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.
| Original language | English |
|---|---|
| Pages (from-to) | 305-316 |
| Number of pages | 12 |
| Journal | American Journal of Human Genetics |
| Volume | 103 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - Aug 2 2018 |
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De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder. / University of Washington Center for Mendelian Genomics.
In: American Journal of Human Genetics, Vol. 103, No. 2, 02.08.2018, p. 305-316.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder
AU - University of Washington Center for Mendelian Genomics
AU - Gregor, Anne
AU - Sadleir, Lynette G
AU - Asadollahi, Reza
AU - Azzarello-Burri, Silvia
AU - Battaglia, Agatino
AU - Ousager, Lilian Bomme
AU - Boonsawat, Paranchai
AU - Bruel, Ange-Line
AU - Buchert, Rebecca
AU - Calpena, Eduardo
AU - Cogné, Benjamin
AU - Dallapiccola, Bruno
AU - Distelmaier, Felix
AU - Elmslie, Frances
AU - Faivre, Laurence
AU - Haack, Tobias B
AU - Harrison, Victoria
AU - Henderson, Alex
AU - Hunt, David
AU - Isidor, Bertrand
AU - Joset, Pascal
AU - Kumada, Satoko
AU - Lachmeijer, Augusta M A
AU - Lees, Melissa
AU - Lynch, Sally Ann
AU - Martinez, Francisco
AU - Matsumoto, Naomichi
AU - McDougall, Carey
AU - Mefford, Heather C
AU - Miyake, Noriko
AU - Myers, Candace T
AU - Moutton, Sébastien
AU - Nesbitt, Addie
AU - Novelli, Antonio
AU - Orellana, Carmen
AU - Rauch, Anita
AU - Rosello, Monica
AU - Saida, Ken
AU - Santani, Avni B
AU - Sarkar, Ajoy
AU - Scheffer, Ingrid E
AU - Shinawi, Marwan
AU - Steindl, Katharina
AU - Symonds, Joseph D
AU - Zackai, Elaine H
AU - Reis, André
AU - Sticht, Heinrich
AU - Zweier, Christiane
N1 - Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
PY - 2018/8/2
Y1 - 2018/8/2
N2 - 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.
AB - 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.
U2 - 10.1016/j.ajhg.2018.07.003
DO - 10.1016/j.ajhg.2018.07.003
M3 - Article
C2 - 30057029
VL - 103
SP - 305
EP - 316
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 2
ER -