a‐3p/SMC1A axis. 3.These results suggest that this axis can be used as a promising therapeutic target to mitigate the progression of AML. [ABSTRACT FROM AUTHOR]

The differential diagnostics in Rett syndrome has evolved with the development of next generation sequencing‐based techniques and many patients have been diagnosed with other syndromes or variants in newly described genes where the associated phenotype(s) is yet to be fully explored. The term Rett‐like refers to phenotypes with distinct overlapping features of Rett syndrome where the clinical criteria are not completely fulfilled. In this study we have combined a review of Rett‐like disorders with data from a Danish cohort of 35 patients with Rett‐like phenotypes emphasizing the diagnostic overlap with Pitt‐Hopkins syndrome, Cornelia de Lange syndrome with SMC1A variants, and epileptic encephalopathies, for example, due to STXBP1 variants. We also found a patient with a pathogenic variant in KCNB1, which has not been previously linked to a Rett‐like phenotype. This study underlines the clinical and genetic heterogeneity of a Rett syndrome spectrum, and provides an overview of the Rett syndrome‐related genes described to date, and hence serves as a guide for diagnosing patients with Rett‐like phenotypes. Exploring the genes in Rett‐like phenotypes. [ABSTRACT FROM AUTHOR]

Developmental and epileptic encephalopathies (DEE) are conditions in which a mutated gene may cause abnormal functioning of the central nervous system, resulting in both encephalopathy and epileptogenesis. We present a case of a girl with a DEE characterized by a Rett-like phenotype in association with febrile and afebrile clusters of focal seizures. The girl presented typical development until the age of 18 months, followed by regression. The first febrile bilateral tonic-clonic seizure was observed at 30 months of age, and the following month seizures recurred in clusters of several episodes per day every 10 days. These seizures were characterized by behavioural arrest, emotional symptoms, head turning, and followed by bilateral tonic-clonic seizures. The administration of valproic acid and levetiracetam led to prolonged seizure control. However, from the age of 7 years, she had monthly recurrent clusters of focal seizures and non-convulsive status epilepticus which occurred at different ages. Brain and spinal cord MRI showed mild non-progressive hemispheric cerebellar atrophy. A next generation sequencing panel for epilepsy identified the de novo splicing mutation c.2973+1G>A of the SMC1A gene., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Syndromic craniosynostosis is a group of multiple conditions with high heterogeneity, and many rare syndromes still remain to be characterized. To identify and analyze causative genetic variants in nine unrelated probands mainly manifested as syndromic craniosynostosis, we reviewed the relevant medical information of the patients and performed the whole exome sequencing, further verified with Sanger sequencing and parental background. Bioinformatics analysis was used to evaluate the potential deleterious or benign effect of each genetic variant through evolutionary conservation alignment, multi-lines of computer predication and the allele frequency in population dataset (control and patient). The Standards and guidelines from American College of Medical Genetics and Genomics was used to classify and interpret the pathogenicity for each genetic variant. All the nine probands were found to carry the possibly causative variants, among which three variants including two missense mutations (c.3385C > T in IFT122 gene, c.3581A > G in SMC1A gene) and a frameshift mutation (c.434dupA in TWIST1 gene) have never been reported in patients before. We suggested Cornelia de Lange syndrome caused by SMC1A variant is a neglected syndromic craniosynostosis. Our study not only expanded genotypic and phenotypic spectrum of the rare syndromes, but also confirmed that there existed an underlying genetic mechanism. We emphasized that deliberate selection of both the potential candidates and comprehensive detection methods for genetic analysis is important to increase the genetic diagnosis yield of syndromic craninosynostosis. [ABSTRACT FROM AUTHOR]

SMC1A encodes one of the proteins of the cohesin complex. SMC1A variants are known to cause a phenotype resembling Cornelia de Lange syndrome (CdLS). Exome sequencing has allowed recognizing SMC1A variants in individuals with encephalopathy with epilepsy who do not resemble CdLS. We performed an international, interdisciplinary study on 51 individuals with SMC1A variants for physical and behavioral characteristics, and compare results to those in 67 individuals with NIPBL variants. For the Netherlands all known individuals with SMC1A variants were studied, both with and without CdLS phenotype. Individuals with SMC1A variants can resemble CdLS, but manifestations are less marked compared to individuals with NIPBL variants: growth is less disturbed, facial signs are less marked (except for periocular signs and thin upper vermillion), there are no major limb anomalies, and they have a higher level of cognitive and adaptive functioning. Self-injurious behavior is more frequent and more severe in the NIPBL group. In the Dutch group 5 of 13 individuals (all females) had a phenotype that shows a remarkable resemblance to Rett syndrome: epileptic encephalopathy, severe or profound intellectual disability, stereotypic movements, and (in some) regression. Their missense, nonsense, and frameshift mutations are evenly spread over the gene. We conclude that SMC1A variants can result in a phenotype resembling CdLS and a phenotype resembling Rett syndrome. Resemblances between the SMC1A group and the NIPBL group suggest that a disturbed cohesin function contributes to the phenotype, but differences between these groups may also be explained by other underlying mechanisms such as moonlighting of the cohesin genes. [ABSTRACT FROM AUTHOR]

Objective The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (Cd LS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation. Method Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders ( DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained. Results Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of Cd LS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. Significance Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males. [ABSTRACT FROM AUTHOR]