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

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; Darrah Haffner; Parthiv Haldipur; Suhair Hanna; Gunnar Houge; Wendy D. Jones; Cornelia Kraus; Birgit Elisabeth Kristiansen; James Lespinasse; Karen J. Low; Sally Ann Lynch; Sofia Maia; Rong Mao; Ruta Kalinauskiene; Catherine Melver; Kimberly Mcdonald; Tara Montgomery; Manuela Morleo; Constance Motter; Amanda S. Openshaw; Janice Cox Palumbos; Aditi Shah Parikh; Yezmin Perilla-Young; Cynthia M. Powell; Richard Person; Megha Desai; Juliette Piard; Rolph Pfundt; Marcello Scala; Margaux Serey-Gaut; Deborah Shears; Anne Slavotinek; Mohnish Suri; Claire Turner; Tatiana Tvrdik; Karin Weiss; Ingrid M. Wentzensen; Marcella Zollino; Tzung-Chien Hsieh; Keri Ramsey; Marcella Zollino; Marcello Scala; Valeria Capra; Angela Peron; Bert B. A. De Vries; Francois Guillemot; William B. Dobyns; David Viskochil; Cristina Dias

doi:10.1038/s41431-024-01701-z

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

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 CarmichaelAnna Chassevent, Jill Clayton-Smith, Michael J. Bamshad, Dawn L. Earl, Laurence Faivre, Christophe Philippe, Patrick Ferreira, Luitgard Graul-Neumann, Mary J. Green, Darrah Haffner, Parthiv Haldipur, Suhair Hanna, Gunnar Houge, Wendy D. Jones, Cornelia Kraus, Birgit Elisabeth Kristiansen, James Lespinasse, Karen J. Low, Sally Ann Lynch, Sofia Maia, Rong Mao, Ruta Kalinauskiene, Catherine Melver, Kimberly Mcdonald, Tara Montgomery, Manuela Morleo, Constance Motter, Amanda S. Openshaw, Janice Cox Palumbos, Aditi Shah Parikh, Yezmin Perilla-Young, Cynthia M. Powell, Richard Person, Megha Desai, Juliette Piard, Rolph Pfundt, Marcello Scala, Margaux Serey-Gaut, Deborah Shears, Anne Slavotinek, Mohnish Suri, Claire Turner, Tatiana Tvrdik, Karin Weiss, Ingrid M. Wentzensen, Marcella Zollino, Tzung-Chien Hsieh, Keri Ramsey, Marcella Zollino, Marcello Scala, Valeria Capra, Angela Peron, Bert B. A. De Vries, Francois Guillemot, William B. Dobyns, David Viskochil, Cristina Dias

Risultato della ricerca: Contributo in rivista › Articolo in rivista

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.

Lingua originale	English
pagine (da-a)	N/A-N/A
Rivista	European Journal of Human Genetics
DOI	https://doi.org/10.1038/s41431-024-01701-z
Stato di pubblicazione	Pubblicato - 2024

Keywords

BCL11A-Related Intellectual Disability

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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., Carlston, C., ... Dias, C. (2024). BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations. European Journal of Human Genetics, N/A-N/A. https://doi.org/10.1038/s41431-024-01701-z

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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{\textquoteright}s role in brain development.",

keywords = "BCL11A-Related Intellectual Disability, BCL11A-Related Intellectual Disability",

author = "Angela Peron and Felice D{\textquoteright}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 Darrah Haffner and Parthiv Haldipur and Suhair Hanna and Gunnar Houge and Jones, {Wendy D.} and Cornelia Kraus and Kristiansen, {Birgit Elisabeth} and James Lespinasse and Low, {Karen J.} and Lynch, {Sally Ann} and Sofia Maia and Rong Mao and Ruta Kalinauskiene and Catherine Melver and Kimberly Mcdonald and Tara Montgomery and Manuela Morleo and Constance Motter and Openshaw, {Amanda S.} and Palumbos, {Janice Cox} and Parikh, {Aditi Shah} and Yezmin Perilla-Young and Powell, {Cynthia M.} and Richard Person and Megha Desai and Juliette Piard and Rolph Pfundt and Marcello Scala and Margaux Serey-Gaut and Deborah Shears and Anne Slavotinek and Mohnish Suri and Claire Turner and Tatiana Tvrdik and Karin Weiss and Wentzensen, {Ingrid M.} and Marcella Zollino and Tzung-Chien Hsieh and Keri Ramsey and Marcella Zollino and Marcello Scala and Valeria Capra and Angela Peron and {De Vries}, {Bert B. A.} and Francois Guillemot and Dobyns, {William B.} and David Viskochil and Cristina Dias",

year = "2024",

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

language = "English",

pages = "N/A--N/A",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

publisher = "-NATURE PUBLISHING GROUP, MACMILLAN BUILDING, 4 CRINAN ST, LONDON, ENGLAND, N1 9XW -S Karger AG:Allschwilerstrasse 10, CH-4009 Basel Switzerland:011 41 61 3061111, EMAIL: [email protected], INTERNET: http://www.karger.com, Fax: 011 41 61 3061234",

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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, Haffner, D, Haldipur, P, Hanna, S, Houge, G, Jones, WD, Kraus, C, Kristiansen, BE, Lespinasse, J, Low, KJ, Lynch, SA, Maia, S, Mao, R, Kalinauskiene, R, Melver, C, Mcdonald, K, Montgomery, T, Morleo, M, Motter, C, Openshaw, AS, Palumbos, JC, Parikh, AS, Perilla-Young, Y, Powell, CM, Person, R, Desai, M, Piard, J, Pfundt, R, Scala, M, Serey-Gaut, M, Shears, D, Slavotinek, A, Suri, M, Turner, C, Tvrdik, T, Weiss, K, Wentzensen, IM, Zollino, M, Hsieh, T-C, Ramsey, K, Zollino, M, Scala, M, Capra, V, Peron, A, De Vries, BBA, Guillemot, F, Dobyns, WB, Viskochil, D & Dias, C 2024, 'BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations', European Journal of Human Genetics, pagg. N/A-N/A. https://doi.org/10.1038/s41431-024-01701-z

TY - JOUR

T1 - BCL11A intellectual developmental disorder: defining the clinical spectrum and genotype-phenotype correlations

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 - 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

AU - Perilla-Young, Yezmin

AU - Powell, Cynthia M.

AU - Person, Richard

AU - Desai, Megha

AU - Piard, Juliette

AU - Pfundt, Rolph

AU - Scala, Marcello

AU - Serey-Gaut, Margaux

AU - Shears, Deborah

AU - Slavotinek, Anne

AU - Suri, Mohnish

AU - Turner, Claire

AU - Tvrdik, Tatiana

AU - Weiss, Karin

AU - Wentzensen, Ingrid M.

AU - Zollino, Marcella

AU - Hsieh, Tzung-Chien

AU - Ramsey, Keri

AU - Zollino, Marcella

AU - Scala, Marcello

AU - Capra, Valeria

AU - Peron, Angela

AU - De Vries, Bert B. A.

AU - Guillemot, Francois

AU - Dobyns, William B.

AU - Viskochil, David

AU - Dias, Cristina

PY - 2024

Y1 - 2024

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.

KW - BCL11A-Related Intellectual Disability

UR - http://hdl.handle.net/10807/298396

U2 - 10.1038/s41431-024-01701-z

DO - 10.1038/s41431-024-01701-z

M3 - Article

SN - 1018-4813

SP - N/A-N/A

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

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