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Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.
LaFlamme, Christy W; Rastin, Cassandra; Sengupta, Soham; Pennington, Helen E; Russ-Hall, Sophie J; Schneider, Amy L; Bonkowski, Emily S; Almanza Fuerte, Edith P; Allan, Talia J; Zalusky, Miranda Perez-Galey; Goffena, Joy; Gibson, Sophia B; Nyaga, Denis M; Lieffering, Nico; Hebbar, Malavika; Walker, Emily V; Darnell, Daniel; Olsen, Scott R; Kolekar, Pandurang; Djekidel, Mohamed Nadhir; Rosikiewicz, Wojciech; McConkey, Haley; Kerkhof, Jennifer; Levy, Michael A; Relator, Raissa; Lev, Dorit; Lerman-Sagie, Tally; Park, Kristen L; Alders, Marielle; Cappuccio, Gerarda; Chatron, Nicolas; Demain, Leigh; Genevieve, David; Lesca, Gaetan; Roscioli, Tony; Sanlaville, Damien; Tedder, Matthew L; Gupta, Sachin; Jones, Elizabeth A; Weisz-Hubshman, Monika; Ketkar, Shamika; Dai, Hongzheng; Worley, Kim C; Rosenfeld, Jill A; Chao, Hsiao-Tuan; Neale, Geoffrey; Carvill, Gemma L; Wang, Zhaoming; Berkovic, Samuel F; Sadleir, Lynette G.
Affiliation
  • LaFlamme CW; Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Rastin C; Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Sengupta S; Department of Pathology & Laboratory Medicine, Western University, London, ON, N5A 3K7, Canada.
  • Pennington HE; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
  • Russ-Hall SJ; Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Schneider AL; Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Bonkowski ES; Department of Mathematics & Statistics, Rhodes College, Memphis, TN, 38112, USA.
  • Almanza Fuerte EP; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.
  • Allan TJ; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.
  • Zalusky MP; Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Goffena J; Center for Pediatric Neurological Disease Research, Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Gibson SB; Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC, 3084, Australia.
  • Nyaga DM; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.
  • Lieffering N; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.
  • Hebbar M; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.
  • Walker EV; Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA, 98195, USA.
  • Darnell D; Department of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.
  • Olsen SR; Department of Paediatrics and Child Health, University of Otago, Wellington, 6242, New Zealand.
  • Kolekar P; Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, WA, 98195, USA.
  • Djekidel MN; Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital Memphis, Memphis, TN, 38105, USA.
  • Rosikiewicz W; Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital Memphis, Memphis, TN, 38105, USA.
  • McConkey H; Hartwell Center for Bioinformatics and Biotechnology, St. Jude Children's Research Hospital Memphis, Memphis, TN, 38105, USA.
  • Kerkhof J; Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Levy MA; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Relator R; Center for Applied Bioinformatics, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA.
  • Lev D; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
  • Lerman-Sagie T; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
  • Park KL; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
  • Alders M; Verspeeten Clinical Genome Centre, London Health Science Centre, London, ON, N6A 5W9, Canada.
  • Cappuccio G; Institute of Medical Genetics, Wolfson Medical Center, Holon, 58100, Israel.
  • Chatron N; Fetal Neurology Clinic, Pediatric Neurology Unit, Wolfson Medical Center, Holon, 58100, Israel.
  • Demain L; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
  • Genevieve D; Departments of Pediatrics and Neurology, University of Colorado School of Medicine, Aurora, CO, 80045, USA.
  • Lesca G; Department of Human Genetics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC, University of Amsterdam, Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.
  • Roscioli T; Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
  • Sanlaville D; Department of Translational Medicine, Federico II University of Naples, Naples, Italy.
  • Tedder ML; Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France.
  • Gupta S; Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 - INSERM, U1315, Lyon, France.
  • Jones EA; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
  • Weisz-Hubshman M; Montpellier University, Inserm Unit 1183, Reference Center for Rare Diseases Developmental Anomaly and Malformative Syndrome, Clinical Genetic Department, CHU Montpellier, Montpellier, France.
  • Ketkar S; Department of Medical Genetics, Member of the ERN EpiCARE, University Hospital of Lyon and Claude Bernard Lyon I University, Lyon, France.
  • Dai H; Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 - INSERM, U1315, Lyon, France.
  • Worley KC; Neuroscience Research Australia (NeuRA), Sydney, NSW, Australia.
  • Rosenfeld JA; Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia.
  • Chao HT; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
  • Neale G; Pathophysiology and Genetics of Neuron and Muscle (PNMG), UCBL, CNRS UMR5261 - INSERM, U1315, Lyon, France.
  • Carvill GL; Greenwood Genetic Center, Greenwood, SC, 29646, USA.
  • Wang Z; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
  • Berkovic SF; Division of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • Sadleir LG; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
Nat Commun ; 15(1): 6524, 2024 Aug 06.
Article in En | MEDLINE | ID: mdl-39107278
ABSTRACT
Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Methylation / Epilepsy / DNA Copy Number Variations Limits: Adolescent / Child / Child, preschool / Female / Humans / Infant / Male Language: En Journal: Nat Commun / Nature communications Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: DNA Methylation / Epilepsy / DNA Copy Number Variations Limits: Adolescent / Child / Child, preschool / Female / Humans / Infant / Male Language: En Journal: Nat Commun / Nature communications Journal subject: BIOLOGIA / CIENCIA Year: 2024 Document type: Article Affiliation country: Estados Unidos Country of publication: Reino Unido