Collaborative Clinical Research calls

• Title:SWAS  IN PHELAN-MCDERMID SYNDROME
• Targeted gene(s)/phenotype under study (to be quoted in the newsletter):Phelan-McDermid syndrome (PMS), caused by deletions or pathogenic variants involving SHANK3 gene (OMIM # 606232)
• Summary (1000 characters max): 

Background and Rationale

Phelan-McDermid syndrome (PMS), caused by deletions or pathogenic variants involving SHANK3, is a rare neurodevelopmental disorder characterized by global developmental delay, intellectual disability, autism spectrum disorder, and a variable risk of epilepsy. The pooled prevalence of seizures in PMS, is approximately 32% (Holder & Quach, 2016), while lifetime prevalence at adult age may reach up to 60% (de Coo 2023). Seizure onset can occur at any age, with no clearly identified developmental period at higher risk. Both febrile and non-febrile seizures have been reported, with atypical absences being the most frequently described seizure type.

EEG abnormalities are common in PMS; deletion of SHAK3 increases the risk of all types of seizures, irrespective the size of deletion (de Coo 2023).  Neither seizures nor EEG abnormalities per se have been consistently linked to developmental regression. To date, no clinical, electrophysiological, or biological markers have been identified to predict regression or psychiatric deterioration in individuals with PMS (Kohlenberg et al., 2020). Furthermore, no antiepileptic drug has demonstrated clear superiority in the treatment of epilepsy in PMS, supporting a multifactorial model in which SHANK3 haploinsufficiency may alter excitation–inhibition balance or energy utilization in specific brain circuits, while additional genetic or environmental factors are likely required to precipitate seizures (de Coo 2023).

SWAS and PMS: a Potentially Under-recognized Association

Several monogenic causes of SWAS have been described, most notably GRIN2A, as well as SCN2A, FRRS1L, CNKSR2, CDKL5, and recurrent CNVs such as dup15q. In contrast, the association between SWAS and SHANK3 alterations remains largely unexplored, with only one isolated report describing SWAS in an individuals with PMS (deletion).

Recent clinical experience at the Mondino Hospital with a patient affected by PMS and SWAS, presenting with concomitant psychomotor regression and showing a marked and sustained response to intravenous steroid therapy, raises the possibility that SWAS in PMS may be underdiagnosed or misinterpreted. Subsequently, other Italian centers have shared similar clinical experiences, further supporting this hypothesis. Importantly, current treatment guidelines for PMS-associated epilepsy do not specifically address SWAS, nor do they recommend steroid therapy in this context.

Study objectives

The primary aim of this multicenter descriptive study is to investigate the prevalence of SWAS in Phelan-McDermid syndrome.

Secondary objectives include:

• Describing the electroclinical features of SWAS in PMS, including age at onset, seizure types, and EEG characteristics.
• Evaluating the temporal relationship between SWAS onset and the natural history of PMS (developmental trajectory, regression, behavioral changes).
• Exploring genotype–phenotype correlations, including SHANK3 deletion size or variant type, and the presence of additional genetic modifiers.
• Collecting real-world data on treatment strategies for SWAS in PMS, with particular focus on response to steroid therapy (e.g. intravenous corticosteroids), including efficacy and tolerability.

Call for Collaboration

We invite colleagues to contribute cases of individuals with genetically confirmed Phelan-McDermid syndrome who have demonstrated SWAS.  By pooling clinical, EEG, genetic, and treatment response data, this study aims to improve recognition of SWAS in PMS, refine its clinical characterization, and generate preliminary evidence to inform future diagnostic and therapeutic recommendations.

• Coordinating clinician:LUDOVICA PASCA & VALENTINA DE GIORGIS
• Institution (dept, hospital, city, country): FONDAZIONE MONDINO, PAVIA, ITALY
• Contact email: [email protected], [email protected]
• Specific requirements beyond clinical and genotype data: 

Call published on 12 February 2026.