Genome Sequencing Uncovers Additional Findings in Phelan‐<scp>McDermid</scp> Syndrome

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.

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Publication Details

Journal
American Journal of Medical Genetics Part B Neuropsychiatric Genetics
Published
2025-06-16
DOI
https://doi.org/10.1002/ajmg.b.33036
Primary Topic
Genomic variations and chromosomal abnormalities
Type
article
Field-Weighted Citation Impact
0.00

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article

Genome Sequencing Uncovers Additional Findings in Phelan‐McDermid Syndrome

Maria T. Acosta, Deena Zeltser, Elizabeth Berry‐Kravis, Alexander Kolevzon et al.
American Journal of Medical Genetics Part B Neuropsychiatric Genetics
Genomic variations and chromosomal abnormalities
article

Genome Sequencing Uncovers Additional Findings in Phelan‐McDermid Syndrome

Maria T. Acosta, Deena Zeltser, Elizabeth Berry‐Kravis, Alexander Kolevzon, Nadjalisse Reynolds‐Lallement, Rajarshi Ghosh, Alain Hehn, Joseph D. Buxbaum, Latha Soorya, Rylee Duncan, Audrey Thurm, Craig M. Powell, Mari Tokita, Eliza M. Gordon‐Lipkin, Magdalena Walkiewicz, Tess Levy, Mustafa Şahin, Bryce A. Seifert, Morgan N. Similuk, Rachel Gore Moses, Jonathan A. Bernstein, Margaret Pekar
article en

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.

American Journal of Medical Genetics Part B Neuropsychiatric GeneticsVol. 198(7)
Rush University Medical Center (US), Boston Children's Hospital (US), National Institutes of Health (US), Harvard University (US), Civitan International (US), University of Alabama at Birmingham (US), National Human Genome Research Institute (US), National Institute of Allergy and Infectious Diseases (US), Eunice Kennedy Shriver National Institute of Child Health and Human Development (US), National Institute of Mental Health (US), The Ohio State University (US), Stanford University (US), Icahn School of Medicine at Mount Sinai (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Rare Diseases Clinical Research Network, National Institutes of Health, National Institute of Mental Health, National Institute of Allergy and Infectious Diseases, National Institute of Neurological Disorders and Stroke, NIH Clinical Center, National Center for Advancing Translational Sciences, NHLBI Division of Intramural Research
Openalex Percentile: Top 84%
Genomic variations and chromosomal abnormalities
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