BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations
Creators: name: D’Arco, Felice
name: Pfundt, Rolph
name: Kristiansen, Birgit Elisabeth
name: Green, Mary J.
name: Lynch, Sally Ann
name: Openshaw, Amanda S.
name: Tvrdik, Tatiana
name: Slavotinek, Anne
name: Maia, Sofia
name: Morleo, Manuela
name: Person, Richard
name: Andersen, Erica F.
name: Wentzensen, Ingrid M.
name: Busk, Øyvind Løvold
name: Motter, Constance
name: Shears, Deborah
name: Zollino, Marcella
name: Perilla-Young, Yezmin
name: Zweier, Christiane
name: Carlston, Colleen
name: Bamshad, Michael J.
name: Hsieh, Tzung-Chien
name: Bradbury, Kimberley
name: Bruel, Ange-Line
name: Ferreira, Patrick
name: Earl, Dawn L.
name: Viskochil, David
name: Melver, Catherine
name: Parikh, Aditi Shah
name: Aldinger, Kimberly A.
name: Clayton-Smith, Jill
name: Campeau, Philippe M.
name: Hanna, Suhair
name: Capra, Valeria
name: Dias, Cristina
name: Houge, Gunnar
name: Haldipur, Parthiv
name: Serey-Gaut, Margaux
name: de Vries, Bert B. A.
name: Kalinauskiene, Ruta
name: Desai, Megha
name: Bouman, Arjan
name: Accogli, Andrea
name: Jones, Wendy D.
name: Piard, Juliette
name: Smith-Hicks, Constance
name: Montgomery, Tara
name: Beleford, Daniah
name: Suri, Mohnish
name: Gradek, Gyri A.
name: Chassevent, Anna
name: Powell, Cynthia M.
name: Lespinasse, James
name: Weiss, Karin
name: Palumbos, Janice Cox
name: Peron, Angela
name: Philippe, Christophe
name: Mao, Rong
name: McDonald, Kimberly
name: Carmichael, Jenny
name: Battini, Roberta
name: Guillemot, Francois
name: Haffner, Darrah
name: Scala, Marcello
name: Bird, Lynne M.
name: Dobyns, William B.
name: Graul-Neumann, Luitgard
name: Faivre, Laurence
name: Low, Karen J.
name: Kraus, Cornelia
name: Au, Ping Yee Billie
name: Turner, Claire
Publisher: name: Springer Nature
Year: 2024

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.