Please use this identifier to cite or link to this item:
https://hdl.handle.net/2440/139349
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Type: | Journal article |
Title: | Aicardi Syndrome Is a Genetically Heterogeneous Disorder |
Author: | Ha, T.T. Burgess, R. Newman, M. Moey, C. Mandelstam, S.A. Gardner, A.E. Ivancevic, A.M. Pham, D. Kumar, R. Smith, N. Patel, C. Malone, S. Ryan, M.M. Calvert, S. van Eyk, C.L. Lardelli, M. Berkovic, S.F. Leventer, R.J. Richards, L.J. Scheffer, I.E. et al. |
Citation: | Genes, 2023; 14(8):1565-1565 |
Publisher: | MDPI AG |
Issue Date: | 2023 |
ISSN: | 2073-4425 2073-4425 |
Statement of Responsibility: | Thuong T. Ha ... Mark A. Corbett ... Jozef Gecz ... Michael Lardelli ... Clare L. van Eyk ... Raman Sharma ... et al. |
Abstract: | Aicardi Syndrome (AIC) is a rare neurodevelopmental disorder recognized by the classical triad of agenesis of the corpus callosum, chorioretinal lacunae and infantile epileptic spasms syndrome. The diagnostic criteria of AIC were revised in 2005 to include additional phenotypes that are frequently observed in this patient group. AIC has been traditionally considered as X-linked and male lethal because it almost exclusively affects females. Despite numerous genetic and genomic investigations on AIC, a unifying X-linked cause has not been identified. Here, we performed exome and genome sequencing of 10 females with AIC or suspected AIC based on current criteria. We identified a unique de novo variant, each in different genes: KMT2B, SLF1, SMARCB1, SZT2 and WNT8B, in five of these females. Notably, genomic analyses of coding and non-coding single nucleotide variants, short tandem repeats and structural variation highlighted a distinct lack of X-linked candidate genes. We assessed the likely pathogenicity of our candidate autosomal variants using the TOPflash assay for WNT8B and morpholino knockdown in zebrafish (Danio rerio) embryos for other candidates. We show expression of Wnt8b and Slf1 are restricted to clinically relevant cortical tissues during mouse development. Our findings suggest that AIC is genetically heterogeneous with implicated genes converging on molecular pathways central to cortical development. |
Keywords: | X-linked; sex bias; DNA sequencing; developmental epileptic encephalopathy; wnt signalling; DNA repair |
Rights: | © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/) |
DOI: | 10.3390/genes14081565 |
Grant ID: | http://purl.org/au-research/grants/nhmrc/1091593 http://purl.org/au-research/grants/nhmrc/1104831 http://purl.org/au-research/grants/nhmrc/1172897 http://purl.org/au-research/grants/nhmrc/2010562 http://purl.org/au-research/grants/nhmrc/1155224 http://purl.org/au-research/grants/nhmrc/1120615 http://purl.org/au-research/grants/nhmrc/1159783 http://purl.org/au-research/grants/arc/DP200102363 |
Published version: | http://dx.doi.org/10.3390/genes14081565 |
Appears in Collections: | Medicine publications |
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File | Description | Size | Format | |
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hdl_139349.pdf | Published version | 3.2 MB | Adobe PDF | View/Open |
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