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    Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome

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    URI
    https://rde.dspace-express.com/handle/11287/622405
    Author
    Angelozzi, M.
    Karvande, A.
    Molin, A. N.
    Ritter, A. L.
    Leonard, J. M. M.
    Savatt, J. M.
    Douglass, K.
    Myers, S. M.
    Grippa, M.
    Tolchin, D.
    Zackai, E.
    Donoghue, S.
    Hurst, A. C. E.
    Descartes, M.
    Smith, K.
    Velasco, D.
    Schmanski, A.
    Crunk, A.
    Tokita, M. J.
    de Lange, I. M.
    van Gassen, K.
    Robinson, H.
    Guegan, K.
    Suri, M.
    Patel, C.
    Bournez, M.
    Faivre, L.
    Tran-Mau-Them, F.
    Baker, J.
    Fabie, N.
    Weaver, K.
    Shillington, A.
    Hopkin, R. J.
    Barge-Schaapveld, Dqcm
    Ruivenkamp, C. A.
    Bökenkamp, R.
    Vergano, S.
    Seco Moro, M. N.
    Díaz de Bustamante, A.
    Misra, V. K.
    Kennelly, K.
    Rogers, C.
    Friedman, J.
    Wigby, K. M.
    Lenberg, J.
    Graziano, C.
    Ahrens-Nicklas, R. C.
    Lefebvre, V.
    Date
    2022-03-01
    Journal
    Journal of medical genetics
    Type
    Journal Article
    Publisher
    BMJ
    DOI
    10.1136/jmedgenet-2021-108375
    Rights
    © Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.
    Metadata
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    Abstract
    BACKGROUND: A neurodevelopmental syndrome was recently reported in four patients with SOX4 heterozygous missense variants in the high-mobility-group (HMG) DNA-binding domain. The present study aimed to consolidate clinical and genetic knowledge of this syndrome. METHODS: We newly identified 17 patients with SOX4 variants, predicted variant pathogenicity using in silico tests and in vitro functional assays and analysed the patients' phenotypes. RESULTS: All variants were novel, distinct and heterozygous. Seven HMG-domain missense and five stop-gain variants were classified as pathogenic or likely pathogenic variant (L/PV) as they precluded SOX4 transcriptional activity in vitro. Five HMG-domain and non-HMG-domain missense variants were classified as of uncertain significance (VUS) due to negative results from functional tests. When known, inheritance was de novo or from a mosaic unaffected or non-mosaic affected parent for patients with L/PV, and from a non-mosaic asymptomatic or affected parent for patients with VUS. All patients had neurodevelopmental, neurological and dysmorphic features, and at least one cardiovascular, ophthalmological, musculoskeletal or other somatic anomaly. Patients with L/PV were overall more affected than patients with VUS. They resembled patients with other neurodevelopmental diseases, including the SOX11-related and Coffin-Siris (CSS) syndromes, but lacked the most specific features of CSS. CONCLUSION: These findings consolidate evidence of a fairly non-specific neurodevelopmental syndrome due to SOX4 haploinsufficiency in neurogenesis and multiple other developmental processes.
    Citation
    J Med Genet. 2022 Mar 1:jmedgenet-2021-108375. doi: 10.1136/jmedgenet-2021-108375.
    Publisher URL
    https://jmg.bmj.com/lookup/pmidlookup?view=long&pmid=35232796
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    RD&E staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted.
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