ArticleAmerican journal of human genetics2021
Variants in the degron of AFF3 are associated with intellectual disability, mesomelic dysplasia, horseshoe kidney, and epileptic encephalopathy.
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Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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21 citing papers in PubMed, 44 citations in OpenAlex.
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- Shared genetic architecture between grip strength and cognitive function: insights from large-scale genome-wide cross-trait analysis.Frontiers in genetics · 2025Article
- A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability.Nature genetics · 2024Article
- Integrative Multi-omics Analysis to Characterize Herpes Virus Infection Increases the Risk of Alzheimer's Disease.Molecular neurobiology · 2024Article
- Integrated mendelian randomization analyses highlight AFF3 as a novel eQTL-mediated susceptibility gene in renal cancer and its potential mechanisms.BMC cancer · 2024Article
- Molecular evolution of transcription factors AF4/FMR2 family member (AFF) gene family and the role of lamprey AFF3 in cell proliferation.Development genes and evolution · 2024Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.Genome medicine · 2024Article
- Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.American journal of human genetics · 2024Article
- Variant-specific pathophysiological mechanisms of AFF3 differently influence transcriptome profiles.medRxiv : the preprint server for health sciences · 2024Article
- Unravelling the link between neurodevelopmental disorders and short tandem CGG-repeat expansions.Emerging topics in life sciences · 2023Review
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- Six years' accomplishment of the Initiative on Rare and Undiagnosed Diseases: nationwide project in Japan to discover causes, mechanisms, and cures.Journal of human genetics · 2022Article
- Complex Diagnostics of Non-Specific Intellectual Developmental Disorder.International journal of molecular sciences · 2022Article
- Possible association of 16p11.2 copy number variation with altered lymphocyte and neutrophil counts.NPJ genomic medicine · 2022Article
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Authors and funding
68 authors at 20 institutions in 12 countries.
Norine VoisinCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland.
Rhonda E SchnurGeneDx, Gaithersburg, MD 20877, USA; Cooper Medical School of Rowan University, Division of Genetics, Camden, NJ 08103, USA.
Sofia DouzgouManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9NT, UK.
Susan M HiattHudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
Cecilie F RustadDepartment of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
Natasha J BrownVictorian Clinical Genetics Services, Flemington Road, Parkville, VIC 3052, Australia; Murdoch Children's Research Institute, Flemington Road, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, VIC 3052, Australia.
Dawn L EarlSeattle Children's, Seattle, WA 98105, USA.
Boris KerenDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Groupe de Recherche Clinique Déficience Intellectuelle et Autisme UPMC, Paris 75013, France.
Olga LevchenkoResearch Centre for Medical Genetics, Moscow 115522, Russia.
Sinje GeuerMax Planck Institute for Molecular Genetics, Berlin 14195, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
Sarah VerheyenInstitute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, 8010 Graz, Austria.
Diana JohnsonSheffield Clinical Genetics Service, Sheffield S10 2TQ, UK.
Yuri A ZarateSection of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72701, USA.
Miroslava HančárováCharles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
David J AmorMurdoch Children's Research Institute, Flemington Road, Parkville, VIC 3052, Australia; Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Flemington Road, Parkville, VIC 3052, Australia.
E Martina BebinDepartment of Neurology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
Jasmin BlattererInstitute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, 8010 Graz, Austria.
Alfredo BruscoDepartment of Medical Sciences, University of Torino, Torino 10126, Italy; Medical Genetics Unit, Città della Salute e della Scienza University Hospital, Torino 10126, Italy.
Gerarda CappuccioDepartment of Translational Medicine, Section of Pediatrics, Federico II University, Naples 80131, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Naples 80078, Italy.
Joel CharrowDivision of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Nicolas ChatronCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland; Genetics Department, Lyon University Hospital, Lyon 69007, France.
Gregory M CooperHudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
Thomas CourtinDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Groupe de Recherche Clinique Déficience Intellectuelle et Autisme UPMC, Paris 75013, France.
Elena DadaliResearch Centre for Medical Genetics, Moscow 115522, Russia.
Julien DelafontaineSwiss Institute of Bioinformatics, Lausanne 1015, Switzerland.
Ennio Del GiudiceDepartment of Translational Medicine, Section of Pediatrics, Federico II University, Naples 80131, Italy.
Martine DocoSecteur Génétique, CHU Reims, EA3801, SFR CAPSANTE, 51092 Reims, France.
Ganka DouglasGeneDx, Gaithersburg, MD 20877, USA.
Astrid EisenkölblDepartment of Pediatrics and Adolescent Medicine, Johannes Kepler University, Kepler University Hospital Linz, Krankenhausstraße 26-30, 4020 Linz, Austria.
Tara FunariGeneDx, Gaithersburg, MD 20877, USA.
Giuliana GiannuzziCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland.
Ursula Gruber-SedlmayrDivision of General Pediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, 8036 Graz, Austria.
Nicolas GuexCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland; Bioinformatics Competence Center, University of Lausanne, Lausanne 1015, Switzerland.
Delphine HeronDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Groupe de Recherche Clinique Déficience Intellectuelle et Autisme UPMC, Paris 75013, France.
Øystein L HollaDepartment of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
Anna C E HurstDepartment of Genetics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
Jane JuusolaGeneDx, Gaithersburg, MD 20877, USA.
David KronnNew York Medical College, Valhalla, NY 10595, USA.
Alexander LavrovResearch Centre for Medical Genetics, Moscow 115522, Russia.
Crystle LeeVictorian Clinical Genetics Services, Flemington Road, Parkville, VIC 3052, Australia.
Séverine LorrainCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland; Protein Analysis Facility, University of Lausanne, Lausanne 1015, Switzerland.
Else MerckollDepartment of Radiology, Oslo University Hospital, 0424 Oslo, Norway.
Anna MikhalevaCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland.
Jennifer NormanIntegris Pediatric Neurology, Oklahoma City, OK 73112, USA.
Sylvain PradervandCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland; Institute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste 34100, Italy.
Darina PrchalováCharles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
Lindsay RhodesGeneDx, Gaithersburg, MD 20877, USA.
Victoria R SandersDivision of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Zdeněk SedláčekCharles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
Heidelis A SeebacherInstitute of Human Genetics, Diagnostic and Research Center for Molecular Biomedicine, Medical University of Graz, 8010 Graz, Austria.
Elizabeth A SellarsSection of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR 72701, USA.
Fabio SirchiaInstitute for Maternal and Child Health - IRCCS Burlo Garofolo, Trieste 34100, Italy.
Toshiki TakenouchiCenter for Medical Genetics, Department of Pediatrics, Keio University School of Medicine, Tokyo 1608582, Japan.
Akemi J TanakaDepartment of Pediatrics, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA.
Heidi Taska-TenchDivision of Genetics, Birth Defects & Metabolism, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
Elin TønneDepartment of Medical Genetics, Oslo University Hospital, 0424 Oslo, Norway.
Kristian TvetenDepartment of Medical Genetics, Telemark Hospital Trust, 3710 Skien, Norway.
Giuseppina VitielloDepartment of Translational Medicine, Section of Pediatrics, Federico II University, Naples 80131, Italy.
Markéta VlčkováCharles University Second Faculty of Medicine and University Hospital Motol, 150 06 Prague, Czech Republic.
Tomoko UeharaCenter for Medical Genetics, Department of Pediatrics, Keio University School of Medicine, Tokyo 1608582, Japan.
Caroline NavaDepartment of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique - Hôpitaux de Paris, Groupe de Recherche Clinique Déficience Intellectuelle et Autisme UPMC, Paris 75013, France.
Binnaz YalcinCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland; Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch 67404, France.
Kenjiro KosakiCenter for Medical Genetics, Department of Pediatrics, Keio University School of Medicine, Tokyo 1608582, Japan.
Dian DonnaiManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester M13 9WL, UK; Division of Evolution and Genomic Sciences, School of Biological Sciences, University of Manchester, Manchester M13 9NT, UK.
Stefan MundlosMax Planck Institute for Molecular Genetics, Berlin 14195, Germany; Institute for Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin 10117, Germany.
Nicola Brunetti-PierriDepartment of Translational Medicine, Section of Pediatrics, Federico II University, Naples 80131, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Naples 80078, Italy.
Wendy K ChungDepartment of Pediatrics, Columbia University, New York, NY 10032, USA; Department of Medicine, Columbia University, New York, NY 10032, USA.
Alexandre ReymondCenter for Integrative Genomics, University of Lausanne, Lausanne 1015, Switzerland. Electronic address: alexandre.reymond@unil.ch.
University of Lausanne · CHCharles University · CZFederico II University Hospital · ITMedical University of Graz · ATSorbonne Université · FRKeio University · JPLurie Children's Hospital · USOslo University Hospital · NOResearch Centre for Medical Genetics · RUColumbia University · USHudsonAlpha Institute for Biotechnology · USIRCCS Materno Infantile Burlo Garofolo · ITManchester Academic Health Science Centre · GBMax Planck Institute for Molecular Genetics · DERoyal Children's Hospital · AUTelemark Hospital · NOUniversity of Alabama at Birmingham · USUniversity of Arkansas for Medical Sciences · USAzienda Ospedaliera Citta' della Salute e della Scienza di Torino · ITCentre Hospitalier Universitaire de Reims · FR
Funding
Genomic Diagnosis in Children with Developmental DelayUM1HG007301 · NHGRI · HUDSON-ALPHA INSTITUTE FOR BIOTECHNOLOGY · PI COOPER, GREGORY MICHAEL, MYERS, RICHARD M · 2013 to 2016
$7.5MNHGRI NIH HHS UM1 HG007301Wellcome Trust
Abstract
The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
Indexed as
Mutation, MissenseAdolescentAmino Acid SequenceAnimalsBrain DiseasesChildChild, PreschoolEpilepsyEvolution, MolecularFemaleFused KidneyGene FrequencyHumansInfantIntellectual DisabilityMaleAFF3 protein, humanAFF4 protein, humanNuclear ProteinsTranscriptional Elongation FactorsAFF3AFF4horseshoe kidneyintellectual disabilitymesomelic dysplasia
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