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Ha TT, Burgess R, Newman M, Moey C, Mandelstam SA, Gardner AE, Ivancevic AM, Pham D, Kumar R, Smith N, Patel C, Malone S, Ryan MM, Calvert S, van Eyk CL, Lardelli M, Berkovic SF, Leventer RJ, Richards LJ, Scheffer IE, Gecz J, Corbett MA. Aicardi Syndrome Is a Genetically Heterogeneous Disorder. Genes (Basel) 2023; 14:1565. [PMID: 37628618 PMCID: PMC10454071 DOI: 10.3390/genes14081565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Revised: 07/25/2023] [Accepted: 07/26/2023] [Indexed: 08/27/2023] Open
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.
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Affiliation(s)
- Thuong T. Ha
- School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, Australia
- Department of Genetics and Molecular Pathology, Centre for Cancer Biology, An Alliance between SA Pathology and the University of South Australia, Adelaide, SA 5000, Australia
| | - Rosemary Burgess
- Epilepsy Research Centre, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia (S.F.B.); (I.E.S.)
| | - Morgan Newman
- Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, Australia (M.L.)
| | - Ching Moey
- The Queensland Brain Institute, The School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4000, Australia
| | - Simone A. Mandelstam
- Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia
- Department of Medical Imaging, The Royal Children’s Hospital, Melbourne, VIC 3052, Australia
| | - Alison E. Gardner
- Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia (M.A.C.)
| | - Atma M. Ivancevic
- Department of Molecular, Cellular, and Developmental Biology, College of Arts and Sciences, University of Colorado, Boulder, CO 80309, USA
| | - Duyen Pham
- Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia (M.A.C.)
| | - Raman Kumar
- Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia (M.A.C.)
| | - Nicholas Smith
- Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia (M.A.C.)
- Department of Neurology, Women’s and Children’s Hospital, North Adelaide, SA 5006, Australia
| | - Chirag Patel
- Genetic Health Queensland, Royal Brisbane and Women’s Hospital, Herston, QLD 4029, Australia
| | - Stephen Malone
- Queensland Children’s Hospital, South Brisbane, QLD 4101, Australia
| | - Monique M. Ryan
- Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia
- Department of Neurology, The Royal Children’s Hospital, Parkville, VIC 3052, Australia
- Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia
| | - Sophie Calvert
- Department of Neurosciences, Queensland Children’s Hospital, South Brisbane, QLD 4101, Australia;
| | - Clare L. van Eyk
- Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia (M.A.C.)
| | - Michael Lardelli
- Alzheimer’s Disease Genetics Laboratory, School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, Australia (M.L.)
| | - Samuel F. Berkovic
- Epilepsy Research Centre, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia (S.F.B.); (I.E.S.)
| | - Richard J. Leventer
- Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia
- Department of Neurology, The Royal Children’s Hospital, Parkville, VIC 3052, Australia
- Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia
| | - Linda J. Richards
- The Queensland Brain Institute, The School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4000, Australia
- Department of Neuroscience, School of Medicine, Washington University, St Louis, MO 63110, USA
| | - Ingrid E. Scheffer
- Epilepsy Research Centre, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia (S.F.B.); (I.E.S.)
- Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Parkville, VIC 3052, Australia
- Department of Neurology, The Royal Children’s Hospital, Parkville, VIC 3052, Australia
- Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
| | - Jozef Gecz
- School of Biological Sciences, Faculty of Science, University of Adelaide, Adelaide, SA 5005, Australia
- Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia (M.A.C.)
- South Australian Health and Medical Research Institute, Adelaide, SA 5000, Australia
| | - Mark A. Corbett
- Adelaide Medical School and Robinson Research Institute, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5005, Australia (M.A.C.)
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Jones KL, McNamara EA, Longoni M, Miller DE, Rohanizadegan M, Newman LA, Hayes F, Levitsky LL, Herrington BL, Lin AE. Dual diagnoses in 152 patients with Turner syndrome: Knowledge of the second condition may lead to modification of treatment and/or surveillance. Am J Med Genet A 2018; 176:2435-2445. [PMID: 30079495 DOI: 10.1002/ajmg.a.40470] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 05/10/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023]
Abstract
Turner syndrome is a sex chromosome abnormality in which a female has a single X chromosome or structurally deficient second sex chromosome. The phenotypic spectrum is broad, and atypical features prompt discussion of whether the known features of Turner syndrome should be further expanded. With the advent of clinical whole exome sequencing, there has been increased realization that some patients with genetic disorders carry a second genetic disorder, leading us to hypothesize that a "dual diagnosis" may be more common than suspected for Turner syndrome. We report five new patients with Turner syndrome and a co-occurring genetic disorder including one patient with Li-Fraumeni syndrome, Li-Fraumeni and Noonan syndrome, mosaic trisomy 8, pathogenic variant in RERE, and blepharophimosis-ptosis-epicanthanus inversus syndrome. We also undertook an extensive literature review of 147 reports of patients with Turner syndrome and a second genetic condition. A total of 47 patients (31%) had trisomy 21, followed by 36 patients (24%) had one of 11 X-linked disorders. Notably, 80% of the 147 reported patients with a dual diagnosis had mosaicism for Turner syndrome, approximately twice the frequency in the general Turner syndrome population. This article demonstrates the potential for co-occurring syndromes in patients with Turner syndrome, prompting us to recommend a search for an additional genetic disorder in Turner patients with unusual features. Knowledge of the second condition may lead to modification of treatment and/or surveillance. We anticipate that increased awareness and improved diagnostic technologies will lead to the identification of more cases of Turner syndrome with a co-occurring genetic syndrome.
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Affiliation(s)
- Kelly L Jones
- Division of Medical Genetics and Metabolism, Children's Hospital of The King's Daughters, Norfolk, Virginia.,Department of Pediatrics, Eastern Virginia Medical School, Norfolk, Virginia
| | - Erin A McNamara
- Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts
| | - Mauro Longoni
- Pediatric Surgical Research Laboratories, Massachusetts General Hospital, Boston, Massachusetts
| | - Danny E Miller
- Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington
| | - Mersedeh Rohanizadegan
- Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Laura A Newman
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Mississippi, Jackson, Mississippi
| | - Frances Hayes
- Department of Medicine, Reproductive Endocrinology, Massachusetts General Hospital, Boston, Massachusetts
| | - Lynne L Levitsky
- Pediatric Endocrinology, MassGeneral Hospital for Children, Boston, Massachusetts
| | - Betty L Herrington
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Mississippi, Jackson, Mississippi
| | - Angela E Lin
- Genetics Unit, MassGeneral Hospital for Children, Boston, Massachusetts
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