Broad‐spectrum next‐generation sequencing‐based diagnosis of a case of Nager syndrome

Zhao, Jingbo; Yang, Liwei

doi:10.1002/jcla.23426

Cited by 6 publications

(6 citation statements)

References 12 publications

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“…Through interaction with another SF3b subunit, spliceosome-associated protein 145 (SAP145), SF3B4 mediates the tethering of the U2 complex to the branch site of pre-mRNA splicing ( Gozani et al, 1996 ). The haploinsufficiency or mutation of SF3B4 is a major genetic cause of the Nager syndrome, characterized by a defective craniofacial formation and preaxial upper limb defect ( Bernier et al, 2012 ; Cassina et al, 2017 ; Castori et al, 2014 ; Drozniewska et al, 2020 ; Hayata et al, 2019 ; Zhao and Yang, 2020 ). Even though the molecular basis by which SF3B4 mutation leads to the phenotypes of Nager syndrome is yet to be identified, a recent study indicates that SF3B4 is involved in the translational control of secretory proteins, such as collagen 1 or fibronectin, as cofactors for p180 in the endoplasmic reticulum ( Ueno et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression

Kim

Lee

Jung

et al. 2022

Molecules and Cells

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Splicing factor B subunit 4 (SF3B4), a component of the U2-pre-mRNA spliceosomal complex, contributes to tumorigenesis in several types of tumors. However, the oncogenic potential of SF3B4 in lung cancer has not yet been determined. The in vivo expression profiles of SF3B4 in nonsmall cell lung cancer (NSCLC) from publicly available data revealed a significant increase in SF3B4 expression in tumor tissues compared to that in normal tissues. The impact of SF3B4 deletion on the growth of NSCLC cells was determined using a siRNA strategy in A549 lung adenocarcinoma cells. SF3B4 silencing resulted in marked retardation of the A549 cell proliferation, accompanied by the accumulation of cells at the G0/G1 phase and increased expression of p27, p21, and p53. Double knockdown of SF3B4 and p53 resulted in the restoration of p21 expression and partial recovery of cell proliferation, indicating that the p53/p21 axis is involved, at least in part, in the SF3B4-mediated regulation of A549 cell proliferation. We also provided ubiquitination factor E4B (UBE4B) is essential for p53 accumulation after SF3B4 depletion based on followings. First, co-immunoprecipitation showed that SF3B4 interacts with UBE4B. Furthermore, UBE4B levels were decreased by SF3B4 depletion. UBE4B depletion, in turn, reproduced the outcome of SF3B4 depletion, including reduction of polyubiquitinated p53 levels, subsequent induction of p53/p21 and p27, and proliferation retardation. Collectively, our findings indicate the important role of SF3B4 in the regulation of A549 cell proliferation through the UBE4B/p53/p21 axis and p27, implicating the therapeutic strategies for NSCLC targeting SF3B4 and UBE4B.

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Section: Introductionmentioning

confidence: 99%

SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression

Kim

Lee

Jung

et al. 2022

Molecules and Cells

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“…A fully independent validation set was designed using publicly available data published in the literature. We included patients with MFDM ( 6 , 14 , 17 ), NAFD ( 18 – 20 ), CHARGE syndrome ( 21 – 24 ) and TC syndrome ( 25 , 26 ); all had genetic confirmation of their syndromes.…”

Section: Methodsmentioning

confidence: 99%

AI-based diagnosis in mandibulofacial dysostosis with microcephaly using external ear shapes

Hennocq,

Bongibault,

Marlin

et al. 2023

Front. Pediatr.

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IntroductionMandibulo-Facial Dysostosis with Microcephaly (MFDM) is a rare disease with a broad spectrum of symptoms, characterized by zygomatic and mandibular hypoplasia, microcephaly, and ear abnormalities. Here, we aimed at describing the external ear phenotype of MFDM patients, and train an Artificial Intelligence (AI)-based model to differentiate MFDM ears from non-syndromic control ears (binary classification), and from ears of the main differential diagnoses of this condition (multi-class classification): Treacher Collins (TC), Nager (NAFD) and CHARGE syndromes.MethodsThe training set contained 1,592 ear photographs, corresponding to 550 patients. We extracted 48 patients completely independent of the training set, with only one photograph per ear per patient. After a CNN-(Convolutional Neural Network) based ear detection, the images were automatically landmarked. Generalized Procrustes Analysis was then performed, along with a dimension reduction using PCA (Principal Component Analysis). The principal components were used as inputs in an eXtreme Gradient Boosting (XGBoost) model, optimized using a 5-fold cross-validation. Finally, the model was tested on an independent validation set.ResultsWe trained the model on 1,592 ear photographs, corresponding to 1,296 control ears, 105 MFDM, 33 NAFD, 70 TC and 88 CHARGE syndrome ears. The model detected MFDM with an accuracy of 0.969 [0.838–0.999] (p < 0.001) and an AUC (Area Under the Curve) of 0.975 within controls (binary classification). Balanced accuracies were 0.811 [0.648–0.920] (p = 0.002) in a first multiclass design (MFDM vs. controls and differential diagnoses) and 0.813 [0.544–0.960] (p = 0.003) in a second multiclass design (MFDM vs. differential diagnoses).ConclusionThis is the first AI-based syndrome detection model in dysmorphology based on the external ear, opening promising clinical applications both for local care and referral, and for expert centers.

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“…Zhao and Yang (2020) described a case of a newborn with Nager syndrome, who was first diagnosed with TCS. They detected a c.1A>G substitution in the SF3B4 gene [21]. Drendel et al (2021) described the deletion of the SF3B4 gene, spanning exons 3-6, in one person.…”

Section: Molecular Diagnosismentioning

confidence: 99%

Children with Rare Nager Syndrome—Literature Review, Clinical and Physiotherapeutic Management

Marszałek-Kruk,

Myśliwiec,

Lipowicz

et al. 2023

Genes

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Nager syndrome is a rare human developmental disorder characterized by craniofacial defects including the downward slanting of the palpebral fissures, cleft palate, limb deformities, mandibular hypoplasia, hypoplasia or absence of thumbs, microretrognathia, and ankylosis of the temporomandibular joint. The prevalence is very rare and the literature describes only about a hundred cases of Nager syndrome. There is evidence of autosomal dominant and autosomal recessive inheritance for Nager syndrome, suggesting genetic heterogeneity. The majority of the described causes of Nager syndrome include pathogenic variants in the SF3B4 gene, which encodes a component of the spliceosome; therefore, the syndrome belongs to the spliceosomopathy group of diseases. The diagnosis is made on the basis of physical and radiological examination and detection of mutations in the SF3B4 gene. Due to the diversity of defects associated with Nager syndrome, patients require multidisciplinary, complex, and long-lasting treatment. Usually, it starts from birth until the age of twenty years. The surgical procedures vary over a patient’s lifetime and are related to the needed function. First, breathing and feeding must be facilitated; then, oral and facial clefts should be addressed, followed by correcting eyelid deformities and cheekbone reconstruction. In later age, a surgery of the nose and external ear is performed. Speech and hearing disorders require specialized logopedic treatment. A defect of the thumb is treated by transplanting a tendon and muscle or transferring the position of the index finger. In addition to surgery, in order to maximize a patient’s benefit and to reduce functional insufficiency, complementary treatments such as rehabilitation and physiotherapy are recommended. In our study, we describe eight patients of different ages with various cases of Nager syndrome. The aim of our work was to present the actual genetic knowledge on this disease and its treatment procedures.

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Broad‐spectrum next‐generation sequencing‐based diagnosis of a case of Nager syndrome

Cited by 6 publications

References 12 publications

SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression

SF3B4 Depletion Retards the Growth of A549 Non-Small Cell Lung Cancer Cells via UBE4B-Mediated Regulation of p53/p21 and p27 Expression

AI-based diagnosis in mandibulofacial dysostosis with microcephaly using external ear shapes

Children with Rare Nager Syndrome—Literature Review, Clinical and Physiotherapeutic Management

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