BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
Authors: Peron Angela , 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 , Ferreira Patrick , Graul-Neumann Luitgard , Green Mary J. , Haffner Darrah , Haldipur Parthiv , Hanna Suhair , Houge Gunnar , Jones Wendy D. , Kraus Cornelia , Kristiansen Birgit Elisabeth , Lespinasse James , Low Karen J. , Lynch Sally Ann , Maia Sofia , Mao Rong , Kalinauskiene Ruta , Melver Catherine , McDonald Kimberly , Montgomery Tara , Morleo Manuela , Motter Constance , Openshaw Amanda S. , Palumbos Janice Cox , Parikh Aditi Shah , Perilla-Young Yezmin , Powell Cynthia M. , Person Richard , Desai Megha , Piard Juliette , Pfundt Rolph , Scala Marcello , Serey-Gaut Margaux , Shears Deborah , Slavotinek Anne , Suri Mohnish , Turner Claire , Tvrdik Tatiana , Weiss Karin , Wentzensen Ingrid M. , Zollino Marcella , Hsieh Tzung-Chien ,   C4RCD Research Group, Ramsey Keri ,   Telethon Undiagnosed Disease Program (TUDP), Peron Angela , Accogli Andrea , Capra Valeria , Morleo Manuela , Scala Marcello , Zollino Marcella ,   University of Washington Center for Mendelian Genomics (UW-CMG), de Vries Bert B. A. , Guillemot Francois , Dobyns William B. , Viskochil David , Dias Cristina 
Published: October 2024

AbstractAn 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.