BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
Author:
Peron AngelaORCID, D’Arco Felice, Aldinger Kimberly A., Smith-Hicks Constance, Zweier Christiane, Gradek Gyri A., Bradbury Kimberley, Accogli Andrea, Andersen Erica F., Au Ping Yee Billie, Battini Roberta, Beleford Daniah, Bird Lynne M., Bouman Arjan, Bruel Ange-Line, Busk Øyvind Løvold, Campeau Philippe M., Capra Valeria, Carlston Colleen, Carmichael Jenny, Chassevent Anna, Clayton-Smith Jill, Bamshad Michael J, Earl Dawn L., Faivre Laurence, Philippe Christophe, Ferrerira Patrick, Graul-Neumann Luitgard, Green Mary J., Haffner Darrah, Haldipur Parthiv, Hanna Suhair, Houge Gunnar, Hurst Jane, Kraus Cornelia, Kristiansen Birgit Elisabeth, Lespinasse James, Low Karen J., Lynch Sally Ann, Maia Sofia, Mao Rong, Marcinkute Ruta, Melver Catherine, McDonald Kimberly, Montgomery Tara, Morleo Manuela, Motter Constance, Openshaw Amanda S., Palumbos Janice Cox, Parikh Aditi Shah, Person Richard, Desai Megha, Piard Juliette, Pfundt Rolph, Scala Marcello, Serey-Gaut Margaux, Slavotinek Anne, Suri Mohnish, Turner Claire, Tvrdik Tatiana, Weiss Karin, Wentzensen Ingrid M., Zollino Marcella, de Vries Bert B.A., Guillemot Francois, Dobyns William B., Viskochil David, Dias CristinaORCID, , ,
Abstract
AbstractPurposeHeterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD.MethodsWe performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information.ResultsMolecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity.ConclusionsWe expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.
Publisher
Cold Spring Harbor Laboratory
Reference62 articles.
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