Genome Sequencing Uncovers Additional Findings in Phelan-McDermid Syndrome

Rachel Gore Moses¹, Morgan Similuk¹, Alexandra Hehn², Rylee Duncan³, Margaret Pekar², Eliza Gordon-Lipkin⁴, Maria T Acosta⁵, Deena Zeltser⁶, Nadjalisse Reynolds-Lallement¹, Latha Soorya⁷, Mustafa Sahin^{8

9}, Tess Levy^{10

11}, Alexander Kolevzon^{10

11}, Joseph D Buxbaum^{10

11

12

13}, Elizabeth Berry-Kravis^{14

15}, Craig M Powell^{16

17}, Jonathan A Bernstein¹⁸, Mari Tokita¹, Bryce A Seifert¹, Rajarshi Ghosh¹, Magdalena A Walkiewicz¹, Audrey Thurm²

Affiliations

¹ Centralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
² Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
³ Department of Psychology, Ohio State University, Columbus, Ohio, USA.
⁴ Metabolic Medicine Branch, National Genome Research Institute, NIH, Bethesda, Maryland, USA.
⁵ Undiagnosed Disease Program, National Genome Research Institute, NIH, Bethesda, Maryland, USA.
⁶ National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
⁷ Department of Psychiatry, Rush University Medical Center, Chicago, Illinois, USA.
⁸ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Pediatrics, Rush University Medical Center, Chicago, Illinois, USA.
¹⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
¹⁶ Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
¹⁷ Civitan International Research Center for Neurodevelopmental Disorders, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
¹⁸ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

PMID: 40519070
PMCID: PMC12235757 (available on 2026-06-16)
DOI: 10.1002/ajmg.b.33036

Genome Sequencing Uncovers Additional Findings in Phelan-McDermid Syndrome

Rachel Gore Moses et al. Am J Med Genet B Neuropsychiatr Genet. 2025 Oct.

. 2025 Oct;198(7):126-134.

doi: 10.1002/ajmg.b.33036. Epub 2025 Jun 16.

Authors

Affiliations

¹ Centralized Sequencing Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
² Neurodevelopmental and Behavioral Phenotyping Service, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland, USA.
³ Department of Psychology, Ohio State University, Columbus, Ohio, USA.
⁴ Metabolic Medicine Branch, National Genome Research Institute, NIH, Bethesda, Maryland, USA.
⁵ Undiagnosed Disease Program, National Genome Research Institute, NIH, Bethesda, Maryland, USA.
⁶ National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
⁷ Department of Psychiatry, Rush University Medical Center, Chicago, Illinois, USA.
⁸ Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
⁹ Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
¹⁰ Seaver Autism Center for Research and Treatment, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹¹ Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹² Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹³ Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
¹⁴ Department of Pediatrics, Rush University Medical Center, Chicago, Illinois, USA.
¹⁵ Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois, USA.
¹⁶ Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
¹⁷ Civitan International Research Center for Neurodevelopmental Disorders, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.
¹⁸ Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.

PMID: 40519070
PMCID: PMC12235757 (available on 2026-06-16)
DOI: 10.1002/ajmg.b.33036

Abstract

Phelan-McDermid syndrome (PMS) is a genetic condition caused by deletions of chromosome 22q13.3 or pathogenic variants in the SHANK3 gene. Neurologic features typically include intellectual disability, autism spectrum disorder, hypotonia, and absent speech, though there is considerable variability even among individuals with the same molecular cause. This prospective study aimed to explore the utility of genome sequencing to identify additional molecular diagnoses that may contribute to variability in a cohort of patients with PMS. Twenty probands diagnosed with PMS (60% with a 22q13 deletion, 40% with a SHANK3 variant) underwent trio or duo genome sequencing and chromosomal microarray. This analysis identified a second molecular finding associated with a neurological condition in 3/20 participants. Molecular diagnoses related to neurological phenotypes included: (1) spinal muscular atrophy, lower extremity-predominant, 2A, autosomal dominant (SMALED2A), (2) spastic paraplegia 7, and (3) 16p11.2 deletion syndrome. Five additional new molecular diagnoses were associated with a clinically actionable secondary or incidental finding. This exploratory study provides early evidence for the potential utility of expanded sequencing among individuals with PMS, even for those without phenotypic features outside of the expected range.

Keywords: Phelan‐McDermid syndrome; dual diagnosis; genome sequencing; neurodevelopment.

© 2025 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

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Conflict of interest statement

Competing Interests

The authors have no conflicts of interest to declare.

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Genome Sequencing Uncovers Additional Findings in Phelan-McDermid Syndrome

Affiliations

Genome Sequencing Uncovers Additional Findings 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