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Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency

Ash Zawerton 1 Cyril Mignot 2, 3 Ashley Sigafoos Patrick Blackburn Abdul Haseeb Kirsty Mcwalter Shoji Ichikawa Caroline Nava 3, 2 Boris Keren 2, 3 Perrine Charles 3 Isabelle Marey 3 Anne-Claude Tabet 4, 5 Jonathan Levy 5 Laurence Perrin 5 Andreas Hartmann 2 Gaetan Lesca 6 Caroline Schluth-Bolard 6 Pauline Monin 7 Sophie Dupuis-Girod 7 Maria Guillen Sacoto Rhonda Schnur Zehua Zhu Alice Poisson 8 Salima El Chehadeh Yves Alembik Ange-Line Bruel 9 Daphne Lehalle 9 Sophie Nambot 10, 9 Sébastien Moutton 9, 10 Sylvie Odent 11, 12 Sylvie Jaillard 13, 12 Christèle Dubourg 11, 12 Yvonne Hilhorst-Hofstee 14 Tina Barbaro-Dieber Lucia Ortega Elizabeth Bhoj Diane Masser-Frye Lynne Bird Kristin Lindstrom Keri Ramsey Vinodh Narayanan Emily Fassi Marcia Willing Trevor Cole Claire Salter Rhoda Akilapa Anthony Vandersteen Natalie Canham Patrick Rump Erica Gerkes Jolien Klein Wassink-Ruiter Emilia Bijlsma Mariëtte Hoffer Marcelo Vargas Antonina Wojcik Florian Cherik Christine Francannet Jill Rosenfeld Keren Machol Daryl Scott Carlos Bacino Xia Wang Gary Clark Marta Bertoli Simon Zwolinski Rhys Thomas Ela Akay Richard Chang Rebekah Bressi Rossana Sanchez Russo Myriam Srour Laura Russell Anne-Marie Goyette Lucie Dupuis Roberto Mendoza-Londono Catherine Karimov Maries Joseph Mathilde Nizon 15, 16 Benjamin Cogné 16 Alma Kuechler Amélie Piton 17 Eric Klee 18 Véronique Lefebvre * Karl Clark 18 Christel Depienne 2, 17, *
* Corresponding author
1 Cleveland Clinic
2 ICM - Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute
3 Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière]
4 GHFC (UMR_3571 / U-Pasteur_1) - Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions
5 Département de génétique [Robert Debré]
6 CRNL - Centre de recherche en neurosciences de Lyon
7 HCL - Hospices Civils de Lyon
8 CERMEP - Centre d'Exploration et de Recherche Médicales par Émission de Positons
9 LNC - Lipides - Nutrition - Cancer [Dijon - U1231]
10 Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon)
11 IGDR - Institut de Génétique et Développement de Rennes
12 CHU Pontchaillou [Rennes]
13 Irset - Institut de recherche en santé, environnement et travail
14 Center for Human and Clinical Genetics
15 Service de génétique médicale - Unité de génétique clinique [Nantes]
16 ITX - unité de recherche de l'institut du thorax UMR1087 UMR6291
17 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
18 HSR - Department of Health Sciences Research [Mayo Clinic]
Abstract : 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.
Keywords : autism developmental delay epilepsy missense variants intellectual disability
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https://hal-univ-rennes1.archives-ouvertes.fr/hal-02364647
Contributor : Laurent Jonchère <>
Submitted on : Friday, November 15, 2019 - 9:37:41 AM
Last modification on : Friday, April 2, 2021 - 3:30:47 AM

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UNIV-RENNES1 | UNIV-BOURGOGNE | IGBMC | HCL | IGDR | IRSET | CNRS | UNIV-ST-ETIENNE | LNC-UMR866 | UNIV-LYON1 | BIOSIT | UR1-UFR-SVE | ICM | UNIV-NANTES | SITE-ALSACE | UNIV-RENNES | THORAX-UMR | SORBONNE-UNIVERSITE | SU-MEDECINE | UNIV-ANGERS | PASTEUR | UDL | IRSET-8 | UNIV-PARIS | UP-SCIENCES | SU-TI

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Ash Zawerton, Cyril Mignot, Ashley Sigafoos, Patrick Blackburn, Abdul Haseeb, et al.. Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency. Genetics in Medicine, Nature Publishing Group, 2020, 22 (3), pp.524-537. ⟨10.1038/s41436-019-0657-0⟩. ⟨hal-02364647⟩

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