Phelan-McDermid Syndrome

Payne et al. “Behavioral Features in Phelan–McDermid Syndrome: Characteristics and Genetic and Metabolic Contributions in a Cohort of 56 Individuals”. “Genes.” 2026, v. 17, 202

Phelan-McDermid syndrome is a neurodevelopmental disorder characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, intellectual disability, autism spectrum disorder, and minor dysmorphic facial features. It is caused by either chromosome 22q13.3 deletions or pathogenic/likely pathogenic variants in the SHANK3 gene. Most Phelan-McDermid syndrome deletions include the gene SHANK3, which is the primary candidate gene for autism spectrum disorder (ASD) and other behavioral concerns (restricted and repetitive behaviors, difficulties with social and communication skills, self-injury, impulsive behavior).

Thus, Phelan-McDermid syndrome can sometimes also be referred to as SHANK3-related disorder. To expand its phenotypic spectrum, Payne et al. conducted a cross-sectional analysis of data on 56 individuals with Phelan-McDermid syndrome. Forty-seven of these 56 individuals (84%) carried 22q13 deletions: 33 with known and 14 with unknown deletion sizes. Of the 33 with known deletion sizes, a SHANK3-unrelated deletion was found in one individual (3%). The remaining nine individuals without 22q13 deletions had a confirmed pathogenic variant within SHANK3 (16%). Nine individuals had deletions greater than 6 Mb. Every patient in the cohort presented with either prominent autistic behavior or adaptive behavior impairment: 55.4% (31/56) of them meeting the cutoff for a diagnosis of ASD and 92.9% (52/56) scoring in the lowest level of adaptive behavior (or skills individuals use daily to navigate life, work, and social activities).

Overall, the authors findings support previous studies associating greater severity of symptoms in males and lower standard scores on adaptive behavior skills in older subjects with Phelan-McDermid syndrome. Notably, in the study, individuals with SHANK3 variants scored significantly lower for adaptive behaviors compared to individuals with 22q13 deletions regardless of deletion size, suggesting that disruptions in SHANK3 are the primary genetic contributor to the adaptive behavior impairments affecting their daily functioning. The authors also suggest that deletion size plays a role in adaptive skills in Phelan-McDermid syndrome. All in all, future research remains necessary to better characterize the symptoms and management of Phelan-McDermid syndrome.

Chromosome Disorder Outreach Inc. medical geneticist and medical advisor Dr. Iosif Lurie M.D. Ph.D examines newly published research studies to locate the most important and relevant for our members. Synopses of these articles are then posted to our website’s research pages. Review and formatting by Nicole Talaba, MS CGC. For more information on any article please contact info@chromodisorder.org