SYN1, encoding synapsin I, is a neuronal phosphoprotein. It is crucial for regulating axonogenesis and synaptogenesis, playing a significant role in the development and function of the nervous system [1,2]. Pathogenic SYN1 variants are associated with X-linked neurodevelopmental disorders [1,2,3,4,5].

Most reported patients with SYN1-related disorders are male, inheriting significant SYN1 variants from asymptomatic or mildly affected mothers [1]. The disorder encompasses mental deficiency, easily controlled reflex seizure, and behavior problems, with great phenotypic variability among genders and individuals, even within the same pedigree [1]. Behavioral disturbances like autism spectrum disorder or attention deficit hyperactivity disorder are seen in 91% of individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70% [2]. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness, and reflex seizures are a representative manifestation, often triggered by contact with water, but also other factors such as rubbing with a towel, fever, toothbrushing, etc. [2]. The molecular spectrum of SYN1 variants is broad, including truncating and non-truncating variants, and genotype-phenotype correlation shows epileptic phenotypes are enriched in individuals with truncating variants, and early seizure onset is associated with severe-to-profound intellectual disability [2]. In a Chinese family, a novel SYN1 exon 12 mutant gene was identified in patients with toothbrushing epilepsy [4]. In another Chinese pedigree, a pathogenic SYN1 variant showed variable clinical phenotypes in siblings, and truncating variants were associated with the pathogenicity of reflex epilepsies, while non-truncating variants were more related to developmental delay/intellectual disability [5].

In summary, SYN1 is essential for axonogenesis and synaptogenesis in the nervous system. Studies on SYN1-related disorders, especially those involving genetic variants, have provided insights into the complex relationship between SYN1 genotypes and the diverse neurodevelopmental and epileptic phenotypes, highlighting the importance of SYN1 in understanding X-linked neurodevelopmental disorders.

References:

1. Xiong, Juan, Duan, Haolin, Chen, Shimeng, Peng, Jing, Yin, Fei. 2021. Familial SYN1 variants related neurodevelopmental disorders in Asian pediatric patients. In BMC medical genomics, 14, 182. doi:10.1186/s12920-021-01028-4. https://pubmed.ncbi.nlm.nih.gov/34243774/

2. Parenti, Ilaria, Leitão, Elsa, Kuechler, Alma, Lesca, Gaetan, Depienne, Christel. 2022. The different clinical facets of SYN1-related neurodevelopmental disorders. In Frontiers in cell and developmental biology, 10, 1019715. doi:10.3389/fcell.2022.1019715. https://pubmed.ncbi.nlm.nih.gov/36568968/

3. Bernardo, Pia, Cuccurullo, Claudia, Rubino, Marica, Bilo, Leonilda, Coppola, Antonietta. 2024. X-Linked Epilepsies: A Narrative Review. In International journal of molecular sciences, 25, . doi:10.3390/ijms25074110. https://pubmed.ncbi.nlm.nih.gov/38612920/

4. Zhou, Qin, Wang, Jingwei, Xia, Li, Zhang, Qiumin, Pan, Songqing. 2021. SYN1 Mutation Causes X-Linked Toothbrushing Epilepsy in a Chinese Family. In Frontiers in neurology, 12, 736977. doi:10.3389/fneur.2021.736977. https://pubmed.ncbi.nlm.nih.gov/34616357/

5. Ren, Bin, Wu, Xiaoyan, Zhou, Yuqiang, Chen, Lijuan, Jiang, Jingzi. 2024. SYN1 variant causes X-linked neurodevelopmental disorders: a case report of variable clinical phenotypes in siblings. In Frontiers in neurology, 15, 1359287. doi:10.3389/fneur.2024.1359287. https://pubmed.ncbi.nlm.nih.gov/38576531/