TY - JOUR
T1 - De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder
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 - Funding Information:
I.E.S. has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, Biomarin, and Nutricia; editorial boards of the Annals of Neurology, Neurology, and Epileptic Disorders; may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has received speaker honoraria from GlaxoSmithKline, Athena Diagnostics, UCB, Eisai, and Transgenomics; has received funding for travel from Athena Diagnostics, UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai; and receives/has received research support from the National Health and Medical Research Council of Australia, National Institutes of Health, Australian Research Council, Health Research Council of New Zealand, CURE, and March of Dimes.
Funding Information:
We thank all affected individuals and their families for participating in this study. We thank Laila Distel for excellent technical assistance. We thank Christian T. Thiel for the in-house NGS tool and Arif Ekici and Steffen Uebe from the NGS facility in the Institute of Human Genetics, Erlangen. This study makes use of data generated by the DECIPHER community (for additional information see Supplemental Acknowledgements). Studies regarding individuals 18 and 11 were supported by grant PI14/00350 (Instituto de Salud Carlos III -Acción Estratégica en Salud 2013–2016; FEDER -Fondo Europeo de Desarrollo Regional) and by PARI 2012 from Regional Council of Burgundy / Dijon University Hospital, respectively. Exome sequencing for individual 7 was performed at the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the NHRGI and the NHLBI (grant HG006493). L.G.S. is supported by grants from the Health Research Council and Cure Kids New Zealand. A. Rauch was supported by the ERA-NET grant “Euromicro” (SNF 31ER30_154238). A. Reis was supported by the German Ministry of Education and Research (01GS08160) and the Interdisciplinary Center for Clinical Research (IZKF) Erlangen (E16). F.D. was supported by a grant of the German Research Foundation (DFG) (DI 1731/2-1). T.B.H. is supported by the German Federal Ministry of Education and Research (BMBF) through the Juniorverbund in der Systemmedizin “mitOmics” (01ZX1405C). N. Matsumoto is supported by grants from AMED (JP18ek0109280, JP18dm0107090, and JP18ek0109301). C.Z. is supported by grants from the DFG (ZW184/1-2, ZW184/3-1, and GRK2162) and by the IZKF Erlangen (E26). E.C. was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme.
Funding Information:
We thank all affected individuals and their families for participating in this study. We thank Laila Distel for excellent technical assistance. We thank Christian T. Thiel for the in-house NGS tool and Arif Ekici and Steffen Uebe from the NGS facility in the Institute of Human Genetics, Erlangen. This study makes use of data generated by the DECIPHER community (for additional information see Supplemental Acknowledgements ). Studies regarding individuals 18 and 11 were supported by grant PI14/00350 ( Instituto de Salud Carlos III -Acción Estratégica en Salud 2013–2016; FEDER -Fondo Europeo de Desarrollo Regional ) and by PARI 2012 from Regional Council of Burgundy / Dijon University Hospital , respectively. Exome sequencing for individual 7 was performed at the University of Washington Center for Mendelian Genomics (UW-CMG) and was funded by the NHRGI and the NHLBI (grant HG006493 ). L.G.S. is supported by grants from the Health Research Council and Cure Kids New Zealand . A. Rauch was supported by the ERA-NET grant “Euromicro” ( SNF 31ER30_154238 ). A. Reis was supported by the German Ministry of Education and Research ( 01GS08160 ) and the Interdisciplinary Center for Clinical Research (IZKF) Erlangen ( E16 ). F.D. was supported by a grant of the German Research Foundation (DFG) ( DI 1731/2-1 ). T.B.H. is supported by the German Federal Ministry of Education and Research (BMBF) through the Juniorverbund in der Systemmedizin “mitOmics” ( 01ZX1405C ). N. Matsumoto is supported by grants from AMED ( JP18ek0109280 , JP18dm0107090 , and JP18ek0109301 ). C.Z. is supported by grants from the DFG ( ZW184/1-2 , ZW184/3-1 , and GRK2162 ) and by the IZKF Erlangen ( E26 ). E.C. was supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Programme.
Publisher Copyright:
© 2018 American Society of Human Genetics
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.
KW - FBXO11
KW - intellectual disability
KW - neurodevelopmental disorder
UR - http://www.scopus.com/inward/record.url?scp=85053847998&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.07.003
DO - 10.1016/j.ajhg.2018.07.003
M3 - Article
C2 - 30057029
AN - SCOPUS:85053847998
SN - 0002-9297
VL - 103
SP - 305
EP - 316
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -