Familial SYNGAP1 variants define the boundaries of a complex neurodevelopmental disorder with epilepsy

Abstract

Objective: SYNGAP1-related disorders are common neurodevelopmental conditions characterized by autism spectrum disorder, developmental delay, intellectual disability, and a range of generalized seizure types. Disease-causing variants in SYNGAP1 typically occur de novo. This study aims to characterize inherited cases of SYNGAP1-related disorders.

Methods: Here we report three families including eight total individuals with inherited, protein-truncating variants in SYNGAP1, recruited through a natural history study. In two of the families, the proband inherited their pathogenic variant from a heterozygous parent. In the remaining family, the variant was inherited from a mosaic parent. This study additionally reports two families with inherited missense variants classified as variants of uncertain significance, which are not clearly diagnostic at this time.

Results: Phenotypes in affected children and parents included both typical and attenuated SYNGAP1 presentations, including a single individual with a mosaic SYNGAP1 variant who was clinically unaffected. Among the individuals with protein-truncating variants, generalized epilepsy was observed in six individuals, autism spectrum disorder in two individuals, and developmental delay or intellectual disability in all individuals with germline variants.

Significance: We demonstrate that SYNGAP1-related disorder can occur in families and that clinical presentations of familial cases are not limited to milder phenotypes. We estimate that 3% of cases of SYNGAP1-related disorder are inherited. Recognition of familial SYNGAP1-related disorders delineates edge cases of a relatively common neurodevelopmental disorder and has implications for variant interpretation and clinical practice.

Keywords: SYNGAP1; ACMG variant classification; developmental and epileptic encephalopathy; eyelid myoclonia; generalized epilepsy; synapse disorders.

FIGURE 1

Distribution of familial variants in SYNGAP1 highlighting the five familial variants identified in this study against the backdrop of other SYNGAP1 variants identified in individuals in the SYNGAP1 Prospective Multidisciplinary Multi‐Site (ProMMiS) natural history study. Exons and protein functional domains are visualized for the MANE (Matched Annotation betwen NCBI and EMBL‐EBI) Select transcript of SYNGAP1 as well as three additional transcripts.

FIGURE 2

Inheritance of familial variants in SYNGAP1 is visualized for the five families identified in this study. Genotypes are visualized for all individuals for whom genetic testing reports were available: Wildtype (wt) or harboring the familial variant (+). Families 1–3 harbor pathogenic, protein‐truncating variants, which have a clear loss‐of‐function effect in SYNGAP1 (A). Families 4–5 harbor missense variants of unclear clinical significance in SYNGAP1. These variants are not conclusively explanatory for the neurodevelopmental symptoms reported in these individuals (B).