BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations.
Creators: name: Peron, Angela
name: D'Arco, Felice
name: Aldinger, Kimberly A
name: Smith-Hicks, Constance
name: Zweier, Christiane
name: Gradek, Gyri A
name: Bradbury, Kimberley
name: Accogli, Andrea
name: Andersen, Erica F
name: Au, Ping Yee Billie
name: Battini, Roberta
name: Beleford, Daniah
name: Bird, Lynne M
name: Bouman, Arjan
name: Bruel, Ange-Line
name: Busk, Øyvind Løvold
name: Campeau, Philippe M
name: Capra, Valeria
name: Carlston, Colleen
name: Carmichael, Jenny
name: Chassevent, Anna
name: Clayton-Smith, Jill
name: Bamshad, Michael J
name: Earl, Dawn L
name: Faivre, Laurence
name: Philippe, Christophe
name: Ferreira, Patrick
name: Graul-Neumann, Luitgard
name: Green, Mary J
name: Haffner, Darrah
name: Haldipur, Parthiv
name: Hanna, Suhair
name: Houge, Gunnar
name: Jones, Wendy D
name: Kraus, Cornelia
name: Kristiansen, Birgit Elisabeth
name: Lespinasse, James
name: Low, Karen J
name: Lynch, Sally Ann
name: Maia, Sofia
name: Mao, Rong
name: Kalinauskiene, Ruta
name: Melver, Catherine
name: McDonald, Kimberly
name: Montgomery, Tara
name: Morleo, Manuela
name: Motter, Constance
name: Openshaw, Amanda S
name: Palumbos, Janice Cox
name: Parikh, Aditi Shah
name: Perilla-Young, Yezmin
name: Powell, Cynthia M
name: Person, Richard
name: Desai, Megha
name: Piard, Juliette
name: Pfundt, Rolph
name: Scala, Marcello
name: Serey-Gaut, Margaux
name: Shears, Deborah
name: Slavotinek, Anne
name: Suri, Mohnish
name: Turner, Claire
name: Tvrdik, Tatiana
name: Weiss, Karin
name: Wentzensen, Ingrid M
name: Zollino, Marcella
name: Hsieh, Tzung-Chien
name: Group, C4RCD Research
name: (TUDP, Telethon Undiagnosed Disease Program
name: (UW-CMG, University of Washington Center for Mendelian Genomics
name: de Vries, Bert BA
name: Guillemot, Francois
name: Dobyns, William B
name: Viskochil, David
name: Dias, Cristina
Publisher: name: The Francis Crick Institute
Year: 2025
Subjects: classificationCode: Stem Cells
subject: Stem Cells
classificationCode: Gene Expression
subject: Gene Expression
classificationCode: Genetics & Genomics
subject: Genetics &amp; Genomics
classificationCode: Developmental Biology
subject: Developmental Biology
classificationCode: Neurosciences
subject: Neurosciences
subject: FOS: Clinical medicine
classificationCode: Human Biology & Physiology
subject: Human Biology &amp; Physiology
classificationCode: Model organisms
subject: Model organisms

description: 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.