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


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.

SUBMITTER: Gregor A 

PROVIDER: S-EPMC6080769 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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

Gregor Anne A   Sadleir Lynette G LG   Asadollahi Reza R   Azzarello-Burri Silvia S   Battaglia Agatino A   Ousager Lilian Bomme LB   Boonsawat Paranchai P   Bruel Ange-Line AL   Buchert Rebecca R   Calpena Eduardo E   Cogné Benjamin B   Dallapiccola Bruno B   Distelmaier Felix F   Elmslie Frances F   Faivre Laurence L   Haack Tobias B TB   Harrison Victoria V   Henderson Alex A   Hunt David D   Isidor Bertrand B   Joset Pascal P   Kumada Satoko S   Lachmeijer Augusta M A AMA   Lees Melissa M   Lynch Sally Ann SA   Martinez Francisco F   Matsumoto Naomichi N   McDougall Carey C   Mefford Heather C HC   Miyake Noriko N   Myers Candace T CT   Moutton Sébastien S   Nesbitt Addie A   Novelli Antonio A   Orellana Carmen C   Rauch Anita A   Rosello Monica M   Saida Ken K   Santani Avni B AB   Sarkar Ajoy A   Scheffer Ingrid E IE   Shinawi Marwan M   Steindl Katharina K   Symonds Joseph D JD   Zackai Elaine H EH   Reis André A   Reis André A   Sticht Heinrich H   Zweier Christiane C  

American journal of human genetics 20180726 2


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 in  ...[more]

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