Portal de investigación
De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder
Fecha de publicación:
Autores de IIS La Fe
Participantes ajenos a IIS La Fe
- Gregor, A
- Sadleir, LG
- Asadollahi, R
- Azzarello-Burri, S
- Battaglia, A
- Ousager, LB
- Boonsawat, P
- Bruel, AL
- Buchert, R
- Calpena, E
- Cogne, 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, SA
- Matsumoto, N
- McDougall, C
- Mefford, HC
- Miyake, N
- Myers, CT
- Moutton, S
- Nesbitt, A
- Novelli, A
- Rauch, A
- Saida, K
- Santani, AB
- Sarkar, A
- Scheffer, IE
- Shinawi, M
- Steindl, K
- Symonds, JD
- Zackai, EH
- Univ, WCMGD
- Reis, A
- Sticht, H
- Zweier, C
Grupos
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.
Datos de la publicación
- ISSN/ISSNe:
- 0002-9297, 1537-6605
- Tipo:
- Article
- Páginas:
- 305-316
- Factor de Impacto:
- 6,970 SCImago ℠
- Cuartil:
- Q1 SCImago ℠
AMERICAN JOURNAL OF HUMAN GENETICS CELL PRESS
Citas Recibidas en Web of Science: 27
Documentos
- No hay documentos
Filiaciones
Keywords
- FBXO11, intellectual disability, neurodevelopmental disorder
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Cita
Gregor A,Sadleir LG,Asadollahi R,Azzarello S,Battaglia A,Ousager LB,Boonsawat P,Bruel AL,Buchert R,Calpena E,Cogne B,Dallapiccola B,Distelmaier F,Elmslie F,Faivre L,Haack TB,Harrison V,Henderson A,Hunt D,Isidor B,Joset P,Kumada S,Lachmeijer A,Lees M,Lynch SA,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,Univ WCMGD,Reis A,Sticht H,Zweier C. De Novo Variants in the F-Box Protein FBXO11 in 20 Individuals with a Variable Neurodevelopmental Disorder. Am J Hum Genet. 2018. 103. (2):p. 305-316. IF:9,924. (1).