BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

C4RCD Research Group; Angela Peron; Felice D'Arco; Kimberly A Aldinger; Constance Smith-Hicks; Christiane Zweier; Gyri A Gradek; Kimberley Bradbury; Andrea Accogli; Erica F Andersen; Ping Yee Billie Au; Roberta Battini; Daniah Beleford; Lynne M Bird; Arjan Bouman; Ange-Line Bruel; Øyvind Løvold Busk; Philippe M Campeau; Valeria Capra; Colleen Carlston; Jenny Carmichael; Anna Chassevent; Jill Clayton-Smith; Michael J Bamshad; Dawn L Earl; Laurence Faivre; Christophe Philippe; Patrick Ferreira; Luitgard Graul-Neumann; Mary J Green; Karen J Low

doi:10.1038/s41431-024-01701-z

BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

C4RCD Research Group, Angela Peron^*, Felice D'Arco, Kimberly A Aldinger, Constance Smith-Hicks, Christiane Zweier, Gyri A Gradek, Kimberley Bradbury, Andrea Accogli, Erica F Andersen, Ping Yee Billie Au, Roberta Battini, Daniah Beleford, Lynne M Bird, Arjan Bouman, Ange-Line Bruel, Øyvind Løvold Busk, Philippe M Campeau, Valeria Capra, Colleen CarlstonJenny Carmichael, Anna Chassevent, Jill Clayton-Smith, Michael J Bamshad, Dawn L Earl, Laurence Faivre, Christophe Philippe, Patrick Ferreira, Luitgard Graul-Neumann, Mary J Green, Karen J Low

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

10 Citations (Scopus)

Abstract

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.

Original language	English
Number of pages	13
Journal	European Journal of Human Genetics
Early online date	24 Oct 2024
DOIs	https://doi.org/10.1038/s41431-024-01701-z
Publication status	E-pub ahead of print - 24 Oct 2024

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Publisher Copyright:
© The Author(s) 2024.

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C4RCD Research Group, Peron, A., D'Arco, F., Aldinger, K. A., Smith-Hicks, C., Zweier, C., Gradek, G. A., Bradbury, K., Accogli, A., Andersen, E. F., Au, P. Y. B., Battini, R., Beleford, D., Bird, L. M., Bouman, A., Bruel, A.-L., Busk, Ø. L., Campeau, P. M., Capra, V., ... Low, K. J. (2024). BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations. European Journal of Human Genetics. Advance online publication. https://doi.org/10.1038/s41431-024-01701-z

@article{98c7e99d4ac946b99c98b4057e8c0b9d,

title = "BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations",

abstract = "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.",

author = "\{C4RCD Research Group\} and Angela Peron and Felice D'Arco and Aldinger, \{Kimberly A\} and Constance Smith-Hicks and Christiane Zweier and Gradek, \{Gyri A\} and Kimberley Bradbury and Andrea Accogli and Andersen, \{Erica F\} and Au, \{Ping Yee Billie\} and Roberta Battini and Daniah Beleford and Bird, \{Lynne M\} and Arjan Bouman and Ange-Line Bruel and Busk, \{{\O}yvind L{\o}vold\} and Campeau, \{Philippe M\} and Valeria Capra and Colleen Carlston and Jenny Carmichael and Anna Chassevent and Jill Clayton-Smith and Bamshad, \{Michael J\} and Earl, \{Dawn L\} and Laurence Faivre and Christophe Philippe and Patrick Ferreira and Luitgard Graul-Neumann and Green, \{Mary J\} and Low, \{Karen J\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = oct,

day = "24",

doi = "10.1038/s41431-024-01701-z",

language = "English",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "Springer Nature",

}

C4RCD Research Group, Peron, A, D'Arco, F, Aldinger, KA, Smith-Hicks, C, Zweier, C, Gradek, GA, Bradbury, K, Accogli, A, Andersen, EF, Au, PYB, Battini, R, Beleford, D, Bird, LM, Bouman, A, Bruel, A-L, Busk, ØL, Campeau, PM, Capra, V, Carlston, C, Carmichael, J, Chassevent, A, Clayton-Smith, J, Bamshad, MJ, Earl, DL, Faivre, L, Philippe, C, Ferreira, P, Graul-Neumann, L, Green, MJ & Low, KJ 2024, 'BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations', European Journal of Human Genetics. https://doi.org/10.1038/s41431-024-01701-z

TY - JOUR

T1 - BCL11A intellectual developmental disorder

T2 - defining the clinical spectrum and genotype-phenotype correlations

AU - C4RCD Research Group

AU - Peron, Angela

AU - D'Arco, Felice

AU - Aldinger, Kimberly A

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 - Low, Karen J

PY - 2024/10/24

Y1 - 2024/10/24

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.

U2 - 10.1038/s41431-024-01701-z

DO - 10.1038/s41431-024-01701-z

M3 - Article (Academic Journal)

C2 - 39448799

SN - 1018-4813

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

ER -

BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

Abstract

Bibliographical note

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