Abstract
Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a deletion of the distal long arm of chromosome 22. These included terminal and interstitial deletions, as well as other structural rearrangements. Later, pathogenetic variants and deletions of the SHANK3 gene were found to result in a phenotype consistent with PMS. The association between SHANK3 and PMS led investigators to consider disruption/deletion of SHANK3 to be a prerequisite for diagnosing PMS. This narrow definition of PMS based on the involvement of SHANK3 has the adverse effect of causing patients with interstitial deletions of chromosome 22 to “lose” their diagnosis. It also results in underreporting of individuals with interstitial deletions of 22q13 that preserve SHANK3. To reduce the confusion for families, clinicians, researchers, and pharma, a simple classification for PMS has been devised. PMS and will be further classified as PMS-SHANK3 related or PMS-SHANK3 unrelated. PMS can still be used as a general term, but this classification system is inclusive. It allows researchers, regulatory agencies, and other stakeholders to define SHANK3 alterations or interstitial deletions not affecting the SHANK3 coding region.
Highlights
Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a dele‐ tion of the distal long arm of chromosome 22
The purpose of this article is to define a classification system for Phelan-McDermid syndrome (PMS) [OMIM #606232] that distinguishes between cases involving deletion or pathogenic variants of SHANK3 and cases in which SHANK3 is not disrupted
This system ensures that individuals previously diagnosed with PMS based on an interstitial deletion of 22q13 proximal to SHANK3 will meet the criteria for the syndrome, and that those with deletion of 22q13 and intact SHANK3 whose clinician did not feel they fit the definition of PMS will have a diagnosis
Summary
Phelan-McDermid syndrome (PMS) was initially called the 22q13 deletion syndrome based on its etiology as a dele‐ tion of the distal long arm of chromosome 22. The purpose of this article is to define a classification system for Phelan-McDermid syndrome (PMS) [OMIM #606232] that distinguishes between cases involving deletion or pathogenic variants of SHANK3 and cases in which SHANK3 is not disrupted. *Correspondence: kphelan@flcancer.com; thomas.bourgeron@pasteur.fr 1 Genetics Laboratory, Florida Cancer Specialists, Fort Myers, FL 33916, USA 12 Human Genetics and Cognitive Functions, Institut Pasteur, UMR3571 CNRS, Université de Paris, 75015 Paris, France Full list of author information is available at the end of the article
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