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

Deciphering Developmental Disorder Study

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalGenetics in Medicine
DOIs
StateAccepted/In press - Jan 1 2019

Fingerprint

Haploinsufficiency
Language Development Disorders
Neurogenesis
Intellectual Disability
Transcriptional Activation
Cell Differentiation
Transcription Factors
DNA
Genes
Neurodevelopmental Disorders

Keywords

  • autism
  • developmental delay
  • epilepsy
  • intellectual disability
  • missense variants

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

Widening of the genetic and clinical spectrum of Lamb–Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency. / Deciphering Developmental Disorder Study.

In: Genetics in Medicine, 01.01.2019.

Research output: Contribution to journalArticle

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title = "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 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, intellectual disability, missense variants",
author = "{Deciphering Developmental Disorder Study} and Ash Zawerton and Cyril Mignot and Ashley Sigafoos and Blackburn, {Patrick R.} and Abdul Haseeb and Kirsty McWalter and Shoji Ichikawa and Caroline Nava and Boris Keren and Perrine Charles and Isabelle Marey and Tabet, {Anne Claude} and Jonathan Levy and Laurence Perrin and Andreas Hartmann and Gaetan Lesca and Caroline Schluth-Bolard and Pauline Monin and Sophie Dupuis-Girod and {Guillen Sacoto}, {Maria J.} and Schnur, {Rhonda E.} and Zehua Zhu and Alice Poisson and {El Chehadeh}, Salima and Yves Alembik and Bruel, {Ange Line} and Daphn{\'e} Lehalle and Sophie Nambot and S{\'e}bastien Moutton and Sylvie Odent and Sylvie Jaillard and Christ{\`e}le Dubourg and Yvonne Hilhorst-Hofstee and Tina Barbaro-Dieber and Lucia Ortega and Bhoj, {Elizabeth J.} and Diane Masser-Frye and Bird, {Lynne M.} and Kristin Lindstrom and Ramsey, {Keri M.} and Vinodh Narayanan and Emily Fassi and Marcia Willing and Trevor Cole and Salter, {Claire G.} and Rhoda Akilapa and Anthony Vandersteen and Natalie Canham and Patrick Rump and Clark, {Karl J.}",
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AU - Deciphering Developmental Disorder Study

AU - Zawerton, Ash

AU - Mignot, Cyril

AU - Sigafoos, Ashley

AU - Blackburn, Patrick R.

AU - Haseeb, Abdul

AU - McWalter, Kirsty

AU - Ichikawa, Shoji

AU - Nava, Caroline

AU - Keren, Boris

AU - Charles, Perrine

AU - Marey, Isabelle

AU - Tabet, Anne Claude

AU - Levy, Jonathan

AU - Perrin, Laurence

AU - Hartmann, Andreas

AU - Lesca, Gaetan

AU - Schluth-Bolard, Caroline

AU - Monin, Pauline

AU - Dupuis-Girod, Sophie

AU - Guillen Sacoto, Maria J.

AU - Schnur, Rhonda E.

AU - Zhu, Zehua

AU - Poisson, Alice

AU - El Chehadeh, Salima

AU - Alembik, Yves

AU - Bruel, Ange Line

AU - Lehalle, Daphné

AU - Nambot, Sophie

AU - Moutton, Sébastien

AU - Odent, Sylvie

AU - Jaillard, Sylvie

AU - Dubourg, Christèle

AU - Hilhorst-Hofstee, Yvonne

AU - Barbaro-Dieber, Tina

AU - Ortega, Lucia

AU - Bhoj, Elizabeth J.

AU - Masser-Frye, Diane

AU - Bird, Lynne M.

AU - Lindstrom, Kristin

AU - Ramsey, Keri M.

AU - Narayanan, Vinodh

AU - Fassi, Emily

AU - Willing, Marcia

AU - Cole, Trevor

AU - Salter, Claire G.

AU - Akilapa, Rhoda

AU - Vandersteen, Anthony

AU - Canham, Natalie

AU - Rump, Patrick

AU - Clark, Karl J.

PY - 2019/1/1

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N2 - 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.

AB - 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.

KW - autism

KW - developmental delay

KW - epilepsy

KW - intellectual disability

KW - missense variants

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