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Lookup NU author(s): Dr Parthiv Haldipur, Dr Tara Montgomery
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024.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.
Author(s): 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 A-L, Busk OL, 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 T-C, Ramsey K, Zollino M, Scala M, Capra V, Peron A, de Vries BBA, Guillemot F, Dobyns WB, Viskochil D, Dias C
Publication type: Article
Publication status: Published
Journal: European Journal of Human Genetics
Year: 2024
Pages: epub ahead of print
Online publication date: 24/10/2024
Acceptance date: 23/09/2024
Date deposited: 12/11/2024
ISSN (print): 1018-4813
ISSN (electronic): 1476-5438
Publisher: Springer Nature
URL: https://doi.org/10.1038/s41431-024-01701-z
DOI: 10.1038/s41431-024-01701-z
Data Access Statement: All clinical and molecular data included in this study are provided in Supplementary Material and Supplementary Tables. Aggregate data is publicly available at https://humandiseasegenes.nl/bcl11a. Genetic analyses had been previously performed. For access, please contact the authors who will refer to the appropriate center (data availability is subject to each individual study’s ethics and consent).
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