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Lookup NU author(s): Dr Marta Bertoli,
Dr Simon Zwolinski,
Dr Rhys ThomasORCiD
This is the authors' accepted manuscript of an article that has been published in its final definitive form by Nature Publishing Group, 2020.
For re-use rights please refer to the publisher's terms and conditions.
© 2019, American College of Medical Genetics and Genomics. Purpose: Lamb–Shaffer syndrome (LAMSHF) is a neurodevelopmental disorder described in just over two dozen patients with heterozygous genetic alterations involving SOX5, a gene encoding a transcription factor regulating cell fate and differentiation in neurogenesis and other discrete developmental processes. The genetic alterations described so far are mainly microdeletions. The present study was aimed at increasing our understanding of LAMSHF, its clinical and genetic spectrum, and the pathophysiological mechanisms involved. Methods: Clinical and genetic data were collected through GeneMatcher and clinical or genetic networks for 41 novel patients harboring various types of SOX5 alterations. Functional consequences of selected substitutions were investigated. Results: Microdeletions and truncating variants occurred throughout SOX5. In contrast, most missense variants clustered in the pivotal SOX-specific high-mobility-group domain. The latter variants prevented SOX5 from binding DNA and promoting transactivation in vitro, whereas missense variants located outside the high-mobility-group domain did not. Clinical manifestations and severity varied among patients. No clear genotype–phenotype correlations were found, except that missense variants outside the high-mobility-group domain were generally better tolerated. Conclusions: This study extends the clinical and genetic spectrum associated with LAMSHF and consolidates evidence that SOX5 haploinsufficiency leads to variable degrees of intellectual disability, language delay, and other clinical features.
Author(s): Zawerton A, Mignot C, Sigafoos A, Blackburn PR, Haseeb A, McWalter K, Ichikawa S, Nava C, Keren B, Charles P, Marey I, Tabet A-C, Levy J, Perrin L, Hartmann A, Lesca G, Schluth-Bolard C, Monin P, Dupuis-Girod S, Guillen Sacoto MJ, Schnur RE, Zhu Z, Poisson A, El Chehadeh S, Alembik Y, Bruel A-L, Lehalle D, Nambot S, Moutton S, Odent S, Jaillard S, Dubourg C, Hilhorst-Hofstee Y, Barbaro-Dieber T, Ortega L, Bhoj EJ, Masser-Frye D, Bird LM, Lindstrom K, Ramsey KM, Narayanan V, Fassi E, Willing M, Cole T, Salter CG, Akilapa R, Vandersteen A, Canham N, Rump P, Gerkes EH, Wassink-Ruiter JSK, Bijlsma E, Hoffer MJV, Vargas M, Wojcik A, Cherik F, Francannet C, Rosenfeld JA, Machol K, Scott DA, Bacino CA, Wang X, Clark GD, Bertoli M, Zwolinski S, Thomas RH, Akay E, Chang RC, Bressi R, Sanchez Russo R, Srour M, Russell L, Goyette A-ME, Dupuis L, Mendoza-Londono R, Karimov C, Joseph M, Nizon M, Cogne B, Kuechler A, Piton A, Klee EW, Lefebvre V, Clark KJ, Depienne C
Publication type: Article
Publication status: Published
Journal: Genetics in Medicine
Print publication date: 01/03/2020
Online publication date: 03/10/2019
Acceptance date: 10/09/2019
Date deposited: 15/11/2019
ISSN (print): 1098-3600
ISSN (electronic): 1530-0366
Publisher: Nature Publishing Group
PubMed id: 31578471
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