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De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder

Anne Gregor 1 Lynette Sadleir Reza Asadollahi Silvia Azzarello-Burri Agatino Battaglia Lilian Bomme Ousager Paranchai Boonsawat Ange-Line Bruel 2 Rebecca Buchert Eduardo Calpena Benjamin Cogné 3, 4 Bruno Dallapiccola 5 Felix Distelmaier Frances Elmslie 6 Laurence Faivre 7, 2 Tobias B Haack 8 Victoria Harrison Alex Henderson 9 David Hunt Bertrand Isidor 4 Pascal Joset Satoko Kumada Augusta M.A. Lachmeijer Melissa Lees Sally Ann Lynch 10 Francisco Martinez Naomichi Matsumoto 11 Carey Mcdougall Heather Mefford Noriko Miyake 11 Candace Myers Sébastien Moutton 2, 7 Addie I. Nesbitt 12 Antonio Novelli 13 Carmen Orellana Anita Rauch 14 Monica Rosello Ken Saida Avni B. Santani 15 Ajoy Sarkar 16 Ingrid E. Scheffer 17 Marwan Shinawi Katharina Steindl Joseph Symonds Elaine Zackai 18 Ddd Study3 University of Washington Center For Mendelian Genomics André Reis 1 Heinrich Sticht 19 Christiane Zweier 1, * 
Abstract : Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.
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Soumis le : lundi 11 mars 2019 - 11:33:50
Dernière modification le : dimanche 4 septembre 2022 - 18:15:39

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Anne Gregor, Lynette Sadleir, Reza Asadollahi, Silvia Azzarello-Burri, Agatino Battaglia, et al.. De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder. American Journal of Human Genetics, 2018, 103 (2), pp.305-316. ⟨10.1016/j.ajhg.2018.07.003⟩. ⟨hal-02063487⟩



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