Purpose: Heterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD. Methods: We performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information. Results: Molecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity. Conclusions: We expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.

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 (O)yvind L(o)vold 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 Ferrerira; Luitgard Graul-Neumann; Mary J. Green; Darrah Haffner; Parthiv Haldipur; Suhair Hanna; Gunnar Houge; Jane Hurst; Cornelia Kraus; Birgit Elisabeth Kristiansen; James Lespinasse; Karen J. Low; Sally Ann Lynch; Sofia Maia; Rong Mao; Ruta Marcinkute; Catherine Melver; Kimberly McDonald; Tara Montgomery; Manuela Morleo; Constance Motter; Amanda S. Openshaw; Janice Cox Palumbos; Aditi Shah Parikh; Richard Person; Megha Desai; Juliette Piard; Rolph Pfundt; Marcello Scala; Margaux Serey-Gaut; Anne Slavotinek; Mohnish Suri; Claire Turner; Tatiana Tvrdik; Karin Weiss; Ingrid M. Wentzensen; Marcella Zollino; Bert B. A. de Vries; Francois Guillemot; William B. Dobyns; David Viskochil; Cristina Dias. - (2021). [10.1101/2021.09.06.21262776]

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

Angela Peron;
2021

Abstract

Purpose: Heterozygous variants in BCL11A underlie an intellectual developmental disorder with persistence of fetal hemoglobin (BCL11A-IDD, a.k.a. Dias-Logan syndrome). We sought to delineate the genotypic and phenotypic spectrum of BCL11A-IDD. Methods: We performed an in-depth analysis of 42 patients with BCL11A-IDD ascertained through a collaborative network of clinical and research colleagues. We also reviewed 33 additional affected individuals previously reported in the literature or available through public repositories with clinical information. Results: Molecular and clinical data analysis of 75 patients with BCL11A-IDD identified 60 unique variants (30 frameshift, 7 missense, 6 splice-site, 17 stop-gain) and 8 unique CNVs (microdeletions involving BCL11A only). We redefined the most frequent manifestations of the condition: intellectual disability, hypotonia, behavioral abnormalities, postnatal microcephaly and autism spectrum disorder. Two thirds of patients have brain MRI abnormalities, and we identified a recurrent posterior fossa phenotype of vermian hypoplasia and/or small brainstem. Truncating BCL11A variants, particularly those affecting the long (BCL11A-L) and extra-long (-XL) isoforms, sparing the short (-S) isoform, were associated with increased severity. Conclusions: We expand the clinical delineation of BCL11A-IDD and identify a potential isoform-specific genotype-phenotype correlation. We show that BCL11A-IDD is associated with posterior fossa anomalies and highlight the differences between BCL11A-IDD and 2p16.1p15 microdeletion syndrome.
2021
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 (O)yvind L(o)vold 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 Ferrerira; Luitgard Graul-Neumann; Mary J. Green; Darrah Haffner; Parthiv Haldipur; Suhair Hanna; Gunnar Houge; Jane Hurst; Cornelia Kraus; Birgit Elisabeth Kristiansen; James Lespinasse; Karen J. Low; Sally Ann Lynch; Sofia Maia; Rong Mao; Ruta Marcinkute; Catherine Melver; Kimberly McDonald; Tara Montgomery; Manuela Morleo; Constance Motter; Amanda S. Openshaw; Janice Cox Palumbos; Aditi Shah Parikh; Richard Person; Megha Desai; Juliette Piard; Rolph Pfundt; Marcello Scala; Margaux Serey-Gaut; Anne Slavotinek; Mohnish Suri; Claire Turner; Tatiana Tvrdik; Karin Weiss; Ingrid M. Wentzensen; Marcella Zollino; Bert B. A. de Vries; Francois Guillemot; William B. Dobyns; David Viskochil; Cristina Dias
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