ArticleAmerican journal of human genetics2025
DNA-binding affinity and specificity determine the phenotypic diversity in BCL11B-related disorders.
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Article in American journal of human genetics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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5 citing papers in PubMed.
- The clinical and molecular spectrum of AGO2-associated Lessel-Kreienkamp neurodevelopmental syndrome.Genome medicine · 2026Article
- Expanding the phenotypic spectrum associated with ZIC1 variants: A neurodevelopmental disorder with and without craniosynostosis.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Bipartite DNA binding domain of transcription factor BCL11B binds clustered short DNA sequence motifs.bioRxiv : the preprint server for biology · 2026Article
- Dental rehabilitation under general anesthesia in an outpatient setting for a child with a heterozygous BCL11B variant: a case report.BMC oral health · 2026Article
- MALT1 in cerebrospinal fluid: a prognostic biomarker and potential therapeutic target in Alzheimer's disease.Frontiers in neurology · 2025Article
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Authors and funding
97 authors.
Ivana LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.
Anja BaresicDivision of Computing and Data Science, Ruđer Bošković Institute, 10000 Zagreb, Croatia.
Ivan K ChinnDepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Section of Immunology, Allergy, and Retrovirology, Texas Children's Hospital, Houston, TX 77030, USA.
Jonathan MayInstitute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Anu GoenkaManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Kate E ChandlerManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
Jennifer E PoseyDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Alexandra AfenjarDépartement de Génétique Paris, Centre de Référence Malformations et maladies congénitales du cervelet et déficiences intellectuelles de causes rares, APHP, Sorbonne Université, Paris, France.
Luisa AverdunkInstitute of Human Genetics, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany; Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine-University, 40225 Düsseldorf, Germany.
Maria Francesca BedeschiFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Medical Genetics Unit, Milan, Italy.
Thomas BesnardL'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France; Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes, France.
Rae BragerDivision of Rheumatology, Immunology and Allergy, McMaster Children's Hospital, Hamilton, ON L8S 4K1, Canada.
Lauren BrickDivision of Genetics and Metabolics, McMaster Children's Hospital, Hamilton, ON L8S 4K1, Canada.
Melanie BruggerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Department of Obstetrics and Gynecology, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany.
Theresa BrunetInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany.
Susan ByrneDepartment of Paediatric Neurology, Neuromuscular Service, Evelina's Children Hospital, Guy's & St. Thomas' Hospital NHS Foundation Trust, London, UK.
Oscar de la Calle-MartínImmunology Department, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
Valeria CapraGenomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Paul CardenasNicklaus Children's Hospital, Miami, FL, USA.
Céline ChappéService d'oncohematologie pédiatrique, CHU Rennes, 35000 Rennes, France.
Hey J ChongDepartment of Pediatrics, University of Pittsburgh School of Medicine, UPMC Children's Hospital, Pittsburgh, PA 15224, USA.
Benjamin CogneL'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France; Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes, France.
Erin ConboyDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Heidi CopeDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Thomas CourtinDépartement de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Wallid DebL'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France; Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes, France.
Robertino DilenaFondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Neuropathophysiology Unit, Milan, Italy.
Christèle DubourgService de Génétique Moléculaire et Génomique, CHU, 35033 Rennes, France; University Rennes, CNRS, IGDR, UMR 6290, 35000 Rennes, France.
Magdeldin ElgizouliInstitut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Erica FernandesDivision of Genetics, Department of Pediatrics, Nemours Children's Health, Wilmington, DE, USA.
Kristi K FitzgeraldDepartment of Cardiology, Nemours Children's Hospital, Wilmington, DE, USA.
Silvana GangiNeonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via Francesco Sforza, 28, 20122 Milan, Italy.
Jaya K George-AbrahamDell Children's Medical Group, Austin, TX, USA; Department of Pediatrics, The University of Texas at Austin Dell Medical School, Austin, TX, USA.
Muge Gucsavas-CalikogluDivision of Genetics and Metabolism, Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Tobias B HaackInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Medard HadonouSouth West Thames Centre for Genomics, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
Britta HankerInstitute of Human Genetics, University of Lübeck, Lübeck, Germany.
Irina HüningInstitute of Human Genetics, University of Lübeck, Lübeck, Germany.
Maria IasconeMedical Genetics Laboratory, ASST Papa Giovanni XXIII, 24128 Bergamo, Italy.
Bertrand IsidorL'Institut du Thorax, INSERM, CNRS, Université de Nantes, 44007 Nantes, France; Service de Génétique Médicale, CHU Nantes, 9 quai Moncousu, 44093 Nantes, France.
Irma JärveläDepartment of Medical Genetics, University of Helsinki, P.O. Box 720, 00251 Helsinki, Finland.
Jay J JinDivision of Pediatric Pulmonology, Allergy, and Sleep Medicine, Riley Hospital for Children, Indiana University School of Medicine, Indianapolis, IN, USA.
Alexander A L JorgeUnidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular (LIM42), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil; Unidade de Endocrinologia Genetica (LIM25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.
Dragana JosifovaDepartment of Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
Ruta KalinauskieneDepartment of Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
Erik-Jan KamsteegDepartment of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Boris KerenDépartement de Génétique, Hôpital La Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France.
Elena KesslerDivision of Pediatric Hematology/Oncology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Heike KölbelDepartment of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Hospital Essen, Essen, Germany.
Mariya KozenkoDivision of Genetics and Metabolics, McMaster Children's Hospital, Hamilton, ON L8S 4K1, Canada.
Christian KubischInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Alma KuechlerInstitut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, Essen, Germany.
Suzanne M LealDepartment of Neurology, Center for Statistical Genetics, Gertrude H. Sergievsky Center, Columbia University Medical Center, Columbia University, New York, NY 10032, USA; Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, NY, USA.
Juha LeppäläThe Wellbeing Services County of South Ostrobothnia, 60280 Seinäjoki, Finland.
Sharon M LuuDepartment of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Gholson J LyonDepartment of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, USA; George A. Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, NY, USA; Biology PhD Program, The Graduate Center, The City University of New York, New York, NY, USA.
Suneeta Madan-KhetarpalDepartment of Pediatrics, Division of Medical Genetics and Genomic Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
Margherita MancardiUnit of Child Neuropsychiatry, IRCCS Istituto Giannina Gaslini, Epicare Network for Rare Disease, Genoa, Italy.
Elaine MarchiDepartment of Human Genetics, New York State Institute for Basic Research in Developmental Disabilities, New York, NY, USA.
Lakshmi MehtaDepartment of Pediatrics, Division of Clinical Genetics, Columbia University Irving Medical Center, New York, NY, USA.
Beatriz MenendezDivision of Genetics, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Chantal F MorelFred A. Litwin Family Centre in Genetic Medicine, Department of Medicine, University Health Network, Toronto, ON, Canada.
Sue Moyer HarasinkDivision of Genetics, Department of Pediatrics, Nemours Children's Health, Wilmington, DE, USA.
Dayna-Lynn NevayFred A. Litwin Family Centre in Genetic Medicine, Department of Medicine, University Health Network, Toronto, ON, Canada.
Vincenzo NigroDepartment of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
Sylvie OdentClinical Genetics, Centre de Référence Maladies Rares CLAD-Ouest, ERN-ITHACA, FHU GenOMedS, CHU de Rennes, Rennes, France; University Rennes, CNRS, INSERM, Institut de génétique et développement de Rennes, UMR 6290, ERL U1305, Rennes, France.
Renske OegemaDepartment of Genetics, University Medical Center Utrecht, Utrecht University, 3584 EA Utrecht, the Netherlands.
John PappasDepartment of Pediatrics, New York University Grossman School of Medicine, New York, NY 10016, USA.
Matthew T PastoreDivision of Genetic and Genomic Medicine, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA.
Yezmin Perilla-YoungDivision of Genetics and Metabolism, Department of Pediatrics, University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
Nina Powell-HamiltonDivision of Medical Genetics, Nemours Children's Hospital, Wilmington, DE, USA.
Rachel RabinDepartment of Pediatrics, New York University Grossman School of Medicine, New York, NY 10016, USA.
Aisha RekabDepartment of Pediatrics, Division of Clinical Genetics, Columbia University Irving Medical Center, New York, NY, USA.
Raissa C RezendeUnidade de Endocrinologia Genetica (LIM25), Hospital das Clinicas da Faculdade de Medicina, Universidade de São Paulo (USP), São Paulo, Brazil.
Leema RobertDepartment of Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
Ferruccio RomanoGenomics and Clinical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Marcello ScalaDepartment of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, 16145 Genoa, Italy; U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Karin PothsInstitute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Isabelle SchrauwenDepartment of Translational Neurosciences, University of Arizona College of Medicine - Phoenix, Phoenix, AZ 85004, USA.
Jessica SebastianDepartment of Pediatrics, Division of Medical Genetics and Genomic Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA, USA.
John ShortSouth West Thames Centre for Genomics, St George's University Hospitals NHS Foundation Trust, London SW17 0QT, UK.
Richard SidlowDepartment of Medical Genetics and Metabolism, Valley Children's Hospital, Madera, CA, USA.
Jennifer SullivanDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Katalin SzakszonInstitute of Pediatrics, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary.
Queenie K G TanDivision of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
Undiagnosed Diseases NetworkUndiagnosed Diseases Network, NIH, Bethesda, MD, USA.
Matias WagnerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, Germany; Institute of Neurogenomics, Helmholtz Zentrum München, Neuherberg, Germany; Department of Pediatrics, Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, University Hospital of Munich, Munich, Germany.
Dagmar WieczorekInstitute of Human Genetics, Medical Faculty and University Hospital, Heinrich Heine University, Düsseldorf, Germany.
Bo YuanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Nicole MaedingCell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
Dirk StrunkCell Therapy Institute, Paracelsus Medical University (PMU), 5020 Salzburg, Austria.
Amber BegtrupGeneDx, LLC, Gaithersburg, MD 20877, USA.
Siddharth BankaManchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK; Division of Evolution, Infection & Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
James R LupskiDepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Eva TolosaInstitute of Immunology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; German Center for Child and Adolescent Health (DZKJ), partner site Hamburg, Hamburg, Germany.
Davor LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany; Institute of Human Genetics, University of Regensburg, 93053 Regensburg, Germany; Institute of Clinical Human Genetics, University Hospital Regensburg, 93053 Regensburg, Germany. Electronic address: davor.lessel@klinik.uni-regensburg.de.
Funding
Baylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MFrequency of variants of unknown significance by ancestry groups in the All of Us Research Program cohortU01HG011758 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI RICHARD A GIBBS, JAMES R. LUPSKI · 2021 to 2026
$13.8MAn integrated and diverse genomic medicine program for undiagnosed diseasesU01HG007672 · NHGRI · DUKE UNIVERSITY · PI SHASHI, VANDANA · 2014 to 2022
$13.4MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MAn integrated and diverse genomic medicine program for undiagnosed diseasesU01NS134350 · NINDS · DUKE UNIVERSITY · PI VANDANA SHASHI · 2023 to 2026
$3.6MElucidating the Genetic Etiology of Intellectual Disability in African, Asian, and European FamiliesR01HD109342 · NICHD · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI SUZANNE M LEAL, Isabelle Veerle Suzanne Schrauwen · 2023 to 2026
$2.5MNHGRI NIH HHS U01 HG007672NHGRI NIH HHS U01 HG011758NHGRI NIH HHS UM1 HG006542NICHD NIH HHS R01 HD109342NINDS NIH HHS R35 NS105078NINDS NIH HHS U01 NS134350
Abstract
BCL11B is a Cys2-His2 zinc-finger (C2H2-ZnF) domain-containing, DNA-binding, transcription factor with established roles in the development of various organs and tissues, primarily the immune and nervous systems. BCL11B germline variants have been associated with a variety of developmental syndromes. However, genotype-phenotype correlations along with pathophysiologic mechanisms of selected variants mostly remain elusive. To dissect these, we performed genotype-phenotype correlations of 92 affected individuals harboring a pathogenic or likely pathogenic BCL11B variant, followed by immune phenotyping, analysis of chromatin immunoprecipitation DNA-sequencing data, dual-luciferase reporter assays, and molecular modeling. These integrative analyses enabled us to define three clinical subtypes of BCL11B-related disorders. It is likely that gene-disruptive BCL11B variants and missense variants affecting zinc-binding cysteine and histidine residues cause mild to moderate neurodevelopmental delay with increased propensity for behavioral and dental anomalies, allergies and asthma, and reduced type 2 innate lymphoid cells. Missense variants within C2H2-ZnF DNA-contacting α helices cause highly variable clinical presentations ranging from multisystem anomalies with demise in the first years of life to late-onset, hyperkinetic movement disorder with poor fine motor skills. Those not in direct DNA contact cause a milder phenotype through reduced, target-specific transcriptional activity. However, missense variants affecting C2H2-ZnFs, DNA binding, and "specificity residues" impair BCL11B transcriptional activity in a target-specific, dominant-negative manner along with aberrant regulation of alternative DNA targets, resulting in more severe and unpredictable clinical outcomes. Taken together, we suggest that the phenotypic severity and variability is largely dependent on the DNA-binding affinity and specificity of altered BCL11B proteins.
Indexed as
Developmental DisabilitiesDNA-Binding ProteinsPhenotypeTumor Suppressor ProteinsAdolescentAmino Acid SequenceBinding SitesChildChild, PreschoolFemaleGenome, HumanHEK293 CellsHumansInfantMaleMutationDNA-Binding ProteinsTumor Suppressor ProteinsBCL11BC2H2-type zinc finger proteingenotype-phenotype correlationrecognition codetype 2 innate lymphoid cells
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