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

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 ofSOX5 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.

• Authors: Ash Zawerton, Cyril Mignot, Ashley Sigafoos, Patrick R Blackburn, Abdul Haseeb, Kirsty McWalter, Shoji Ichikawa, Caroline Nava, Boris Keren, Perrine Charles, Isabelle Marey, Anne-Claude Tabet, Jonathan Levy, Laurence Perrin, Andreas Hartmann, Gaetan Lesca, Caroline Schluth-Bolard, Pauline Monin, Sophie Dupuis-Girod, Maria J Guillen Sacoto, Rhonda E Schnur, Zehua Zhu, Alice Poisson, Salima El Chehadeh, Yves Alembik, Ange-Line Bruel, Daphné Lehalle, Sophie Nambot, Sébastien Moutton, Sylvie Odent, Sylvie Jaillard, Christèle Dubourg, Yvonne Hilhorst-Hofstee, Tina Barbaro-Dieber, Lucia Ortega, Elizabeth J Bhoj, Diane Masser-Frye, Lynne M Bird, Kristin Lindstrom, Keri M Ramsey, Vinodh Narayanan, Emily Fassi, Marcia Willing, Trevor Cole, Claire G Salter, Rhoda Akilapa, Anthony Vandersteen, Natalie Canham, Patrick Rump, Erica H Gerkes, Jolien S Klein Wassink-Ruiter, Emilia Bijlsma, Mariëtte J V Hoffer, Marcelo Vargas, Antonina Wojcik, Florian Cherik, Christine Francannet, Jill A Rosenfeld, Keren Machol, Daryl A Scott, Carlos A Bacino, Xia Wang, Gary D Clark, Marta Bertoli, Simon Zwolinski, Rhys H Thomas, Ela Akay, Richard C Chang, Rebekah Bressi, Rossana Sanchez Russo, Myriam Srour, Laura Russell, Anne-Marie E Goyette, Lucie Dupuis, Roberto Mendoza-Londono, Catherine Karimov, Maries Joseph, Mathilde Nizon, Benjamin Cogné, Alma Kuechler, Amélie Piton, Deciphering Developmental Disorder Study, Eric W Klee, Véronique Lefebvre, Karl J Clark, Christel Depienne
• Journal: Genetics in medicine : official journal of the American College of Medical Genetics (Genet Med) Vol. 22 Issue 3 Pg. 524-537 (03 2020) ISSN: 1530-0366 [Electronic] United States
• PMID: 31578471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• SOX5 protein, human
• SOXD Transcription Factors

Topics

• Adolescent
• Adult
• Animals
• Child
• Child, Preschool
• DNA-Binding Proteins (genetics)
• Female
• Genetic Predisposition to Disease
• Haploinsufficiency (genetics)
• Humans
• Infant
• Intellectual Disability (diagnosis, genetics, pathology)
• Language Development Disorders (diagnosis, genetics, pathology)
• Male
• Mutation, Missense (genetics)
• Neurodevelopmental Disorders (diagnosis, genetics, pathology)
• Pedigree
• Phenotype
• SOXD Transcription Factors (genetics)
• Young Adult