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

6533b85efe1ef96bd12c09a5

RESEARCH PRODUCT

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

Ashley N. Sigafoos Salima El Chehadeh Marcia C. Willing Ela Akay Florian Cherik Anne-marie E. Goyette Vinodh Narayanan Diane Masser-frye Catherine Karimov Rhonda E. Schnur Rebekah Bressi Rhys H. Thomas Rhys H. Thomas Gary D. Clark Tina Barbaro-dieber Jill A. Rosenfeld Carlos A. Bacino Maria J. Guillen Sacoto Laura Russell Kristin Lindstrom Caroline Schluth-bolard Xia Wang Yvonne Hilhorst-hofstee Marcelo Vargas Zehua Zhu Ash Zawerton Boris Keren Mariëtte J.v. Hoffer Isabelle Marey Alice Poisson Daphné Lehalle Maries Joseph Gaetan Lesca Simon Zwolinski Laurence Perrin Rhoda Akilapa Emilia K. Bijlsma Christel Depienne Christel Depienne Christel Depienne Amélie Piton Claire G. Salter Lucie Dupuis Daryl A. Scott Jolien S. Klein Wassink-ruiter Benjamin Cogné Mathilde Nizon Richard Chang Kirsty Mcwalter Myriam Srour Perrine Charles Anne-claude Tabet Natalie Canham Sylvie Odent Caroline Nava Karl J. Clark Elizabeth J. Bhoj Jonathan Levy Keri Ramsey Yves Alembik Lucia Ortega Sophie Dupuis-girod Shoji Ichikawa Christine Francannet Marta Bertoli Christèle Dubourg Eric W. Klee Ange-line Bruel Sebastien Moutton Emily Fassi Anthony Vandersteen Abdul Haseeb Antonina Wojcik Patrick R. Blackburn Lynne M. Bird Lynne M. Bird Patrick Rump Véronique Lefebvre Alma Kuechler Sophie Nambot Keren Machol Cyril Mignot Andreas Hartmann Rossana Sanchez Russo Erica H. Gerkes Sylvie Jaillard Roberto Mendoza-londono Trevor Cole Pauline Monin

subject

Male Medizin Haploinsufficiency L-SOX5 VARIANTS 0302 clinical medicine Neurodevelopmental disorder Intellectual disability Missense mutation 2.1 Biological and endogenous factors Aetiology Child Genetics (clinical)Genetics Pediatric Genetics & Heredity 0303 health sciences Pedigree FAMILY DNA-Binding Proteins developmental delay TRANSCRIPTION FACTORS Phenotype intellectual disability Child Preschool missense variants Female missense variants.Haploinsufficiency SOXD Transcription Factors Adult EXPRESSION Adolescent Intellectual and Developmental Disabilities (IDD)Clinical Sciences Mutation Missense autism Cell fate determination Biology LONG FORM SEQUENCE Article 03 medical and health sciences Young Adult Rare Diseases Clinical Research CARTILAGE Intellectual Disability medicine Genetics Animals Humans Language Development Disorders Genetic Predisposition to Disease Preschool Transcription factor Gene 030304 developmental biology [SDV.GEN]Life Sciences [q-bio]/Genetics MUTATIONS Human Genome Infant medicine.disease Brain Disorders Neurodevelopmental Disorders Deciphering Developmental Disorder Study Mutation Autism epilepsy Missense 030217 neurology & neurosurgery GENERATION

description

International audience; 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.

year	journal	country	edition	language
2020-03-01	Genetics in Medicine

10.1038/s41436-019-0657-0 https://doi.org/10.1038/s41436-019-0657-0