Aortic Root Dilation and Genotype Associations in Phelan‐McDermid Syndrome

Author:

Gluckman Jake12ORCID,Levy Tess12,Friedman Kate12,Garces Francesca12,Filip‐Dhima Rajna34,Quinlan Aisling34,Iannotti Isabelle34,Pekar Margaret5,Hernandez Alexandra Lopez678,Nava Madison T.678,Kravets Elijah9,Siegel Abigail12,Bernstein Jonathan A.9ORCID,Berry‐Kravis Elizabeth678,Powell Craig M.1011,Soorya Latha Valluripalli12,Thurm Audrey5,Srivastava Siddharth3ORCID,Buxbaum Joseph D.12131415,Sahin Mustafa34,Kolevzon Alexander121316,Gelb Bruce D.131516ORCID,

Affiliation:

1. Seaver Autism Center for Research and Treatment Icahn School of Medicine at Mount Sinai New York New York USA

2. Department of Psychiatry Icahn School of Medicine at Mount Sinai New York New York USA

3. Department of Neurology, Rosamund Stone Zander Translational Neuroscience Center Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA

4. F.M. Kirby Neurobiology Center Boston Children's Hospital, Harvard Medical School Boston Massachusetts USA

5. Neurodevelopmental and Behavioral Phenotyping Service National Institute of Mental Health, National Institutes of Health Bethesda Maryland USA

6. Department of Pediatrics Rush University Medical Center Chicago Illinois USA

7. Department of Neurological Sciences Rush University Medical Center Chicago Illinois USA

8. Department of Anatomy and Cell Biology Rush University Medical Center Chicago Illinois USA

9. Department of Pediatrics Stanford University School of Medicine Stanford California USA

10. Department of Neurobiology University of Alabama at Birmingham Heersink School of Medicine Birmingham Alabama USA

11. Civitan International Research Center University of Alabama at Birmingham Birmingham Alabama USA

12. Department of Psychiatry & Behavioral Sciences Rush University Medical Center Chicago Illinois USA

13. The Mindich Child Health and Development Institute Icahn School of Medicine at Mount Sinai New York New York USA

14. Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York New York USA

15. Department of Genetics and Genomic Sciences Icahn School of Medicine at Mount Sinai New York New York USA

16. Department of Pediatrics Icahn School of Medicine at Mount Sinai New York New York USA

Abstract

ABSTRACTPhelan‐McDermid syndrome (PMS) is a rare genetic neurodevelopmental disorder that results from the loss of one functional copy of the SHANK3 gene. While many clinical features of PMS are well‐understood, there is currently limited literature on cardiovascular abnormalities in PMS. This report aims to evaluate the prevalence of aortic root dilation (ARD) among individuals with PMS and to understand if underlying genetic variation relates to risk for ARD. We present findings from 59 participants collected from a multisite observational study evaluating the phenotype and natural history of PMS. Individual echocardiographic and genetic reports were analyzed for aortic root measurements and genetic variant data, respectively. Our a priori hypothesis was that participants with chromosome 22 deletions with hg19 start coordinates on or before 49,900,000 (larger deletions) would have more instances of ARD than participants with deletion start coordinates after 49,900,000 (smaller deletions). Eight participants (14%) had ARD, and its presence was statistically significantly associated with large deletions (p = 0.047). Relatedly, participants with ARD had significantly more genes deleted on chromosome 22 than participants without ARD (p = 0.013). These results could aid in the identification of individuals with PMS who are at higher risk for ARD.

Funder

Rare Diseases Clinical Research Network

National Center for Advancing Translational Sciences

National Institutes of Health

Publisher

Wiley

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