Broad phenotypic spectrum of SYNGAP1-related disorder: a case with epilepsy, severe developmental delay, and atypical sensory features

Kwasniewski, M. (2024). Broad phenotypic spectrum of SYNGAP1-related disorder: a case with epilepsy, severe developmental delay, and atypical sensory features (Version 1) [DataSet]. GestaltMatcher Database.

We report a 2.5-year-old male of Eastern European ancestry who exhibited normal development until 6 months of age, followed by global developmental delay and progressive neurological symptoms. Clinical evaluation revealed hypotonia with peripheral hypertonia, postural instability, pes valgus, impaired fine motor skills, and absence of speech. Behavioral and sensory abnormalities included autism spectrum disorder, stereotypic upper limb movements, sensory integration disorder, hypersensitivity to light, wind, and sound during infancy, and poor pain perception. Additional findings comprised sleep disturbances, attention deficits, and excessive salivation. Ophthalmologic assessment revealed spasmus nutans at 8 months, esotropia, hypermetropia, astigmatism, amblyopia, and nystagmus. Dysmorphic features included microcephaly, low-set and slightly protruding ears, downslanting palpebral fissures, long eyelashes, and an open mouth. Gastrointestinal symptoms included chronic constipation, and MRI demonstrated an arachnoid cyst under observation. EEG showed generalized epileptiform discharges, and generalized-onset seizures were suspected. Whole-exome sequencing identified a heterozygous pathogenic de novo variant in SYNGAP1 [NM_006772.3:c.3718C>T p.Arg1240*], consistent with SYNGAP1-related intellectual developmental disorder (MRD5) [MIM:612621]. The phenotype aligns with the classical spectrum of SYNGAP1-related disorders, including intellectual disability, epilepsy, and behavioral abnormalities. Notably, features such as pronounced sensory hypersensitivity, spasmus nutans, and a distinctive urinary odor broaden the clinical spectrum associated with SYNGAP1 pathogenic variants. This case demonstrates the wide range of manifestations that can occur in SYNGAP1-related disorders and underscores the importance of thorough clinical phenotyping combined with genomic analysis for accurate diagnosis and optimized patient care.