BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.

Journal

European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235

Informations de publication

Date de publication:
24 Oct 2024
Historique:
received: 24 01 2024
accepted: 23 09 2024
revised: 27 04 2024
medline: 25 10 2024
pubmed: 25 10 2024
entrez: 25 10 2024
Statut: aheadofprint

Résumé

An increasing number of individuals with intellectual developmental disorder (IDD) and heterozygous variants in BCL11A are identified, yet our knowledge of manifestations and mutational spectrum is lacking. To address this, we performed detailed analysis of 42 individuals with BCL11A-related IDD (BCL11A-IDD, a.k.a. Dias-Logan syndrome) ascertained through an international collaborative network, and reviewed 35 additional previously reported patients. Analysis of 77 affected individuals identified 60 unique disease-causing variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique BCL11A microdeletions. We define the most prevalent features of BCL11A-IDD: IDD, postnatal-onset microcephaly, hypotonia, behavioral abnormalities, autism spectrum disorder, and persistence of fetal hemoglobin (HbF), and identify autonomic dysregulation as new feature. BCL11A-IDD is distinguished from 2p16 microdeletion syndrome, which has a higher incidence of congenital anomalies. Our results underscore BCL11A as an important transcription factor in human hindbrain development, identifying a previously underrecognized phenotype of a small brainstem with a reduced pons/medulla ratio. Genotype-phenotype correlation revealed an isoform-dependent trend in severity of truncating variants: those affecting all isoforms are associated with higher frequency of hypotonia, and those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S), are associated with higher frequency of postnatal microcephaly. With the largest international cohort to date, this study highlights persistence of fetal hemoglobin as a consistent biomarker and hindbrain abnormalities as a common feature. It contributes significantly to our understanding of BCL11A-IDD through an extensive unbiased multi-center assessment, providing valuable insights for diagnosis, management and counselling, and into BCL11A's role in brain development.

Identifiants

DOI: 10.1038/s41431-024-01701-z PMID: 39448799
pubmed: 39448799
doi: 10.1038/s41431-024-01701-z
pii: 10.1038/s41431-024-01701-z
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : U.S. Department of Health & Human Services | NIH | National Human Genome Research Institute (NHGRI)
ID : UM1;HG006493
Organisme : NHGRI NIH HHS
ID : U24 HG008956
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA210561
Organisme : Wellcome Trust (Wellcome)
ID : 209568/Z/17/Z

Investigateurs

Keri Ramsey (K)
Angela Peron (A)
Andrea Accogli (A)
Valeria Capra (V)
Manuela Morleo (M)
Marcello Scala (M)
Marcella Zollino (M)

Informations de copyright

© 2024. The Author(s).

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Auteurs

Angela Peron (A)

Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA. angela.peron@unifi.it.
Medical Genetics, ASST Santi Paolo e Carlo, San Paolo Hospital, Milano, Italy. angela.peron@unifi.it.
Department of Experimental and Clinical Biomedical Sciences, Università degli Studi di Firenze, Firenze, Italy. angela.peron@unifi.it.
Medical Genetics, Meyer Children's Hospital IRCCS, Firenze, Italy. angela.peron@unifi.it.
ORCID: 0000-0002-1769-6548

Felice D'Arco (F)

Department of Radiology, Great Ormond Street Hospital for Children, London, UK.

Kimberly A Aldinger (KA)

Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
ORCID: 0000-0002-5406-8911

Constance Smith-Hicks (C)

Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.

Christiane Zweier (C)

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.
Department of Human Genetics, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
ORCID: 0000-0001-8002-2020

Gyri A Gradek (GA)

Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Kimberley Bradbury (K)

Department of Medical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
Wessex Regional Genetics Service, Princess Anne Hospital, Southampton, UK.

Andrea Accogli (A)

Genomics and Clinical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy.
U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy.

Erica F Andersen (EF)

ARUP Laboratories, Cytogenetics and Genomic Microarray, Salt Lake City, UT, USA.
Department of Pathology, University of Utah, Salt Lake City, UT, USA.
ORCID: 0000-0002-7205-0600

Ping Yee Billie Au (PYB)

Department of Pediatrics, Division of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Roberta Battini (R)

IRCCS Fondazione Stella Maris, Pisa, Italy.
Dipartimento di Medicina Clinica e Sperimentale, University of Pisa, Pisa, Italy.

Daniah Beleford (D)

Division of Medical Genetics, Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, CA, USA.
Department of Pediatrics and Physiology & Membrane Biology, University of California, Davis, CA, USA.

Lynne M Bird (LM)

Department of Pediatrics, University of California San Diego, San Diego, CA, USA.
Division of Genetics/Dysmorphology, Rady Children's Hospital San Diego, San Diego, CA, USA.
ORCID: 0000-0003-4833-3747

Arjan Bouman (A)

Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.

Ange-Line Bruel (AL)

INSERM UMR 1231 Equipe GAD, Université de Bourgogne, Dijon, France.
Unité Fonctionnelle d'Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
ORCID: 0000-0002-0526-465X

Øyvind Løvold Busk (ØL)

Department of Medical Genetics, Telemark Hospital Trust, 3710, Skien, Norway.

Philippe M Campeau (PM)

Department of Pediatrics, CHU Sainte-Justine and University of Montreal, Montreal, QC, Canada.
ORCID: 0000-0001-9713-7107

Valeria Capra (V)

Genomics and Clinical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy.
ORCID: 0000-0002-3097-0388

Colleen Carlston (C)

Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.

Jenny Carmichael (J)

Department of Clinical Genetics, Addenbrooke's Hospital, Cambridge, UK.

Anna Chassevent (A)

Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.

Jill Clayton-Smith (J)

Division of Evolution and Genomic Sciences School of Biological Sciences University of Manchester, Manchester, UK.
Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.

Michael J Bamshad (MJ)

Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
University of Washington, Seattle, WA, USA.

Dawn L Earl (DL)

Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA, USA.
University of Washington, Seattle, WA, USA.

Laurence Faivre (L)

INSERM UMR 1231 Equipe GAD, Université de Bourgogne, Dijon, France.
Centre de Référence Maladies Rares Anomalies du développement et syndromes malformatifs, Centre de Génétique, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
ORCID: 0000-0001-9770-444X

Christophe Philippe (C)

INSERM UMR 1231 Equipe GAD, Université de Bourgogne, Dijon, France.
Unité Fonctionnelle d'Innovation diagnostique des maladies rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France.
ORCID: 0000-0001-7098-6520

Patrick Ferreira (P)

Department of Pediatrics, Division of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Luitgard Graul-Neumann (L)

Universitätsmedizin Berlin, Institut für Medizinische Genetik und Humangenetik, Berlin, Germany.

Mary J Green (MJ)

Experimental Histopathology Laboratory, The Francis Crick Institute, London, UK.

Darrah Haffner (D)

Department of Pediatrics, Division of Pediatric Neurology, Nationwide Children's Hospital and Ohio State University, Columbus, OH, USA.

Parthiv Haldipur (P)

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.

Suhair Hanna (S)

Department of Pediatric Immunology, Rappaport Children's Hospital, Rambam Health Care Campus, Haifa, Israel.
Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.

Gunnar Houge (G)

Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.

Wendy D Jones (WD)

North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK.
ORCID: 0000-0003-4017-3806

Cornelia Kraus (C)

Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany.

Birgit Elisabeth Kristiansen (BE)

Department of Neurohabilitation, Oslo University Hospital, Oslo, Norway.

James Lespinasse (J)

HDR - Service de Génétique Médicale, Centre Hospitalier Métropole Savoie, Chambery, France.

Karen J Low (KJ)

Clinical Genetics Service, University Hospitals Bristol and Weston NHS trust, Bristol, UK.

Sally Ann Lynch (SA)

Department of Clinical Genetics, Children's Health Ireland at Crumlin, Dublin, Ireland.
ORCID: 0000-0003-3540-1333

Sofia Maia (S)

Medical Genetics Unit, Hospital Pediátrico, Centro Hospitalar Universidade de Coimbra, Coimbra, Portugal.

Rong Mao (R)

Department of Pathology, University of Utah, Salt Lake City, UT, USA.

Ruta Kalinauskiene (R)

Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
Department of Medical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.

Catherine Melver (C)

Division of Medical Genetics, Akron Children's Hospital, Akron, OH, USA.

Kimberly McDonald (K)

University of Mississippi Medical Center, Jackson, MS, USA.

Tara Montgomery (T)

Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne NHS Foundation Trust, Newcastle, UK.

Manuela Morleo (M)

Telethon Institute of Genetics and Medicine, Pozzuoli, Napoli, Italy.
Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Napoli, Italy.

Constance Motter (C)

Division of Medical Genetics, Akron Children's Hospital, Akron, OH, USA.

Amanda S Openshaw (AS)

ARUP Laboratories, Cytogenetics and Genomic Microarray, Salt Lake City, UT, USA.

Janice Cox Palumbos (JC)

Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

Aditi Shah Parikh (AS)

Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
Center for Human Genetics, University Hospitals Cleveland Medical Center, Cleveland, OH, USA.

Yezmin Perilla-Young (Y)

Division of Pediatric Genetics and Metabolism, University of North Carolina, Chapel Hill, NC, USA.

Cynthia M Powell (CM)

Division of Pediatric Genetics and Metabolism, University of North Carolina, Chapel Hill, NC, USA.

Richard Person (R)

GeneDx, Gaithersburg, MD, USA.

Megha Desai (M)

GeneDx, Gaithersburg, MD, USA.

Juliette Piard (J)

Centre de Génétique Humaine, Université de Franche-Comté, CHU, Besançon, France.
ORCID: 0000-0001-5244-5325

Rolph Pfundt (R)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.

Marcello Scala (M)

U.O.C. Genetica Medica, IRCCS Istituto Giannina Gaslini, Genova, Italy.
Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genova, Italy.
ORCID: 0000-0003-2194-7239

Margaux Serey-Gaut (M)

Centre de Génétique Humaine, Université de Franche-Comté, CHU, Besançon, France.
Centre de Recherche en Audiologie, Hôpital Necker, AP-HP. CUP, Paris, France.

Deborah Shears (D)

Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Anne Slavotinek (A)

Division of Medical Genetics, Department of Pediatrics, Benioff Children's Hospital, University of California, San Francisco, CA, USA.
Division of Human Genetics, Cincinnati Children's Hospital, and Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA.

Mohnish Suri (M)

Nottingham Clinical Genetics Service; Nottingham University Hospitals NHS Trust, Nottingham, UK.

Claire Turner (C)

Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

Tatiana Tvrdik (T)

Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.

Karin Weiss (K)

Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
Genetics Institute, Rambam Health Care Campus, Haifa, Israel.
ORCID: 0000-0003-0998-810X

Ingrid M Wentzensen (IM)

GeneDx, Gaithersburg, MD, USA.

Marcella Zollino (M)

Dipartimento Universitario Scienze della Vita e Sanità Pubblica, Sezione di Medicina Genomica, Università Cattolica Sacro Cuore, Roma, Italy.
Genetica Medica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Roma, Italy.
ORCID: 0000-0003-4871-9519

Tzung-Chien Hsieh (TC)

Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn, Rheinische Friedrich-Wilhelms-Universität Bonn, Bonn, Germany.
ORCID: 0000-0003-3828-4419

Bert B A de Vries (BBA)

Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands.
ORCID: 0000-0002-0000-2917

Francois Guillemot (F)

Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, UK.

William B Dobyns (WB)

Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Division of Genetics and Metabolism, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
ORCID: 0000-0002-7681-2844

David Viskochil (D)

Division of Medical Genetics, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA.

Cristina Dias (C)

Department of Medical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK. cristina.dias@kcl.ac.uk.
North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children, Great Ormond Street, London, UK. cristina.dias@kcl.ac.uk.
Neural Stem Cell Biology Laboratory, The Francis Crick Institute, London, UK. cristina.dias@kcl.ac.uk.
Department of Medical & Molecular Genetics, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King's College London, London, UK. cristina.dias@kcl.ac.uk.
ORCID: 0000-0001-5411-4984

Classifications MeSH