Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Stephenson, Sarah E. M.; Costain, Gregory; Blok, Laura E.R.; Silk, Michael; Nguyễn, Thanh Bình; Dong, Xiaomin; Alhuzaimi, Dana; Dowling, James J.; Walker, Susan; Amburgey, Kimberly; Hayeems, Robin Z.; Rodan, Lance H.; Schwartz, Marc A.; Picker, Jonathan; Lynch, Sally Ann; Gupta, Aditi; Rasmussen, Kristen; Schimmenti, Lisa A.; Klee, Eric W.; Niu, Zhiyv; Agre, Katherine; Chilton, Ilana; Chung, Wendy K.; Revah‐Politi, Anya; Au, Ping Yee Billie; Griffith, Christopher; Racobaldo, Melissa; Raas‐Rothschild, Annick; Zeev, Bruria Ben; Barel, Ortal; Moutton, Sébastien; Morice‐Picard, Fanny; Carmignac, Virginie; Cornaton, Jenny; Marle, Nathalie; Devinsky, Orrin; Stimach, Chandler; Wechsler, Stephanie Burns; Hainline, Bryan E.; Sapp, Katie; Willems, Marjolaine; Bruel, Ange‐Line; Dias, Kerith-Rae; Evans, Carey‐Anne; Roscioli, Tony; Sachdev, Rani; Temple, Suzanna E.L.; Zhu, Ying; Baker, Joshua; Scheffer, Ingrid E.; Gardiner, Fiona; Schneider, Amy; Muir, Alison M.; Mefford, Heather C; Crunk, Amy; Heise, Elizabeth M; Millan, Francisca; Monaghan, Kristin G.; Person, Richard; Rhodes, Lindsay; Richards, Sarah; Wentzensen, Ingrid M.; Cogné, Benjamin; Isidor, Bertrand; Nizon, Mathilde; Vincent, Marie; Besnard, Thomas; Piton, Amélie; Marcelis, Carlo; Kato, Kohji; Koyama, Norihisa; Ogi, Tomoo; Goh, Elaine Suk-Ying; Richmond, Christopher; Amor, David J.; Boyce, Jessica O; Morgan, Angela; Hildebrand, Michael S.; Kaspi, Antony; Bahlo, Melanie; Friðriksdóttir, Rún; Katrínardóttir, Hildigunnur; Sulem, Patrick; Stefánsson, Kāri; Björnsson, Hans T.; Mandelstam, Simone; Morleo, Manuela; Mariani, Milena; Scala, Marcello; Accogli, Andrea; Torella, Annalaura; Capra, Valeria; Wallis, Mathew; Jansen, Sandra; Weisfisz, Quinten; Haan, Hugoline G. de; Sadedin, Simon; Lim, Sze Chern; White, Susan; Ascher, David B.; Schenck, Annette; Lockhart, Paul J.; Christodoulou, John; Tan, Tiong Yang

doi:10.1016/j.ajhg.2022.03.002

Cited by 23 publications

(15 citation statements)

References 92 publications

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“…FBXW7 variants have so far either been described in a few patients from Wilms tumor cohorts (Mahamdallie et al, 2019;Stoltze et al, 2023) or in patients with FBXW7-associated developmental delay (Stephenson et al, 2022; Figure 2), but it remained unclear if the same variants could give rise to both conditions. Stephenson et al (2022) recently described 35 patients with monoallelic de novo or inherited The FBXW7 gene is highly constrained for loss-of-function variants as highlighted by its loss-of-function observed/expected upper-bound fraction (LOEUF score) of 18.2% (gnomAD v4, n = 807,162 individuals in total). This indicates strong evolutionary pressure on the gene and increases the probability that constitutional FBXW7 loss-of-function variants are associated with a severe prereproductive phenotype (Stoltze et al, 2023).…”

Section: Discussionmentioning

confidence: 99%

“…A tumor-suppressor role was proposed for FBXW7 (Williams, 2010), and it has recently been suggested that germline mutations in FBXW7 might predispose to Wilms tumor formation (Mahamdallie et al, 2019;Stoltze et al, 2023). Independently, heterozygous loss-of-function germline or mosaic variants in FBXW7 have recently been described as underlying a novel neurodevelopmental syndrome with mild to severe global developmental delay and intellectual disability, hypotonia, and gastrointestinal issues (OMIM 620012; Stephenson et al, 2022). In the latter cohort of 35 affected individuals, no incidence of cancer was observed, although 13 of the detected germline variants were also reported in the COSMIC database.…”

Section: Introductionmentioning

confidence: 99%

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Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor

Meier‐Abt,

Kraemer,

Braun

et al. 2024

American J of Med Genetics Pt A

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Somatic variants in the NOTCH pathway regulator FBXW7 are frequently seen in a variety of malignancies. Heterozygous loss‐of‐function germline variants in FBXW7 have recently been described as causative for a neurodevelopmental syndrome. Independently, FBXW7 was also considered as a susceptibility gene for Wilms tumor due to a few observations of heterozygous germline variants in patients with Wilms tumor. Whether the same FBXW7 variants are implicated in both, neurodevelopmental delay and Wilms tumor formation, remained unclear. By clinical testing, we now observed a patient with neurodevelopmental delay due to a de novo constitutional mosaic FBXW7 splice site pathogenic variant who developed Wilms tumor. In the tumor, we identified a second hit frameshift variant in FBXW7. Immunohistochemical staining was consistent with mosaic loss of FBXW7 protein expression in the tumor. Our data support the role of constitutional FBXW7 pathogenic variants in both, neurodevelopmental disorder and the etiology of Wilms tumor. Therefore, Wilms tumor screening should be considered in individuals with constitutional or germline pathogenic variants in FBXW7 and associated neurodevelopmental syndrome.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor

Meier‐Abt,

Kraemer,

Braun

et al. 2024

American J of Med Genetics Pt A

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“…FBXW7 is also an important regulator of the maintenance and differentiation of neural stem cells in the brain ( Matsumoto et al, 2011 ). The gene was associated with neurodevelopmental syndromes and is distinguished by global developmental delays, borderline to severe intellectual disability, hypotonia, and gastrointestinal functions ( Stephenson et al, 2022 ). LINC01107 (Long Intergenic Non-Protein Coding RNA 1107) is an RNA gene affiliated with the lncRNA class.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation signature of psychological resilience in young adults: Constructing a methylation risk score using a machine learning method

Hsieh²,

Yang³

et al. 2023

Front. Genet.

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Resilience is a process associated with the ability to recover from stress and adversity. We aimed to explore the resilience-associated DNA methylation signatures and evaluate the abilities of methylation risk scores to discriminate low resilience (LR) individuals. The study recruited 78 young adults and used Connor-Davidson Resilience Scale (CD-RISC) to divide them into low and high resilience groups. We randomly allocated all participants of two groups to the discovery and validation sets. We used the blood DNA of the subjects to conduct a genome-wide methylation scan and identify the significant methylation differences of CpG Sites in the discovery set. Moreover, the classification accuracy of the DNA methylation probes was confirmed in the validation set by real-time quantitative methylation-specific polymerase chain reaction. In the genome-wide methylation profiling between LR and HR individuals, seventeen significantly differentially methylated probes were detected. In the validation set, nine DNA methylation signatures within gene coding regions were selected for verification. Finally, three methylation probes [cg18565204 (AARS), cg17682313 (FBXW7), and cg07167608 (LINC01107)] were included in the final model of the methylation risk score for LR versus HR. These methylation risk score models of low resilience demonstrated satisfactory discrimination by logistic regression and support vector machine, with an AUC of 0.81 and 0.93, accuracy of 72.3% and 87.1%, sensitivity of 75%, and 87.5%, and specificity of 70% and 80%. Our findings suggest that methylation signatures can be utilized to identify individuals with LR and establish risk score models that may contribute to the field of psychology.

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“…NDDs share commonalities (Chow et al, 2019 ; David et al, 2022 ; Dewey, 2018 ; King, 2016 ; Wagner et al, 2015 ). They also share commonalities with cancer (Li et al, 2020 ; Mogavero et al, 2020 ; Morgan et al, 2021 ; Nussinov et al, 2022c , d ; Qi et al, 2016 ; Roston et al, 2021 ; Stephenson et al, 2022 ; Yang et al, 2021 ; Yehia et al, 2022 ). Examples of NDDs include attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), learning disabilities, intellectual disability, cerebral palsy, and damaged vision and hearing affecting speech, motor skills, behavior, memory, and learning.…”

Section: Introductionmentioning

confidence: 99%

Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

et al. 2023

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Neurodevelopmental disorders (NDDs) and cancer share proteins, pathways, and mutations. Their clinical symptoms are different. However, individuals with NDDs have higher probabilities of eventually developing cancer. Here, we review the literature and ask how the shared features can lead to different medical conditions and why having an NDD first can increase the chances of malignancy. To explore these vital questions, we focus on dysregulated PI3K/mTOR, a major brain cell growth pathway in differentiation, and MAPK, a critical pathway in proliferation, a hallmark of cancer. Differentiation is governed by chromatin organization, making aberrant chromatin remodelers highly likely agents in NDDs. Dysregulated chromatin organization and accessibility influence the lineage of specific cell brain types at specific embryonic development stages. PAK1, with pivotal roles in brain development and in cancer, also regulates MAPK. We review, clarify, and connect dysregulated pathways with dysregulated proliferation and differentiation in cancer and NDDs and highlight PAK1 role in brain development and MAPK regulation. Exactly how PAK1 activation controls brain development, and why specific chromatin remodeler components, e.g., BAF170 encoded by SMARCC2 in autism, await clarification.

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Germline variants in tumor suppressor FBXW7 lead to impaired ubiquitination and a neurodevelopmental syndrome

Cited by 23 publications

References 92 publications

Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor

Further evidence that the neurodevelopmental gene FBXW7 predisposes to Wilms tumor

DNA methylation signature of psychological resilience in young adults: Constructing a methylation risk score using a machine learning method

Neurodevelopmental disorders, like cancer, are connected to impaired chromatin remodelers, PI3K/mTOR, and PAK1-regulated MAPK

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