. 2019 May;27(5):738-746.

doi: 10.1038/s41431-018-0292-2. Epub 2019 Jan 24.

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

Sandra Jansen¹, Ilse M van der Werf², A Micheil Innes³, Alexandra Afenjar^{4

5}, Pankaj B Agrawal⁶, Ilse J Anderson⁷, Paldeep S Atwal⁸, Ellen van Binsbergen⁹, Marie-José van den Boogaard⁹, Lucia Castiglia¹⁰, Zeynep H Coban-Akdemir^{11

12}, Anke van Dijck², Diane Doummar^{13

14

15}, Albertien M van Eerde⁹, Anthonie J van Essen¹⁶, Koen L van Gassen⁹, Maria J Guillen Sacoto¹⁷, Mieke M van Haelst¹⁸, Ivan Iossifov^{19

20}, Jessica L Jackson⁸, Elizabeth Judd²¹, Charu Kaiwar^{22

23}, Boris Keren²⁴, Eric W Klee²⁵, Jolien S Klein Wassink-Ruiter¹⁶, Marije E Meuwissen², Kristin G Monaghan¹⁷, Sonja A de Munnik¹, Caroline Nava^{24

26}, Charlotte W Ockeloen¹, Rosa Pettinato²⁷, Hilary Racher^{3

28}, Tuula Rinne¹, Corrado Romano²⁷, Victoria R Sanders²⁹, Rhonda E Schnur¹⁷, Eric J Smeets³⁰, Alexander P A Stegmann³⁰, Asbjørg Stray-Pedersen^{11

31

32}, David A Sweetser³³, Paulien A Terhal⁹, Kristian Tveten³⁴, Grace E VanNoy⁶, Petra F de Vries¹, Jessica L Waxler³³, Marcia Willing³⁵, Rolph Pfundt¹, Joris A Veltman^{1

36}, R Frank Kooy², Lisenka E L M Vissers¹, Bert B A de Vries³⁷

Affiliations

¹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
² Department of Medical Genetics, University Hospital and University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
³ Alberta Children's Hospital Research Institute and Department of Medical Genetics, Cumming School of Medicine, University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB, T3B 6A8, Canada.
⁴ Centre de Référence Déficiences Intellectuelles de Causes Rares, 75013, Paris, France.
⁵ APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence 'Malformations et maladies congénitales du cervelet', 75012, Paris, France.
⁶ Divisions of Genetics and Genomics and Newborn Medicine, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
⁷ The University of Tennessee Genetics Center, Knoxville, TN, 37920, USA.
⁸ Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, 32224, USA.
⁹ Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
¹⁰ Laboratory of Medical Genetics, Oasi Research Institute, 94018, Troina, Italy.
¹¹ Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX, 77030, USA.
¹² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
¹³ APHP, Service de Neurologie pédiatrique, Hôpital Armand Trousseau, Paris, France.
¹⁴ Sorbonne Université,GRC ConCer-LD, AP-HP, Hôpital Trousseau, Paris, France.
¹⁵ Service de neuropediatrie, Hôpital Trousseau, 26 avenue du dr Arnold Netter, 75012, Paris, France.
¹⁶ Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), 9700 RB, Groningen, The Netherlands.
¹⁷ GeneDx, Gaithersburg, MD, 20877, USA.
¹⁸ Department of Clinical Genetics, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands.
¹⁹ Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, 11724, USA.
²⁰ New York Genome Center, New York, NY, 10013, USA.
²¹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, 63110, USA.
²² Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, 85259, USA.
²³ Invitae, 1400 16th Street, San Francisco, CA, 94103, USA.
²⁴ Département de Génétique, APHP, GH Pitié-Salpêtrière, Paris, 75013, France.
²⁵ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
²⁶ INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Université de Paris 06, 75013, Paris, France.
²⁷ Pediatrics and Medical Genetics, Oasi Research Institute - IRCCS, 94018, Troina, Italy.
²⁸ Impact Genetics, 1100 Bennett Road, Bowmanville, ON, L1C 3K5, Canada.
²⁹ Department of Pediatrics, Division of Genetics, Birth Defects and Metabolism, Ann and Robert H Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Chicago, IL, 60611, USA.
³⁰ Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, 9229 ER, Maastricht, The Netherlands.
³¹ Norwegian National Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Pb 4950 Nydalen, 0424, Oslo, Norway.
³² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway.
³³ Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, MA, 02114, USA.
³⁴ Department of Medical Genetics, Telemark Hospital Trust, 3710, Skien, Norway.
³⁵ Department of Pediatrics, Washington University School of Medicine, St Louis, MO, 63110, USA.
³⁶ Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, UK.
³⁷ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. bert.devries@radboudumc.nl.

PMID: 30679813
PMCID: PMC6462006
DOI: 10.1038/s41431-018-0292-2

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

Sandra Jansen et al. Eur J Hum Genet. 2019 May.

. 2019 May;27(5):738-746.

doi: 10.1038/s41431-018-0292-2. Epub 2019 Jan 24.

Authors

Affiliations

¹ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.
² Department of Medical Genetics, University Hospital and University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
³ Alberta Children's Hospital Research Institute and Department of Medical Genetics, Cumming School of Medicine, University of Calgary, 2888 Shaganappi Trail NW, Calgary, AB, T3B 6A8, Canada.
⁴ Centre de Référence Déficiences Intellectuelles de Causes Rares, 75013, Paris, France.
⁵ APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence 'Malformations et maladies congénitales du cervelet', 75012, Paris, France.
⁶ Divisions of Genetics and Genomics and Newborn Medicine, Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, 02115, USA.
⁷ The University of Tennessee Genetics Center, Knoxville, TN, 37920, USA.
⁸ Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, 32224, USA.
⁹ Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands.
¹⁰ Laboratory of Medical Genetics, Oasi Research Institute, 94018, Troina, Italy.
¹¹ Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX, 77030, USA.
¹² Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
¹³ APHP, Service de Neurologie pédiatrique, Hôpital Armand Trousseau, Paris, France.
¹⁴ Sorbonne Université,GRC ConCer-LD, AP-HP, Hôpital Trousseau, Paris, France.
¹⁵ Service de neuropediatrie, Hôpital Trousseau, 26 avenue du dr Arnold Netter, 75012, Paris, France.
¹⁶ Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), 9700 RB, Groningen, The Netherlands.
¹⁷ GeneDx, Gaithersburg, MD, 20877, USA.
¹⁸ Department of Clinical Genetics, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands.
¹⁹ Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, 11724, USA.
²⁰ New York Genome Center, New York, NY, 10013, USA.
²¹ Department of Psychiatry, Washington University School of Medicine, St Louis, MO, 63110, USA.
²² Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, 85259, USA.
²³ Invitae, 1400 16th Street, San Francisco, CA, 94103, USA.
²⁴ Département de Génétique, APHP, GH Pitié-Salpêtrière, Paris, 75013, France.
²⁵ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA.
²⁶ INSERM, U 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, UPMC Université de Paris 06, 75013, Paris, France.
²⁷ Pediatrics and Medical Genetics, Oasi Research Institute - IRCCS, 94018, Troina, Italy.
²⁸ Impact Genetics, 1100 Bennett Road, Bowmanville, ON, L1C 3K5, Canada.
²⁹ Department of Pediatrics, Division of Genetics, Birth Defects and Metabolism, Ann and Robert H Lurie Children's Hospital of Chicago, 225 East Chicago Avenue, Chicago, IL, 60611, USA.
³⁰ Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, 9229 ER, Maastricht, The Netherlands.
³¹ Norwegian National Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Pb 4950 Nydalen, 0424, Oslo, Norway.
³² Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway.
³³ Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, MA, 02114, USA.
³⁴ Department of Medical Genetics, Telemark Hospital Trust, 3710, Skien, Norway.
³⁵ Department of Pediatrics, Washington University School of Medicine, St Louis, MO, 63110, USA.
³⁶ Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, UK.
³⁷ Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. bert.devries@radboudumc.nl.

PMID: 30679813
PMCID: PMC6462006
DOI: 10.1038/s41431-018-0292-2

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.

PubMed Disclaimer

Conflict of interest statement

M.J.G.S., K.G.M., and R.E.S. are employees of GeneDx Inc. H.R. is an employee of Impact Genetics Inc. The other authors declare that they have no conflict of interest.

Figures

**Fig. 1**
*FBXO11* with deletions and variants identified in our cohort. *FBXO11* is expressed in two different isoforms (NM_001190274.1 and NM_0251433.4), which differ by an alternative exon 1, and of which NM_001190274.1 represents the longest transcript. Variants are annotated based on NM_0011190274.1. FBXO11 protein domains are depicted in color. Individuals 6 and 7 have a partial deletion of *FBXO11* (gray bars)

**Fig. 2**
Photographs of individuals with a variant in *FBXO11*. The first row shows the individuals at a younger age, and the second row shows the respective individual at an older age. Facial features comprise a broad forehead, long palpebral fissures, and a thin upper lip with a broad space between the paramedian peaks of the upper lip. Some individuals show coarsening at an older age. The third row shows the hands of the respective individual with brachydactyly and tapering fingers in several cases

**Fig. 3**
a Detailed photographs of the eyes of individuals with a variant in *FBXO11*. Eyes show long palpebral fissures. b Detailed photographs of the lips of individuals with a variant in *FBXO11*. There is a thin upper lip with a broad space between the paramedian peaks of the upper lip

See this image and copyright information in PMC

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

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

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