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

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.

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Publication Details

Journal
European Journal of Human Genetics
Published
2024-10-24
DOI
https://doi.org/10.1038/s41431-024-01701-z
Citations
15
Primary Topic
Genomic variations and chromosomal abnormalities
Type
article
Field-Weighted Citation Impact
8.25

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article

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

Colleen M. Carlston, Rong Mao, Juliette Piard, Andrea Accogli et al.
15 citations
European Journal of Human Genetics
Genomic variations and chromosomal abnormalities
8.25
article

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

Colleen M. Carlston, Rong Mao, Juliette Piard, Andrea Accogli, Constance Smith‐Hicks, Christiane Zweier, Kimberly A. Aldinger, Cristina Dias, Wendy D. Jones, Margaux Serey‐Gaut, Rolph Pfundt, Lynne M. Bird, Ping Yee Billie Au, Anne Slavotinek, Darrah Haffner, Marcella Zollino, Ingrid M. Wentzensen, Mohnish Suri, Laurence Olivier Faivre, François Guillemot, Megha Desai, Marcello Scala, Keri Ramsey, Constance Motter, Christophe Philippe, Parthiv Haldipur, David H. Viskochil, Angela Peron, Roberta Battini, Claire Turner, Deborah Shears, Luitgard Graul‐Neumann, Karin Weiss, Cynthia M. Powell, Dawn Earl, Amanda Openshaw, Jill Clayton‐Smith, William B. Dobyns, Yezmin Perilla‐Young, Felice D’Arco, Ange‐Line Bruel, Patrick Ferreira, Karen Low, Kimberly S. McDonald, Michael J. Bamshad, Øyvind L. Busk, Tzung‐Chien Hsieh, Tatiana Tvrdik, Bert B.A. de Vries, Jenny Carmichael, Aditi Shah Parikh, Manuela Morleo, Gunnar Houge, Gyri Aasland Gradek, Daniah Beleford, Erica Andersen, Cornelia Kraus, Sally Ann Lynch, Anna Chassevent, Janice C. Palumbos, Arjan Bouman, Birgit Elisabeth Kristiansen, Sofia Maia, Mary J. Green, Ruta Kalinauskiene, Philippe M. Campeau, James Lespinasse, Suhair Hanna, Richard Person, Catherine Melver, Tara Montgomery, Kimberley Bradbury
article en
15 citations

Abstract

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.

European Journal of Human GeneticsVol. 33(3)
Università Cattolica del Sacro Cuore (IT), University of Pisa (IT), University of North Carolina at Chapel Hill (US), University of Bern (CH), Oslo University Hospital (NO), Translational Genomics Research Institute (US), Cincinnati Children's Hospital Medical Center (US), Hôpital Necker-Enfants Malades (FR), Boston Children's Hospital (US), Seattle Children's Hospital (US), Kennedy Krieger Institute (US), University of Minnesota (US), AOL (United States) (US), Nationwide Children's Hospital (US), Nottingham University Hospitals NHS Trust (GB), University of Bonn (DE), Johns Hopkins University (US), Radboud University Nijmegen (NL), Emory University (US), Inserm (FR), University of Calgary (CA), Technion – Israel Institute of Technology (IL), Université de Bourgogne (FR), University of California, San Francisco (US), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), King's College London (GB), University of Campania "Luigi Vanvitelli" (IT), Guy's and St Thomas' NHS Foundation Trust (GB), University of Washington (US), University of Utah (US), University Hospitals of Cleveland (US), University Hospital Bonn (DE), Royal Devon & Exeter NHS Foundation Trust (GB), Johns Hopkins Medicine (US), Great Ormond Street Hospital (GB), Haukeland University Hospital (NO), University Hospitals Bristol NHS Foundation Trust (GB), The Francis Crick Institute (GB), University Hospital of Bern (CH), Rambam Health Care Campus (IL), Istituto Giannina Gaslini (IT), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), Princess Anne Hospital (GB), Erasmus MC (NL), Hospitais da Universidade de Coimbra (PT), Alberta Children's Hospital (CA), Centre Hospitalier Universitaire Sainte-Justine (CA), Agostino Gemelli University Polyclinic (IT), Jackson Memorial Hospital (US), Radboud University Medical Center (NL), University of Manchester (GB), University of Mississippi Medical Center (US), Children's Health Ireland at Crumlin (IE), University of California San Diego (US), Rady Children's Hospital-San Diego (US), St Mary's Hospital (GB), Universitätsklinikum Erlangen (DE), Manchester University NHS Foundation Trust (GB), Assistance Publique – Hôpitaux de Paris (FR), Akron Children's Hospital (US), Center for Human Genetics (US), Centre Hospitalier Métropole Savoie (FR), Ospedale San Paolo (IT), Meyer Children's Hospital (IT), CHU Dijon Bourgogne (FR), Telemark Hospital (NO), Fondazione Stella Maris (IT), UCSF Benioff Children's Hospital (US), Oxford University Hospitals NHS Trust (GB), Telethon Institute Of Genetics And Medicine (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), Addenbrooke's Hospital (GB), St. Mary's Hospital (GB), University Hospitals Bristol and Weston NHS Foundation Trust (GB), University of Florence (IT), University College London (GB), Case Western Reserve University (US), ARUP Laboratories (United States) (US), Université de Montréal (CA), University of California, Davis (US), Université de Franche-Comté (FR), University of Cincinnati Medical Center (US)
University of Washington, Seattle Children's Research Institute, Wellcome Trust, Francis Crick Institute, Children’s Hospital of Wisconsin Research Institute, National Institute for Health and Care Research, National Institutes of Health, Center for Mendelian Genomics, University of Washington, Medical Research Council
Partnerships for the goals
Openalex Percentile: Top 2%
Genomic variations and chromosomal abnormalities
8.25
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