Phelan-McDermid syndrome: a classification system after 30 years of experience

• Published in: Orphanet journal of rare diseases Vol. 17; no. 1; pp. 27 - 4
• Main Authors: Phelan, Katy, Boccuto, Luigi, Powell, Craig M., Boeckers, Tobias M., van Ravenswaaij-Arts, Conny, Rogers, R. Curtis, Sala, Carlo, Verpelli, Chiara, Thurm, Audrey, Bennett, William E., Winrow, Christopher J., Garrison, Sheldon R., Toro, Roberto, Bourgeron, Thomas
• Format: Journal Article
• Language: English
• Published: London BioMed Central 29.01.2022; BioMed Central Ltd; BMC
• Subjects: 22q13 deletion; Autism; Chromosome 22; Chromosome Deletion; Chromosome Disorders - genetics; Chromosome mapping; Chromosomes; Chromosomes, Human, Pair 22 - genetics; Classification; Clinical genetics and genomics; Etiology; Gene deletion; Genes; Genotype & phenotype; Health aspects; Human Genetics; Humans; Identification and classification; Letter to the Editor; Life Sciences; Medical research; Medicine; Medicine & Public Health; Neurons and Cognition; Patients; Pharmacology/Toxicology; Phelan-McDermid syndrome; Phenotype; Phenotypes; PMS; Rare diseases; SHANK3; United States; Europe; Phelan-McDermid syndrome; PMS; 22q13 deletion; SHANK3; Phelan-McDermid syndrome PMS SHANK3 22q13 deletion
• ISSN: 1750-1172; 1750-1172
• DOI: 10.1186/s13023-022-02180-5

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.