Aicardi Syndrome Is a Genetically Heterogeneous Disorder
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 o...
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| Language: | English |
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MDPI AG
2023-07-01
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| Series: | Genes |
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| Online Access: | https://www.mdpi.com/2073-4425/14/8/1565 |
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| author | Thuong T. Ha Rosemary Burgess Morgan Newman Ching Moey Simone A. Mandelstam Alison E. Gardner Atma M. Ivancevic Duyen Pham Raman Kumar Nicholas Smith Chirag Patel Stephen Malone Monique M. Ryan Sophie Calvert Clare L. van Eyk Michael Lardelli Samuel F. Berkovic Richard J. Leventer Linda J. Richards Ingrid E. Scheffer Jozef Gecz Mark A. Corbett |
| author_facet | Thuong T. Ha Rosemary Burgess Morgan Newman Ching Moey Simone A. Mandelstam Alison E. Gardner Atma M. Ivancevic Duyen Pham Raman Kumar Nicholas Smith Chirag Patel Stephen Malone Monique M. Ryan Sophie Calvert Clare L. van Eyk Michael Lardelli Samuel F. Berkovic Richard J. Leventer Linda J. Richards Ingrid E. Scheffer Jozef Gecz Mark A. Corbett |
| author_sort | Thuong T. Ha |
| collection | DOAJ |
| description | 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: <i>KMT2B</i>, <i>SLF1</i>, <i>SMARCB1</i>, <i>SZT2</i> and <i>WNT8B</i>, 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 (<i>Danio rerio</i>) embryos for other candidates. We show expression of <i>Wnt8b</i> and <i>Slf1</i> 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. |
| first_indexed | 2024-03-10T23:55:26Z |
| format | Article |
| id | doaj.art-89718b00c75a4121b61bbb3e4d0cd75d |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T23:55:26Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-89718b00c75a4121b61bbb3e4d0cd75d2023-11-19T01:15:08ZengMDPI AGGenes2073-44252023-07-01148156510.3390/genes14081565Aicardi Syndrome Is a Genetically Heterogeneous DisorderThuong T. Ha0Rosemary Burgess1Morgan Newman2Ching Moey3Simone A. Mandelstam4Alison E. Gardner5Atma M. Ivancevic6Duyen Pham7Raman Kumar8Nicholas Smith9Chirag Patel10Stephen Malone11Monique M. Ryan12Sophie Calvert13Clare L. van Eyk14Michael Lardelli15Samuel F. Berkovic16Richard J. Leventer17Linda J. Richards18Ingrid E. Scheffer19Jozef Gecz20Mark A. Corbett21School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, AustraliaEpilepsy Research Centre, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Austin Health, Heidelberg, VIC 3084, AustraliaAlzheimer’s Disease Genetics Laboratory, School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, AustraliaThe Queensland Brain Institute, The School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4000, AustraliaDepartment of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, AustraliaAdelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, AustraliaDepartment of Molecular, Cellular, and Developmental Biology, College of Arts and Sciences, University of Colorado, Boulder, CO 80309, USAAdelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, AustraliaAdelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, AustraliaAdelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, AustraliaGenetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD 4029, AustraliaQueensland Children’s Hospital, South Brisbane, QLD 4101, AustraliaDepartment of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, AustraliaDepartment of Neurosciences, Queensland Children’s Hospital, South Brisbane, QLD 4101, AustraliaAdelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, AustraliaAlzheimer’s Disease Genetics Laboratory, School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, AustraliaEpilepsy Research Centre, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Austin Health, Heidelberg, VIC 3084, AustraliaDepartment of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, AustraliaThe Queensland Brain Institute, The School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4000, AustraliaEpilepsy Research Centre, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Austin Health, Heidelberg, VIC 3084, AustraliaSchool of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, AustraliaAdelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, AustraliaAicardi 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: <i>KMT2B</i>, <i>SLF1</i>, <i>SMARCB1</i>, <i>SZT2</i> and <i>WNT8B</i>, 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 (<i>Danio rerio</i>) embryos for other candidates. We show expression of <i>Wnt8b</i> and <i>Slf1</i> 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.https://www.mdpi.com/2073-4425/14/8/1565X-linkedsex biasDNA sequencingdevelopmental epileptic encephalopathywnt signallingDNA repair |
| spellingShingle | Thuong T. Ha Rosemary Burgess Morgan Newman Ching Moey Simone A. Mandelstam Alison E. Gardner Atma M. Ivancevic Duyen Pham Raman Kumar Nicholas Smith Chirag Patel Stephen Malone Monique M. Ryan Sophie Calvert Clare L. van Eyk Michael Lardelli Samuel F. Berkovic Richard J. Leventer Linda J. Richards Ingrid E. Scheffer Jozef Gecz Mark A. Corbett Aicardi Syndrome Is a Genetically Heterogeneous Disorder Genes X-linked sex bias DNA sequencing developmental epileptic encephalopathy wnt signalling DNA repair |
| title | Aicardi Syndrome Is a Genetically Heterogeneous Disorder |
| title_full | Aicardi Syndrome Is a Genetically Heterogeneous Disorder |
| title_fullStr | Aicardi Syndrome Is a Genetically Heterogeneous Disorder |
| title_full_unstemmed | Aicardi Syndrome Is a Genetically Heterogeneous Disorder |
| title_short | Aicardi Syndrome Is a Genetically Heterogeneous Disorder |
| title_sort | aicardi syndrome is a genetically heterogeneous disorder |
| topic | X-linked sex bias DNA sequencing developmental epileptic encephalopathy wnt signalling DNA repair |
| url | https://www.mdpi.com/2073-4425/14/8/1565 |
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