L C Schenkel1,2, E Aref-Eshghi1, K Rooney1, J Kerkhof1, M A Levy1, H McConkey1, R C Rogers3, K Phelan4, S M Sarasua5, L Jain6,5, R Pauly6, L Boccuto6,5, B DuPont6, G Cappuccio7,8, N Brunetti-Pierri7,8, C E Schwartz9, B Sadikovic10,11. 1. Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A5W9, Canada. 2. Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A3K7, Canada. 3. Greenville Office, Greenwood Genetic Center, Greenville, SC, 29605, USA. 4. Genetics Laboratory, Florida Cancer Specialists and Research Institute, Fort Myers, FL, 33816, USA. 5. Clemson University, Clemson, SC, 29634, USA. 6. Greenwood Genetic Center, Greenwood, SC, 29646, USA. 7. Department of Translational Medicine, University Federico II, 80131, Naples, NA, Italy. 8. Telethon Institute of Genetics and Medicine, Pozzuoli, NA, Italy. 9. Greenwood Genetic Center, Greenwood, SC, 29646, USA. ceschwartz@ggc.org. 10. Molecular Genetics Laboratory, Molecular Diagnostics Division, London Health Sciences Centre, London, ON, N6A5W9, Canada. bekim.sadikovic@lhsc.on.ca. 11. Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A3K7, Canada. bekim.sadikovic@lhsc.on.ca.
Abstract
BACKGROUND: Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. RESULTS: In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (< 1 Mb) or intragenic variants in SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. CONCLUSION: We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.
BACKGROUND: Phelan-McDermid syndrome is characterized by a range of neurodevelopmental phenotypes with incomplete penetrance and variable expressivity. It is caused by a variable size and breakpoint microdeletions in the distal long arm of chromosome 22, referred to as 22q13.3 deletion syndrome, including the SHANK3 gene. Genetic defects in a growing number of neurodevelopmental genes have been shown to cause genome-wide disruptions in epigenomic profiles referred to as epi-signatures in affected individuals. RESULTS: In this study we assessed genome-wide DNA methylation profiles in a cohort of 22 individuals with Phelan-McDermid syndrome, including 11 individuals with large (2 to 5.8 Mb) 22q13.3 deletions, 10 with small deletions (< 1 Mb) or intragenic variants in SHANK3 and one mosaic case. We describe a novel genome-wide DNA methylation epi-signature in a subset of individuals with Phelan-McDermid syndrome. CONCLUSION: We identified the critical region including the BRD1 gene as responsible for the Phelan-McDermid syndrome epi-signature. Metabolomic profiles of individuals with the DNA methylation epi-signature showed significantly different metabolomic profiles indicating evidence of two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome.
Entities:
Keywords:
BRD1; DNA methylation; Epi-signature; Microdeletion; Phelan-McDermid syndrome
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