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

2022

Stephenson, Sarah E M

Costain, Gregory

Blok, Laura E R

Silk, Michael A

Nguyen, Thanh Binh

Dong, Xiaomin

Alhuzaimi, Dana E

Dowling, James J

Walker, Susan

Amburgey, Kimberly

Hayeems, Robin Z

Björnsson, Hans Tómas

Mandelstam, Simone

Morleo, Manuela

Mariani, Milena

Scala, Marcello

Accogli, Andrea

Torella, Annalaura

Capra, Valeria

Wallis, Mathew J

Jansen, Sandra

Weisfisz, Quinten

de Haan, Hugoline

Sadedin, Simon

Lim, Sze Chern

White, Susan M

Ascher, David B

Schenck, Annette

Lockhart, Paul J

Christodoulou, John

Tan, Tiong Yang

Rodan, Lance H

Schwartz, Marc A

Picker, Jonathan

Lynch, Sally A

Gupta, Aditi

Rasmussen, Kristen J

Schimmenti, Lisa A

Klee, Eric W

Niu, Zhiyv

Agre, Katherine E

Chilton, Ilana

Chung, Wendy K

Revah-Politi, Anya

Au, P Y Billie

Griffith, Christopher

Racobaldo, Melissa

Raas-Rothschild, Annick

Ben Zeev, Bruria

Barel, Ortal

Moutton, Sebastien

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 J

Scheffer, Ingrid E

Gardiner, Fiona J

Schneider, Amy L

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, Amelie

Marcelis, Carlo

Kato, Kohji

Koyama, Norihisa

Ogi, Tomoo

Goh, Elaine Suk-Ying

Richmond, Christopher

Amor, David J

Boyce, Jessica O

Morgan, Angela T

Hildebrand, Michael S

Kaspi, Antony

Bahlo, Melanie

Friðriksdóttir, Rún

Katrínardóttir, Hildigunnur

Sulem, Patrick

Stefánsson, Kári

F-box protein

FBXW7

Neurodevelopment

brain malformation

epilepsy

gastrointestinal issues

global developmental delay

hypotonia

intellectual disability

macrocephaly

Journal Article

10.1016/j.ajhg.2022.03.002

Neurodevelopmental disorders are highly heterogenous conditions resulting from abnormalities of brain architecture and/or function. FBXW7 (F-box and WD-repeat-domain-containing 7), a recognized developmental regulator and tumor suppressor, has been shown to regulate cell-cycle progression and cell growth and survival by targeting substrates including CYCLIN E1/2 and NOTCH for degradation via the ubiquitin proteasome system. We used a genotype-first approach and global data-sharing platforms to identify 35 individuals harboring de novo and inherited FBXW7 germline monoallelic chromosomal deletions and nonsense, frameshift, splice-site, and missense variants associated with a neurodevelopmental syndrome. The FBXW7 neurodevelopmental syndrome is distinguished by global developmental delay, borderline to severe intellectual disability, hypotonia, and gastrointestinal issues. Brain imaging detailed variable underlying structural abnormalities affecting the cerebellum, corpus collosum, and white matter. A crystal-structure model of FBXW7 predicted that missense variants were clustered at the substrate-binding surface of the WD40 domain and that these might reduce FBXW7 substrate binding affinity. Expression of recombinant FBXW7 missense variants in cultured cells demonstrated impaired CYCLIN E1 and CYCLIN E2 turnover. Pan-neuronal knockdown of the Drosophila ortholog, archipelago, impaired learning and neuronal function. Collectively, the data presented herein provide compelling evidence of an F-Box protein-related, phenotypically variable neurodevelopmental disorder associated with monoallelic variants in FBXW7.

link

American Journal of Human Genetics 2022; 109(4): 601-617

American Journal of Human Genetics