Rationale:
SYNGAP1 genetic variants are a well-recognized cause of intellectual disability and developmental and epileptic encephalopathy (DEE). While neurodevelopmental and epileptic features are better described, non-neurological aspects—particularly musculoskeletal abnormalities—remain poorly characterized, despite their functional relevance. There are only vague and anecdotal reports of gait disturbances and orthopedic abnormalities, yet these may significantly impact mobility and quality of life. We aimed to systematically describe the frequency and pattern of hypermobility and musculoskeletal features in individuals with SYNGAP1 variants and to explore genotype–phenotype correlations and potential associations with DEE.
Methods:
We performed a retrospective descriptive analysis of 16 patients (50% F; age 3–26 years) with confirmed SYNGAP1 genetic variants (pathogenic/likely pathogenic). Clinical data included the Beighton Score to assess generalized joint hypermobility, and musculoskeletal features stratified into domains: lower limb hypermobility (via W-sitting), and axial hypermobility (via concave posture). Orthopedic abnormalities included scoliosis, pes planus, and genu valgum. Variants were grouped into frameshift/deletion and missense/nonsense. Frequencies and summary statistics were computed. Exploratory associations with DEE were tested using Fisher’s exact test.
Results:
Mean age was 10.9 ± 6.1 years with median Beighton Score 6.0 (range 0–9). Based on age- and sex-adjusted criteria, 10 patients were classified as having generalized hypermobility. W-sitting was present in 87.5% of the cohort, and concave posture in 43.8%. Musculoskeletal traits were highly prevalent: flat feet (76.9%), genu valgum (78.6%), scoliosis (71.4%), and Trendelenburg sign (56.3%). DEE was present in 6/16 patients. While more frequent in those with scoliosis (40%) and flat feet (50%), no statistically significant associations were found (Fisher’s p > 0.05). Comparing genetic variant types: generalized hypermobility was present in 62.5% (frameshit/deletion) vs 57.1% (missense/nonsense); W-sitting and concave posture did not differ between groups. In this limted sample, patients with frameshit/deletion showed a slightly higher musculoskeletal burden, but no significant differences in DEE frequency (p = 0.61).
Conclusions:
This series show that musculoskeletal abnormalities—including generalized, axial, and lower limb hypermobility—are highly prevalent in individuals with SYNGAP1 neurodevelopmental disorder. In our exploratory analysis, while trends suggest a slightly higher burden in patients with frameshit/deletion, no statistically significant genotype–phenotype or DEE associations were identified. These findings support incorporating systematic musculoskeletal assessment in the clinical evaluation of SYNGAP1-related disorders.
Funding:
The abstract did not receive any funding.