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

Romano Corrado

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
JournalEuropean Journal of Human Genetics
DOIs
Publication statusAccepted/In press - Jan 1 2019

Fingerprint

Intellectual Disability
Lip
Ubiquitin-Protein Ligase Complexes
Cullin Proteins
F-Box Proteins
Genes
Muscle Hypotonia
Comparative Genomic Hybridization
Ubiquitination
Attention Deficit Disorder with Hyperactivity
Aggression
Virulence
Proteins
Anxiety
Joints
Phenotype
Problem Behavior
Autism Spectrum Disorder
Power (Psychology)

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

@article{cd3fc7e926aa486ebf5a64176b80a486,
title = "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.",
author = "{Romano Corrado} and Sandra Jansen and {van der Werf}, {Ilse M.} and Innes, {A. Micheil} and Alexandra Afenjar and Agrawal, {Pankaj B.} and Anderson, {Ilse J.} and Atwal, {Paldeep S.} and {van Binsbergen}, Ellen and {van den Boogaard}, {Marie Jos{\'e}} and Lucia Castiglia and Coban-Akdemir, {Zeynep H.} and {van Dijck}, Anke and Diane Doummar and {van Eerde}, {Albertien M.} and {van Essen}, {Anthonie J.} and {van Gassen}, {Koen L.} and {Guillen Sacoto}, {Maria J.} and {van Haelst}, {Mieke M.} and Ivan Iossifov and Jackson, {Jessica L.} and Elizabeth Judd and Charu Kaiwar and Boris Keren and Klee, {Eric W.} and {Klein Wassink-Ruiter}, {Jolien S.} and Meuwissen, {Marije E.} and Monaghan, {Kristin G.} and {de Munnik}, {Sonja A.} and Caroline Nava and Ockeloen, {Charlotte W.} and Rosa Pettinato and Hilary Racher and Tuula Rinne and Corrado Romano and Sanders, {Victoria R.} and Schnur, {Rhonda E.} and Smeets, {Eric J.} and Stegmann, {Alexander P.A.} and Asbj{\o}rg Stray-Pedersen and Sweetser, {David A.} and Terhal, {Paulien A.} and Kristian Tveten and VanNoy, {Grace E.} and {de Vries}, {Petra F.} and Waxler, {Jessica L.} and Marcia Willing and Rolph Pfundt and Veltman, {Joris A.} and Kooy, {R. Frank} and Vissers, {Lisenka E.L.M.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41431-018-0292-2",
language = "English",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms

AU - Romano Corrado

AU - Jansen, Sandra

AU - van der Werf, Ilse M.

AU - Innes, A. Micheil

AU - Afenjar, Alexandra

AU - Agrawal, Pankaj B.

AU - Anderson, Ilse J.

AU - Atwal, Paldeep S.

AU - van Binsbergen, Ellen

AU - van den Boogaard, Marie José

AU - Castiglia, Lucia

AU - Coban-Akdemir, Zeynep H.

AU - van Dijck, Anke

AU - Doummar, Diane

AU - van Eerde, Albertien M.

AU - van Essen, Anthonie J.

AU - van Gassen, Koen L.

AU - Guillen Sacoto, Maria J.

AU - van Haelst, Mieke M.

AU - Iossifov, Ivan

AU - Jackson, Jessica L.

AU - Judd, Elizabeth

AU - Kaiwar, Charu

AU - Keren, Boris

AU - Klee, Eric W.

AU - Klein Wassink-Ruiter, Jolien S.

AU - Meuwissen, Marije E.

AU - Monaghan, Kristin G.

AU - de Munnik, Sonja A.

AU - Nava, Caroline

AU - Ockeloen, Charlotte W.

AU - Pettinato, Rosa

AU - Racher, Hilary

AU - Rinne, Tuula

AU - Romano, Corrado

AU - Sanders, Victoria R.

AU - Schnur, Rhonda E.

AU - Smeets, Eric J.

AU - Stegmann, Alexander P.A.

AU - Stray-Pedersen, Asbjørg

AU - Sweetser, David A.

AU - Terhal, Paulien A.

AU - Tveten, Kristian

AU - VanNoy, Grace E.

AU - de Vries, Petra F.

AU - Waxler, Jessica L.

AU - Willing, Marcia

AU - Pfundt, Rolph

AU - Veltman, Joris A.

AU - Kooy, R. Frank

AU - Vissers, Lisenka E.L.M.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41431-018-0292-2

DO - 10.1038/s41431-018-0292-2

M3 - Article

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

ER -