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

Author

Øyvind L. Busk, Kimberley Bradbury, Arjan Bouman, Philippe M. Campeau, Lynne M. Bird, Cornelia Kraus, Colleen Carlston, Rong Mao, Juliette Piard, Laurence Faivre, Amanda Openshaw, Catherine Ward Melver, Mohnish Suri, Christiane Zweier, François Guillemot, Rolph Pfundt, Janice C. Palumbos, Parthiv Haldipur, Jane A. Hurst, Kimberly McDonald, Margaux Serey-Gaut, Luitgard Graul-Neumann, Karen J. Low, Jenny Carmichael, Patrick Ferrerira, Birgit Elisabeth Kristiansen, Ange-Line Bruel, Constance Motter, Andrea Accogli, Darrah N. Haffner, Suhair Hanna, Ruta Marcinkute, Angela Peron, Marcella Zollino, Sofia Maia, James Lespinasse, Claire E. Turner, Sally Ann Lynch, Richard E. Person, Valeria Capra, Kimberly A. Aldinger, Constance Smith-Hicks, Gyri Aasland Gradek, Ingrid M. Wentzensen, Megha Desai, Manuela Morleo, Aditi Shah Parikh, Marcello Scala, Cristina Dias, Gunnar Houge, Telethon Undiagnosed Disease Program, Anne Slavotinek, Roberta Battini, Mary J. Green, Anna Chassevent, Tara Montgomery, David Viskochil, Tatiana Tvrdik, Dawn L. Earl, Karin Weiss, Felice D'Arco, William B. Dobyns, Ping Yee Billie Au, Daniah Beleford, Erica F. Andersen, Bert B.A. de Vries, Jill Clayton-Smith, Christophe Philippe, and Michael J. Bamshad

Subjects
business.industry, Postnatal microcephaly, Microdeletion syndrome, medicine.disease, Bioinformatics, Hypotonia, Developmental disorder, Autism spectrum disorder, Intellectual disability, Fetal hemoglobin, medicine, Missense mutation, medicine.symptom, business
Abstract

PurposeHeterozygous 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.MethodsWe 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.ResultsMolecular 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.ConclusionsWe 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.

Published
2021
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2. The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?

Author

Janice Baker, Curtis Rogers, Mark Mintz, Maian Roifman, Vikas Bhambhani, Fiona Haslam McKenzie, Julie S. Cohen, Constance Motter, Amy Calhoun, Benjamin Kamien, Alyssa Ritter, Catherine Ward-Melver, Dong Li, Rebecca C. Ahrens-Nicklas, Sharron Townshend, Matthew A. Deardorff, Kirsten M. Niles, Samantha A. Schrier Vergano, Alberto Fernández-Jaén, and Mahim Jain

Subjects
Hypertrichosis, Male, Adolescent, Chromosomal Proteins, Non-Histone, media_common.quotation_subject, Nonsense, Micrognathism, Biology, Genética humana, Chromatin remodeling, Intellectual Disability, Genetics, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Síndrome de Coffin-lowry, Child, Gene, Coffin–Siris syndrome, Ciencias médicas, Genetics (clinical), Genetic Association Studies, media_common, Coarse facial features, DNA Helicases, Infant, Nuclear Proteins, medicine.disease, Phenotype, DNA-Binding Proteins, Codon, Nonsense, Child, Preschool, Face, SMARCA4, Female, Hand Deformities, Congenital, Neck, Transcription Factors
Abstract

SMARCA4 encodes a central ATPase subunit in the BRG1-/BRM-associated factors (BAF) or polybromo-associated BAF (PBAF) complex in humans, which is responsible in part for chromatin remodeling and transcriptional regulation. Variants in this and other genes encoding BAF/PBAF complexes have been implicated in Coffin–Siris Syndrome, a multiple congenital anomaly syndrome classically characterized by learning and developmental differences, coarse facial features, hypertrichosis, and underdevelopment of the fifth digits/nails of the hands and feet. Individuals with SMARCA4 variants have been previously reported and appear to display a variable phenotype. We describe here a cohort of 15 unrelated individuals with SMARCA4 variants from the Coffin–Siris syndrome/BAF pathway disorders registry who further display variability in severity and degrees of learning impairment and health issues. Within this cohort, we also report two individuals with novel nonsense variants who appear to have a phenotype of milder learning/behavioral differences and no organ-system involvement. Sin financiación 2.802 JCR (2020) Q3, 104/176 Genetics & Heredity 1.064 SJR (2020) Q2, 127/340 Genetics No data IDR 2020 UEM

Published
2020

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