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

Peron A, D’Arco F, Aldinger KA, Smith-Hicks C, Zweier C, Gradek GA, Bradbury K, Accogli A, Andersen EF, Au PYB, Battini R, Beleford D, Bird LM, Bouman A, Bruel AL, Busk ØL, Campeau PM, Capra V, Carlston C, Carmichael J, Chassevent A, Clayton-Smith J, Bamshad MJ, Earl DL, Faivre L, Philippe C, Ferreira P, Graul-Neumann L, Green MJ, Haffner D, Haldipur P, Hanna S, Houge G, Jones WD, Kraus C, Kristiansen BE, Lespinasse J, Low KJ, Lynch SA, Maia S, Mao R, Kalinauskiene R, Melver C, McDonald K, Montgomery T, Morleo M, Motter C, Openshaw AS, Palumbos JC, Parikh AS, Perilla-Young Y, Powell CM, Person R, Desai M, Piard J, Pfundt R, Scala M, Serey-Gaut M, Shears D, Slavotinek A, Suri M, Turner C, Tvrdik T, Weiss K, Wentzensen IM, Zollino M, Hsieh TC, Ramsey K, Zollino M, Scala M, Capra V, Peron A, de Vries BB, Guillemot F, Dobyns WB, Viskochil D, Dias C (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1038/s41431-024-01701-z

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.

Authors with CRIS profile

Involved external institutions

Centro Hospitalar e Universitário de Coimbra (CHUC) Portugal (PT) University of Utah United States (USA) (US) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) Akron Children's Hospital United States (USA) (US) University of Mississippi Medical Center United States (USA) (US) Newcastle upon Tyne Hospitals NHS Foundation Trust United Kingdom (GB) Telethon Institute of Genetics and Medicine (TIGEM) Italy (IT) ARUP Laboratories United States (USA) (US) Case Western Reserve University United States (USA) (US) Royal Devon & Exeter NHS Foundation Trust United Kingdom (GB) Emory University United States (USA) (US) University of North Carolina at Chapel Hill United States (USA) (US) Technion - Israel Institute of Technology Israel (IL) Université de Bourgogne (uB) / University of Burgundy / University of Dijon France (FR) GeneDX United States (USA) (US) Catholic University of the Sacred Heart / Università Cattolica del Sacro Cuore Italy (IT) Universitätsklinikum Bonn Germany (DE) The Francis Crick Institute United Kingdom (GB) Nationwide Children's Hospital United States (USA) (US) Center for Integrative Brain Research United States (USA) (US) Rambam Health Care Campus Israel (IL) Haukeland University Hospital / Haukeland universitetssykehus Norway (NO) Translational Genomics Research Institute (TGen) United States (USA) (US) Donders Institute for Brain, Cognition and Behaviour Netherlands (NL) Université de Franche-Comté France (FR) University of Washington United States (USA) (US) Kennedy Krieger Institute United States (USA) (US) Johns Hopkins Hospital United States (USA) (US) University of Manchester United Kingdom (GB) Seattle Children's Hospital United States (USA) (US) Istituto Giannina Gaslini Italy (IT) Alberta Children's Hospital Research Institute (ACHRI) Canada (CA) IRCCS Fondazione Stella Maris Italy (IT) UCSF Benioff Children’s Hospital United States (USA) (US) Erasmus University Medical Center (MC) Netherlands (NL) Oxford University Hospitals NHS Foundation Trust United Kingdom (GB) Nottingham University Hospitals United Kingdom (GB) Telemark Hospital Trust Norway (NO) Centre Hospitalier Universitaire Sainte-Justine, CHU Sainte-Justine Canada (CA) Boston Children's Hospital United States (USA) (US) Great Ormond Street Hospital (GOSH) United Kingdom (GB) Addenbrooke's Hospital United Kingdom (GB) Oslo University Hospital / Oslo Universitetssykehus Rikshospitalet Norway (NO) Hôpital Chambéry - Centre Hospitalier de Chambéry - Hôpital Savoie France (FR) University Hospitals Bristol NHS Foundation Trust United Kingdom (GB) Temple Street Children's University Hospital / Children's Health Ireland (CHI) Ireland (IE) Charité - Universitätsmedizin Berlin Germany (DE)

How to cite

APA:

Peron, A., D’Arco, F., Aldinger, K.A., Smith-Hicks, C., Zweier, C., Gradek, G.A.,... Dias, C. (2024). BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations. European Journal of Human Genetics. https://doi.org/10.1038/s41431-024-01701-z

MLA:

Peron, Angela, et al. "BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations." European Journal of Human Genetics (2024).

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