TY - JOUR
T1 - BCL11A intellectual developmental disorder
T2 - defining the clinical spectrum and genotype-phenotype correlations
AU - Peron, Angela
AU - D’Arco, Felice
AU - Aldinger, Kimberly A.
AU - University of Washington Center for Mendelian Genomics (UW-CMG)
AU - Telethon Undiagnosed Disease Program (TUDP)
AU - C4RCD Research Group
AU - Smith-Hicks, Constance
AU - Zweier, Christiane
AU - Gradek, Gyri A.
AU - Bradbury, Kimberley
AU - Accogli, Andrea
AU - Andersen, Erica F.
AU - Au, Ping Yee Billie
AU - Battini, Roberta
AU - Beleford, Daniah
AU - Bird, Lynne M.
AU - Bouman, Arjan
AU - Bruel, Ange Line
AU - Busk, Øyvind Løvold
AU - Campeau, Philippe M.
AU - Capra, Valeria
AU - Carlston, Colleen
AU - Carmichael, Jenny
AU - Chassevent, Anna
AU - Clayton-Smith, Jill
AU - Bamshad, Michael J.
AU - Earl, Dawn L.
AU - Faivre, Laurence
AU - Philippe, Christophe
AU - Ferreira, Patrick
AU - Graul-Neumann, Luitgard
AU - Green, Mary J.
AU - Haffner, Darrah
AU - Haldipur, Parthiv
AU - Hanna, Suhair
AU - Houge, Gunnar
AU - Jones, Wendy D.
AU - Kraus, Cornelia
AU - Kristiansen, Birgit Elisabeth
AU - Lespinasse, James
AU - Low, Karen J.
AU - Lynch, Sally Ann
AU - Maia, Sofia
AU - Mao, Rong
AU - Kalinauskiene, Ruta
AU - Melver, Catherine
AU - McDonald, Kimberly
AU - Montgomery, Tara
AU - Morleo, Manuela
AU - Motter, Constance
AU - Openshaw, Amanda S.
AU - Palumbos, Janice Cox
AU - Parikh, Aditi Shah
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2025/3
Y1 - 2025/3
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85207732325
U2 - 10.1038/s41431-024-01701-z
DO - 10.1038/s41431-024-01701-z
M3 - Article
C2 - 39448799
AN - SCOPUS:85207732325
SN - 1018-4813
VL - 33
SP - 312
EP - 324
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
M1 - 103969
ER -
