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

A. Peron; F. D'Arco; K. A. Aldinger; C. Smith-Hicks; C. Zweier; G. A. Gradek; K. Bradbury; A. Accogli; E. F. Andersen; P. Y. B. Au; R. Battini; D. Beleford; L. M. Bird; A. Bouman; Bruel A. -L.; O. L. Busk; P. M. Campeau; V. Capra; C. Carlston; J. Carmichael; A. Chassevent; J. Clayton-Smith; M. J. Bamshad; D. L. Earl; L. Faivre; C. Philippe; P. Ferreira; L. Graul-Neumann; M. J. Green; D. Haffner; P. Haldipur; S. Hanna; G. Houge; W. D. Jones; C. Kraus; B. E. Kristiansen; J. Lespinasse; K. J. Low; S. A. Lynch; S. Maia; R. Mao; R. Kalinauskiene; C. Melver; K. McDonald; T. Montgomery; M. Morleo; C. Motter; A. S. Openshaw; J. C. Palumbos; A. S. Parikh; Y. Perilla-Young; C. M. Powell; R. Person; M. Desai; J. Piard; R. Pfundt; M. Scala; M. Serey-Gaut; D. Shears; A. Slavotinek; M. Suri; C. Turner; T. Tvrdik; K. Weiss; I. M. Wentzensen; Marcella Zollino; Hsieh T. -C.; K. Ramsey; Marcella Zollino; M. Scala; V. Capra; A. Peron; B. B. A. de Vries; F. Guillemot; W. B. Dobyns; D. Viskochil; C. Dias

doi:10.1038/s41431-024-01701-z

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

A. Peron^*, F. D'Arco, K. A. Aldinger, C. Smith-Hicks, C. Zweier, G. A. Gradek, K. Bradbury, A. Accogli, E. F. Andersen, P. Y. B. Au, R. Battini, D. Beleford, L. M. Bird, A. Bouman, Bruel A. -L., O. L. Busk, P. M. Campeau, V. Capra, C. Carlston, J. CarmichaelA. Chassevent, J. Clayton-Smith, M. J. Bamshad, D. L. Earl, L. Faivre, C. Philippe, P. Ferreira, L. Graul-Neumann, M. J. Green, D. Haffner, P. Haldipur, S. Hanna, G. Houge, W. D. Jones, C. Kraus, B. E. Kristiansen, J. Lespinasse, K. J. Low, S. A. Lynch, S. Maia, R. Mao, R. Kalinauskiene, C. Melver, K. McDonald, T. Montgomery, M. Morleo, C. Motter, A. S. Openshaw, J. C. Palumbos, A. S. Parikh, Y. Perilla-Young, C. M. Powell, R. Person, M. Desai, J. Piard, R. Pfundt, M. Scala, M. Serey-Gaut, D. Shears, A. Slavotinek, M. Suri, C. Turner, T. Tvrdik, K. Weiss, I. M. Wentzensen, Marcella Zollino, Hsieh T. -C., K. Ramsey, Marcella Zollino, M. Scala, V. Capra, A. Peron^*, B. B. A. de Vries, F. Guillemot, W. B. Dobyns, D. Viskochil, C. Dias^*

^*Autore corrispondente per questo lavoro

Risultato della ricerca: Contributo in rivista › Articolo

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

All Science Journal Classification (ASJC) codes

Genetica
Genetica (clinica)

Keywords

BCL11A-Related Intellectual Disability

OSS delle Nazioni Unite

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10.1038/s41431-024-01701-z

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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., -L., B. A., Busk, O. 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-N/A. https://doi.org/10.1038/s41431-024-01701-z

@article{0caca7116af145c9b5518aff1b0e1705,

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 = "A. Peron and F. D'Arco and Aldinger, \{K. A.\} and C. Smith-Hicks and C. Zweier and Gradek, \{G. A.\} and K. Bradbury and A. Accogli and Andersen, \{E. F.\} and Au, \{P. Y. B.\} and R. Battini and D. Beleford and Bird, \{L. M.\} and A. Bouman and -L., \{Bruel A.\} and Busk, \{O. L.\} and Campeau, \{P. M.\} and V. Capra and C. Carlston and J. Carmichael and A. Chassevent and J. Clayton-Smith and Bamshad, \{M. J.\} and Earl, \{D. L.\} and L. Faivre and C. Philippe and P. Ferreira and L. Graul-Neumann and Green, \{M. J.\} and D. Haffner and P. Haldipur and S. Hanna and G. Houge and Jones, \{W. D.\} and C. Kraus and Kristiansen, \{B. E.\} and J. Lespinasse and Low, \{K. J.\} and Lynch, \{S. A.\} and S. Maia and R. Mao and R. Kalinauskiene and C. Melver and K. McDonald and T. Montgomery and M. Morleo and C. Motter and Openshaw, \{A. S.\} and Palumbos, \{J. C.\} and Parikh, \{A. S.\} and Y. Perilla-Young and Powell, \{C. M.\} and R. Person and M. Desai and J. Piard and R. Pfundt and M. Scala and M. Serey-Gaut and D. Shears and A. Slavotinek and M. Suri and C. Turner and T. Tvrdik and K. Weiss and Wentzensen, \{I. M.\} and Marcella Zollino and -C., \{Hsieh T.\} and K. Ramsey and Marcella Zollino and M. Scala and V. Capra and A. Peron and \{de Vries\}, \{B. B. A.\} and F. Guillemot and Dobyns, \{W. B.\} and D. Viskochil and C. 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 = "Springer Nature",

number = "N/A",

}

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, -L., BA, Busk, OL, 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, -C., HT, 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, n. N/A, 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, A.

AU - D'Arco, F.

AU - Aldinger, K. A.

AU - Smith-Hicks, C.

AU - Zweier, C.

AU - Gradek, G. A.

AU - Bradbury, K.

AU - Accogli, A.

AU - Andersen, E. F.

AU - Au, P. Y. B.

AU - Battini, R.

AU - Beleford, D.

AU - Bird, L. M.

AU - Bouman, A.

AU - -L., Bruel A.

AU - Busk, O. L.

AU - Campeau, P. M.

AU - Capra, V.

AU - Carlston, C.

AU - Carmichael, J.

AU - Chassevent, A.

AU - Clayton-Smith, J.

AU - Bamshad, M. J.

AU - Earl, D. L.

AU - Faivre, L.

AU - Philippe, C.

AU - Ferreira, P.

AU - Graul-Neumann, L.

AU - Green, M. J.

AU - Haffner, D.

AU - Haldipur, P.

AU - Hanna, S.

AU - Houge, G.

AU - Jones, W. D.

AU - Kraus, C.

AU - Kristiansen, B. E.

AU - Lespinasse, J.

AU - Low, K. J.

AU - Lynch, S. A.

AU - Maia, S.

AU - Mao, R.

AU - Kalinauskiene, R.

AU - Melver, C.

AU - McDonald, K.

AU - Montgomery, T.

AU - Morleo, M.

AU - Motter, C.

AU - Openshaw, A. S.

AU - Palumbos, J. C.

AU - Parikh, A. S.

AU - Perilla-Young, Y.

AU - Powell, C. M.

AU - Person, R.

AU - Desai, M.

AU - Piard, J.

AU - Pfundt, R.

AU - Scala, M.

AU - Serey-Gaut, M.

AU - Shears, D.

AU - Slavotinek, A.

AU - Suri, M.

AU - Turner, C.

AU - Tvrdik, T.

AU - Weiss, K.

AU - Wentzensen, I. M.

AU - Zollino, Marcella

AU - -C., Hsieh T.

AU - Ramsey, K.

AU - Zollino, Marcella

AU - Scala, M.

AU - Capra, V.

AU - Peron, A.

AU - de Vries, B. B. A.

AU - Guillemot, F.

AU - Dobyns, W. B.

AU - Viskochil, D.

AU - Dias, C.

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 - https://publicatt.unicatt.it/handle/10807/298396

UR - https://www.scopus.com/inward/citedby.uri?partnerID=HzOxMe3b&scp=85207732325&origin=inward

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85207732325&origin=inward

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

IS - N/A

ER -

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

Abstract

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