. 2025 Jan;197(1):e63872.

doi: 10.1002/ajmg.a.63872. Epub 2024 Sep 11.

Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome

Jake Gluckman^{1

2}, Tess Levy^{1

2}, Kate Friedman^{1

2}, Francesca Garces^{1

2}, Rajna Filip-Dhima^{3

4}, Aisling Quinlan^{3

4}, Isabelle Iannotti^{3

4}, Margaret Pekar⁵, Alexandra Lopez Hernandez^{6

7

8}, Madison T Nava^{6

7

8}, Elijah Kravets⁹, Abigail Siegel^{1

2}, Jonathan A Bernstein⁹, Elizabeth Berry-Kravis^{6

7

8}, Craig M Powell^{10

11}, Latha Valluripalli Soorya¹², Audrey Thurm⁵, Siddharth Srivastava³, Joseph D Buxbaum^{1

2

13

14

15

16}, Mustafa Sahin^{3

4}, Alexander Kolevzon^{1

2

13

17}, Bruce D Gelb^{13

15

17}; Developmental Synaptopathies Consortium

Affiliations

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 Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 39257296
PMCID: PMC11637948 (available on 2026-01-01)
DOI: 10.1002/ajmg.a.63872

Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome

Jake Gluckman et al. Am J Med Genet A. 2025 Jan.

. 2025 Jan;197(1):e63872.

doi: 10.1002/ajmg.a.63872. Epub 2024 Sep 11.

Authors

Affiliations

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 Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁷ Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

PMID: 39257296
PMCID: PMC11637948 (available on 2026-01-01)
DOI: 10.1002/ajmg.a.63872

Abstract

Phelan-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.

Keywords: 22q13; Phelan‐McDermid syndrome; SHANK3; aortic root dilation; genotype–phenotype correlation.

PubMed Disclaimer

Conflict of interest statement

Conflicts of Interest Disclosure

Tess Levy receives funding from the Phelan-McDermid Syndrome Foundation and is on the advisory board of the CHAMP1 research foundation.

Alexander Kolevzon is on the Advisory Board for the Klingenstein Third Generation Foundation, Ovid Therapeutics, David Lynch Foundation, ADNP Kids Research Foundation, and Ritrova Therapeutics and consults to Acadia, Alkermes, Jaguar Therapeutics, GW Pharmaceuticals, Neuren Pharmaceuticals, Clinilabs Drug Development Corporation, Scioto Biosciences, and Biogen.

Elizabeth Berry-Kravis has received funding from Seaside Therapeutics, Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum, GW, Neurotrope, Marinus, Zynerba, BioMarin, Ovid, Retrophin, AMO, Yamo, Acadia, Avexis, Ionis, Ultragenyx, Lumos, GeneTx, and Vtesse/Sucampo/Mallinkcrodt Pharmaceuticals to consult on trial design or development strategies and/or conduct clinical trials in FXS or other NDDs or neurodegenerative disorders, and from Asuragen Inc to develop testing standards for FMR1 testing. All funding to Elizabeth Berry-Kravis is directed to Rush University Medical Center to support rare disease programs. Elizabeth Berry-Kravis receives no personal funds.

Mustafa Sahin reports grant support from Novartis, Roche, Biogen, Astellas, Aeovian, Bridgebio, Aucta and Quadrant Biosciences. He has served on Scientific Advisory Boards for Roche, Celgene, Regenxbio, Alkermes and Takeda.

Craig M. Powell reports no conflicts relevant to the present study other than having been funded by Novartis in the past to study potential biomarkers in PMS. He has been reimbursed for travel by Psychogenics, Astra-Zeneca, Roche, Pfizer, and Dainippon Sumitomo Pharma Co. in the past.

Siddharth Srivastava has received consulting fees from GLG, Guidepoint (which connected to a client, Fortress Biotech), Novartis, ExpertConnect, Stoke Therapeutics., and Neuren.

Jake Gluckman, Kate Friedman, Francesca Garces, Rajna Filip-Dhima, Aisling Quinlan, Isabelle Iannotti, Margaret Pekar, Alexandra Lopez Hernandez, Madison T. Nava, Elijah Kravets, Abigail Siegel, Jonathan A. Bernstein, Latha Valluripalli Soorya, Audrey Thurm, and Bruce D. Gelb all have no conflicting interests to declare.

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Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome

Affiliations

Aortic Root Dilation and Genotype Associations in Phelan-McDermid Syndrome

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources