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

Autor: Jansen S; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., van der Werf IM; Department of Medical Genetics, University Hospital and University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium., Innes AM; 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., Afenjar A; Centre de Référence Déficiences Intellectuelles de Causes Rares, 75013, Paris, France.; APHP, GHUEP, Hôpital Armand Trousseau, Centre de Référence 'Malformations et maladies congénitales du cervelet', 75012, Paris, France., Agrawal PB; 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., Anderson IJ; The University of Tennessee Genetics Center, Knoxville, TN, 37920, USA., Atwal PS; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, 32224, USA., van Binsbergen E; Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands., van den Boogaard MJ; Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands., Castiglia L; Laboratory of Medical Genetics, Oasi Research Institute, 94018, Troina, Italy., Coban-Akdemir ZH; Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX, 77030, USA.; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA., van Dijck A; Department of Medical Genetics, University Hospital and University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium., Doummar D; APHP, Service de Neurologie pédiatrique, Hôpital Armand Trousseau, Paris, France.; Sorbonne Université,GRC ConCer-LD, AP-HP, Hôpital Trousseau, Paris, France.; Service de neuropediatrie, Hôpital Trousseau, 26 avenue du dr Arnold Netter, 75012, Paris, France., van Eerde AM; Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands., van Essen AJ; Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), 9700 RB, Groningen, The Netherlands., van Gassen KL; Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands., Guillen Sacoto MJ; GeneDx, Gaithersburg, MD, 20877, USA., van Haelst MM; Department of Clinical Genetics, VU University Medical Center, 1081 HV, Amsterdam, The Netherlands., Iossifov I; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, 11724, USA.; New York Genome Center, New York, NY, 10013, USA., Jackson JL; Department of Clinical Genomics, Mayo Clinic, Jacksonville, FL, 32224, USA., Judd E; Department of Psychiatry, Washington University School of Medicine, St Louis, MO, 63110, USA., Kaiwar C; Center for Individualized Medicine, Mayo Clinic, Scottsdale, AZ, 85259, USA.; Invitae, 1400 16th Street, San Francisco, CA, 94103, USA., Keren B; Département de Génétique, APHP, GH Pitié-Salpêtrière, Paris, 75013, France., Klee EW; Center for Individualized Medicine, Mayo Clinic, Rochester, MN, 55905, USA., Klein Wassink-Ruiter JS; Department of Genetics, University of Groningen, University Medical Center Groningen (UMCG), 9700 RB, Groningen, The Netherlands., Meuwissen ME; Department of Medical Genetics, University Hospital and University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium., Monaghan KG; GeneDx, Gaithersburg, MD, 20877, USA., de Munnik SA; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Nava C; Département de Génétique, APHP, GH Pitié-Salpêtrière, Paris, 75013, France.; 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., Ockeloen CW; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Pettinato R; Pediatrics and Medical Genetics, Oasi Research Institute - IRCCS, 94018, Troina, Italy., Racher H; 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.; Impact Genetics, 1100 Bennett Road, Bowmanville, ON, L1C 3K5, Canada., Rinne T; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Romano C; Pediatrics and Medical Genetics, Oasi Research Institute - IRCCS, 94018, Troina, Italy., Sanders VR; 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., Schnur RE; GeneDx, Gaithersburg, MD, 20877, USA., Smeets EJ; Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, 9229 ER, Maastricht, The Netherlands., Stegmann APA; Department of Clinical Genetics, Maastricht University Medical Centre, Universiteitssingel 50, 9229 ER, Maastricht, The Netherlands., Stray-Pedersen A; Baylor-Hopkins Center for Mendelian Genomics, Baylor College of Medicine, Houston, TX, 77030, USA.; Norwegian National Unit for Newborn Screening, Department of Pediatric and Adolescent Medicine, Oslo University Hospital, Pb 4950 Nydalen, 0424, Oslo, Norway.; Institute of Clinical Medicine, University of Oslo, 0318, Oslo, Norway., Sweetser DA; Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, MA, 02114, USA., Terhal PA; Department of Genetics, University Medical Centre Utrecht, P.O. Box 85500, 3508 GA, Utrecht, The Netherlands., Tveten K; Department of Medical Genetics, Telemark Hospital Trust, 3710, Skien, Norway., VanNoy GE; 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., de Vries PF; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Waxler JL; Division of Medical Genetics, Massachusetts General Hospital for Children, Boston, MA, 02114, USA., Willing M; Department of Pediatrics, Washington University School of Medicine, St Louis, MO, 63110, USA., Pfundt R; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., Veltman JA; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.; Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle, NE1 3BZ, UK., Kooy RF; Department of Medical Genetics, University Hospital and University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium., Vissers LELM; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands., de Vries BBA; 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.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2019 May; Vol. 27 (5), pp. 738-746. Date of Electronic Publication: 2019 Jan 24.
DOI: 10.1038/s41431-018-0292-2
Abstrakt: 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.
Databáze: MEDLINE
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