Duplication/triplication mosaicism of EBF3 and expansion of the EBF3 neurodevelopmental disorder phenotype

Ignatius, Erika; Puosi, Riina; Palomäki, Maarit; Forsbom, Noora; Pohjanpelto, Max; Alitalo, Tiina; Anttonen, Anna‐Kaisa; Avela, Kristiina; Haataja, Leena; Carroll, Christopher J.; Lönnqvist, Tuula; Isohanni, Pirjo

doi:10.1016/j.ejpn.2021.12.012

Cited by 5 publications

(6 citation statements)

References 23 publications

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“…Ataxia is present in all patients and may manifest with the whole spectrum of cerebellar impairment: oculomotor anomalies (e.g., oculomotor apraxia, nystagmus, and strabismus), dysarthria, gait unbalance, truncal and appendicular ataxia, a/dysdiadochokinesia, and tremor. A recent article by Ignatius et al 22 investigated the cerebellar signs in patients with EBF3-related ataxia and found that all patients showed signs of cerebellar involvement, although the SARA score of the reported participants was overall lower than in our cohort: the patient with the most severe presentation reached a score of 15, whereas in our cohort, the ataxic features are prominently expressed (SARA scores 9-20). Hypotonia is also often present and should also be considered of cerebellar origin because it was already reported in some previous cases.…”

Section: Discussioncontrasting

confidence: 70%

“…Hypotonia is also often present and should also be considered of cerebellar origin because it was already reported in some previous cases. 22,23 Cerebellar features have been underestimated in a number of articles discussing EBF3-related syndrome as a neurodevelopmental disorder; here, we underline that ataxia must be considered a cardinal sign of the syndrome and taken into full consideration when planning management because children would greatly benefit from a rehabilitation program including exercises to improve gross and fine motor skills.…”

Section: Discussionmentioning

confidence: 95%

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Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3 -Related Syndrome

et al. 2023

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Background and ObjectivesHeterozygous mutations or deletions of theEBF3gene are known to cause a syndrome characterized by intellectual disability, neurodevelopmental disorders, facial dysmorphisms, hypotonia, and ataxia; the latter is quite common despite in most patients brain MRI is reported to be normal. Despite the predominant neurologic involvement ofEBF3-related syndrome, a systematic definition of neurologic, cognitive/behavioral, and neuroradiologic features is lacking.MethodsWe report on 6 patients (2 females and 4 males, age range 2–12 years), of whom 4 carrying a heterozygous point mutation of theEBF3gene and 2 with 10q26 deletion encompassing the gene, diagnosed at Carlo Besta Neurologic Institute of Milan, Italy. Clinical evaluation was performed by a pediatric neurologist and pediatric dysmorphologist; ataxia severity was rated by Scale for the Assessment and Rating of Ataxia (SARA); brain MRIs were reviewed by expert neuroradiologists; general quotient levels were obtained through standardized Griffiths Mental Development Scales. Patients carrying a 10q26.3 deletion were diagnosed by array-CGH, whereasEBF3variants were detected by whole exome sequencing.ResultsPhenotype was consistent in all patients, but with wide variability in severity. Developmental milestones were invariably delayed and resulted in an extremely variable cognitive impairment. All patients showed ataxic signs, as confirmed by SARA scores, often associated with hypotonia. Brain MRI revealed in all children a cerebellar malformation with vermis hypoplasia and a peculiar foliation anomaly characterized by a radial disposition of cerebellar folia (dandelion sign). Neurophysiologic examinations were unremarkable.DiscussionEBF3-related syndrome has been so far described as a neurodevelopmental condition with dysmorphic traits, with limited emphasis on the neurologic features; we highlight the predominant neurologic involvement of these patients, which can be explained at least in part by the underlying cerebellar malformation. We therefore propose thatEBF3-related syndrome should be classified and treated as a congenital, nonprogressive ataxia.

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Section: Discussioncontrasting

confidence: 70%

Section: Discussionmentioning

confidence: 95%

Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3 -Related Syndrome

et al. 2023

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“…Conversely, EBF3 is less studied in the context of cancer, but it has a significant role in B-cell development. 37 The protein that EBF3 encodes inhibits cell survival by managing genes involved in cell cycle arrest and apoptosis. Its aberrant methylation or deletion could contribute to various malignancies.…”

Section: Discussionmentioning

confidence: 99%

Identification of neutrophil‐related genes and development of a prognostic model for cholangiocarcinoma

Xiong

Wang

et al. 2023

The Journal of Gene Medicine

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BackgroundCholangiocarcinoma is a prevalent gastrointestinal tumor with limited effective early diagnostic methods. The role of neutrophils in the context of cholangiocarcinoma remains largely unexplored.MethodsA comprehensive analysis was performed on a cohort of cholangiocarcinoma samples (TCGA‐CHOL) from the TCGA database to investigate the relationship between cholangiocarcinoma and neutrophils. Methodologies included single‐sample gene set enrichment analysis (ssGSEA), differential expression analysis, weighted gene co‐expression network analysis (WGCNA) and gene set enrichment analysis (GSEA).ResultsThe study identified a significant decrease of neutrophils in cholangiocarcinoma via ssGSEA. WGCNA and differential expression analysis led to the identification of a neutrophil‐related gene module comprised of 1059 genes. Cluster 1, showing a higher proportion of neutrophils, was linked to better survival outcomes. GSEA disclosed downregulation of complement, inflammatory response and interferon response pathways in Cluster 2, hinting at possible cholangiocarcinoma development triggers. A notable upregulation of PD1, PD‐L1 and CTLA4 was observed in Cluster 1, suggesting potential benefits from immunotherapy. A prognostic model was developed based on clinical data and expression levels of three prognostic genes (SOWAHD, TNFAIP8 and EBF3) showing satisfactory discrimination, calibration and clinical benefits. An overexpression of TNFAIP8 in cholangiocarcinoma cells was found, with its knockdown significantly inhibiting cell proliferation and migration.ConclusionsThis study elucidates a neutrophil‐related gene module and prognostic genes, offering insights into the role of neutrophils in cholangiocarcinoma development and progression. It also introduces a clinical prediction model for enhanced prognosis assessment. These findings may lay the groundwork for the development of innovative therapeutic strategies in cholangiocarcinoma treatment.

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“…This suggests a potential dominant negative effect of these EBF3 mutants. Patients with large 10qter deletions or whole gene deletions covering EBF3 shared main clinical characteristics with EBF3-related NDD, such as DD and/or ID, hypotonia, strabismus, and triangular face (10,12,(26)(27)(28)(29)(30), which supported haploinsufficiency as one of the possible pathogenic mechanisms of the EBF3 mutations. As there has been one reported case of duplication/triplication mosaicism of EBF3, combined with the duplication we reported in this study, we speculate that triplosensitivity may also help to illustrate how the EBF3 gene mutations causes disease.…”

Section: Discussionmentioning

confidence: 92%

“…Other less common phenotypes included dysarthria, constipation, decreased pain sensitivity during development, and behavioral deficits such as attention deficit and ASD or ASD-like symptoms. Since then, more than 30 additional cases of EBF3-related NDDs have been reported (9)(10)(11)(12)(13)(14)(15)(16). A recent meta-analysis integrated previously published 42 cases with detailed patient information and their 41 new cases, and quantified the risk and severity of patient phenotypes based on these 83 patients (17).…”

Section: Introductionmentioning

confidence: 99%

Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients

Zhu

Li²,

Yu³

et al. 2023

Front. Pediatr.

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Neurodevelopmental disorders (NDDs) have heterogeneity in both clinical characteristics and genetic factors. EBF3 is a recently discovered gene associated with a syndromic form of NDDs characterized by hypotonia, ataxia and facial features. In this study, we report twelve unrelated individuals with EBF3 variants using next-generation sequencing. Five missense variants (four novel variants and one known variant) and seven copy number variations (CNVs) of EBF3 gene were identified. All of these patients exhibited developmental delay/intellectual disability. Ataxia was observed in 33% (6/9) of the patients, and abnormal muscle tone was observed in 55% (6/11) of the patients. Aberrant MRI reports were noted in 64% (7/11) of the patients. Four novel missense variants were all located in the DNA-binding domain. The pathogenicity of these variants was validated by in vitro experiments. We found that the subcellular protein localization of the R152C and F211L mutants was changed, and the distribution pattern of the R163G mutant was changed from even to granular. Luciferase assay results showed that the four EBF3 mutants' transcriptional activities were all significantly decreased (p < 0.01). Our study further expanded the gene mutation spectrum of EBF3-related NDD.

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Duplication/triplication mosaicism of EBF3 and expansion of the EBF3 neurodevelopmental disorder phenotype

Cited by 5 publications

References 23 publications

Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3 -Related Syndrome

Neurologic, Neuropsychologic, and Neuroradiologic Features of EBF3 -Related Syndrome

Identification of neutrophil‐related genes and development of a prognostic model for cholangiocarcinoma

Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients

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