De novo variants in FBXO11 cause a syndromic form of intellectual disability with behavioral problems and dysmorphisms
Sandra Jansen
(1)
,
Ilse van der Werf
(2)
,
a Micheil Innes
(3)
,
Alexandra Afenjar
(4)
,
Pankaj Agrawal
(5)
,
Ilse Anderson
(6)
,
Paldeep Atwal
(7)
,
Ellen van Binsbergen
(8)
,
Marie-José van den Boogaard
(8)
,
Lucia Castiglia
(9)
,
Zeynep Coban-Akdemir
(10)
,
Anke van Dijck
(2)
,
Diane Doummar
(11, 12)
,
Albertien van Eerde
(8)
,
Anthonie van Essen
,
Koen van Gassen
(8)
,
Maria Guillen Sacoto
(13)
,
Mieke van Haelst
(14)
,
Ivan Iossifov
(15)
,
Jessica Jackson
(16)
,
Elizabeth Judd
(17)
,
Charu Kaiwar
(18)
,
Boris Keren
(19)
,
Eric Klee
(20)
,
Jolien Klein Wassink-Ruiter
(9)
,
Marije Meuwissen
,
Kristin Monaghan
,
Sonja de Munnik
(1)
,
Caroline Nava
(20)
,
Charlotte Ockeloen
(1)
,
Rosa Pettinato
(21)
,
Hilary Racher
,
Tuula Rinne
(1, 22)
,
Corrado Romano
(15)
,
Victoria Sanders
(1, 23)
,
Rhonda Schnur
(1)
,
Eric Smeets
(1)
,
Alexander Stegmann
(1)
,
Asbjørg Stray-Pedersen
(1)
,
David Sweetser
(1)
,
Paulien Terhal
(1)
,
Kristian Tveten
(1)
,
Grace Vannoy
(1)
,
Petra de Vries
(1)
,
Jessica Waxler
(1)
,
Marcia Willing
(1)
,
Rolph Pfundt
(1)
,
Joris Veltman
(1)
,
R Frank Kooy
(1)
,
Lisenka Vissers
(1)
,
Bert de Vries
(1)
1
Radboud University Medical Center [Nijmegen]
2 Universiteit Antwerpen = University of Antwerpen [Antwerpen]
3 University of Calgary
4 Centre de Référence Déficiences Intellectuelles de causes rares / Rare Disease Reference Center for Intellectual Disability [CHU Robert Debré, AP-HP]
5 Boston Children's Hospital
6 The University of Tennessee [Knoxville]
7 Mayo Clinic [Jacksonville]
8 UMCU - University Medical Center [Utrecht]
9 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
10 BCM - Baylor College of Medicine
11 CHU Trousseau [APHP]
12 GRC 19 ConCer-LD - Pathologies Congénitales du Cervelet-LeucoDystrophies
13 CSHL - Cold Spring Harbor Laboratory
14 New York Genome Center [New York]
15 Washington University School of Medicine in St. Louis
16 Mayo Clinic [Scottsdale]
17 Invitae Corporation
18 CHU Pitié-Salpêtrière [AP-HP]
19 Mayo Clinic [Rochester]
20 ICM - Institut du Cerveau = Paris Brain Institute
21 UiO - University of Oslo
22 Telemark Hospital Trust [Skien, Norway]
23 Newcastle University [Newcastle]
2 Universiteit Antwerpen = University of Antwerpen [Antwerpen]
3 University of Calgary
4 Centre de Référence Déficiences Intellectuelles de causes rares / Rare Disease Reference Center for Intellectual Disability [CHU Robert Debré, AP-HP]
5 Boston Children's Hospital
6 The University of Tennessee [Knoxville]
7 Mayo Clinic [Jacksonville]
8 UMCU - University Medical Center [Utrecht]
9 I.R.C.C.S. - "Oasi Maria Santissima" Institute for Research and Prevention of Mental Retardation
10 BCM - Baylor College of Medicine
11 CHU Trousseau [APHP]
12 GRC 19 ConCer-LD - Pathologies Congénitales du Cervelet-LeucoDystrophies
13 CSHL - Cold Spring Harbor Laboratory
14 New York Genome Center [New York]
15 Washington University School of Medicine in St. Louis
16 Mayo Clinic [Scottsdale]
17 Invitae Corporation
18 CHU Pitié-Salpêtrière [AP-HP]
19 Mayo Clinic [Rochester]
20 ICM - Institut du Cerveau = Paris Brain Institute
21 UiO - University of Oslo
22 Telemark Hospital Trust [Skien, Norway]
23 Newcastle University [Newcastle]
Sandra Jansen
- Fonction : Auteur
- PersonId : 1377547
- ORCID : 0000-0001-9453-8124
Ilse van der Werf
- Fonction : Auteur
- PersonId : 1377548
- ORCID : 0000-0002-3089-395X
Anke van Dijck
- Fonction : Auteur
- PersonId : 1377549
- ORCID : 0000-0002-6713-2943
Anthonie van Essen
- Fonction : Auteur
Charu Kaiwar
- Fonction : Auteur
- PersonId : 1377550
- ORCID : 0000-0002-0862-9538
Marije Meuwissen
- Fonction : Auteur
Kristin Monaghan
- Fonction : Auteur
Hilary Racher
- Fonction : Auteur
Tuula Rinne
- Fonction : Auteur
- PersonId : 1372119
- ORCID : 0000-0003-4350-8106
Corrado Romano
- Fonction : Auteur
- PersonId : 1377551
- ORCID : 0000-0003-1049-0683
David Sweetser
- Fonction : Auteur
- PersonId : 1377552
- ORCID : 0000-0002-1621-3284
Kristian Tveten
- Fonction : Auteur
- PersonId : 1377553
- ORCID : 0000-0003-1316-5843
Résumé
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.