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Widening of the genetic and clinical spectrum of Lamb-Shaffer syndrome, a neurodevelopmental disorder due to SOX5 haploinsufficiency.
- Source :
-
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2020 Mar; Vol. 22 (3), pp. 524-537. Date of Electronic Publication: 2019 Oct 03. - Publication Year :
- 2020
-
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.<br />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.<br />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.<br />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.
- Subjects :
- Adolescent
Adult
Animals
Child
Child, Preschool
Female
Genetic Predisposition to Disease
Haploinsufficiency genetics
Humans
Infant
Intellectual Disability diagnosis
Intellectual Disability pathology
Language Development Disorders diagnosis
Language Development Disorders genetics
Language Development Disorders pathology
Male
Mutation, Missense genetics
Neurodevelopmental Disorders diagnosis
Neurodevelopmental Disorders pathology
Pedigree
Phenotype
Young Adult
DNA-Binding Proteins genetics
Intellectual Disability genetics
Neurodevelopmental Disorders genetics
SOXD Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0366
- Volume :
- 22
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 31578471
- Full Text :
- https://doi.org/10.1038/s41436-019-0657-0