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De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.

ABSTRACT: Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in, or partial deletion of, the F-box only protein 11 gene (FBXO11, also known as VIT1 and PRMT9). FBXO11 is part of the SCF (SKP1-cullin-F-box) complex, a multi-protein E3 ubiquitin-ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation. Twenty-two variants were identified by next-generation sequencing, comprising 2 in-frame deletions, 11 missense variants, 1 canonical splice site variant, and 8 nonsense or frameshift variants leading to a truncated protein or degraded transcript. The remaining two variants were identified by array-comparative genomic hybridization and consisted of a partial deletion of FBXO11. All individuals had borderline to severe ID and behavioral problems (autism spectrum disorder, attention-deficit/hyperactivity disorder, anxiety, aggression) were observed in most of them. The most relevant common facial features included a thin upper lip and a broad prominent space between the paramedian peaks of the upper lip. Other features were hypotonia and hyperlaxity of the joints. We show that de novo variants in FBXO11 cause a syndromic form of ID. The current series show the power of reverse phenotyping in the interpretation of novel genetic variances in individuals who initially did not appear to have a clear recognizable phenotype.

SUBMITTER: Jansen S 

PROVIDER: S-EPMC6462006 | biostudies-literature | 2019 May

REPOSITORIES: biostudies-literature

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De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms.

Jansen Sandra S   van der Werf Ilse M IM   Innes A Micheil AM   Afenjar Alexandra A   Agrawal Pankaj B PB   Anderson Ilse J IJ   Atwal Paldeep S PS   van Binsbergen Ellen E   van den Boogaard Marie-José MJ   Castiglia Lucia L   Coban-Akdemir Zeynep H ZH   van Dijck Anke A   Doummar Diane D   van Eerde Albertien M AM   van Essen Anthonie J AJ   van Gassen Koen L KL   Guillen Sacoto Maria J MJ   van Haelst Mieke M MM   Iossifov Ivan I   Jackson Jessica L JL   Judd Elizabeth E   Kaiwar Charu C   Keren Boris B   Klee Eric W EW   Klein Wassink-Ruiter Jolien S JS   Meuwissen Marije E ME   Monaghan Kristin G KG   de Munnik Sonja A SA   Nava Caroline C   Ockeloen Charlotte W CW   Pettinato Rosa R   Racher Hilary H   Rinne Tuula T   Romano Corrado C   Sanders Victoria R VR   Schnur Rhonda E RE   Smeets Eric J EJ   Stegmann Alexander P A APA   Stray-Pedersen Asbjørg A   Sweetser David A DA   Terhal Paulien A PA   Tveten Kristian K   VanNoy Grace E GE   de Vries Petra F PF   Waxler Jessica L JL   Willing Marcia M   Pfundt Rolph R   Veltman Joris A JA   Kooy R Frank RF   Vissers Lisenka E L M LELM   de Vries Bert B A BBA  

European journal of human genetics : EJHG 20190124 5

Determining pathogenicity of genomic variation identified by next-generation sequencing techniques can be supported by recurrent disruptive variants in the same gene in phenotypically similar individuals. However, interpretation of novel variants in a specific gene in individuals with mild-moderate intellectual disability (ID) without recognizable syndromic features can be challenging and reverse phenotyping is often required. We describe 24 individuals with a de novo disease-causing variant in,  ...[more]

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