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

TitleDe Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder.
Publication TypeJournal Article
Year of Publication2018
AuthorsGregor, A, Sadleir, LG, Asadollahi, R, Azzarello-Burri, S, Battaglia, A, Ousager, LBomme, Boonsawat, P, Bruel, A-L, Buchert, R, Calpena, E, Cogné, B, Dallapiccola, B, Distelmaier, F, Elmslie, F, Faivre, L, Haack, TB, Harrison, V, Henderson, A, Hunt, D, Isidor, B, Joset, P, Kumada, S, Lachmeijer, AMA, Lees, M, Lynch, SAnn, Martinez, F, Matsumoto, N, McDougall, C, Mefford, HC, Miyake, N, Myers, CT, Moutton, S, Nesbitt, A, Novelli, A, Orellana, C, Rauch, A, Rosello, M, Saida, K, Santani, AB, Sarkar, A, Scheffer, IE, Shinawi, M, Steindl, K, Symonds, JD, Zackai, EH, Reis, A, Sticht, H, Zweier, C
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics, DDD study
JournalAm J Hum Genet
Volume103
Issue2
Pagination305-316
Date Published2018 Aug 02
ISSN1537-6605
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.

DOI10.1016/j.ajhg.2018.07.003
Alternate JournalAm. J. Hum. Genet.
PubMed ID30057029
PubMed Central IDPMC6080769
Grant ListU54 HG006493 / HG / NHGRI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States