The different clinical facets of SYN1-related neurodevelopmental disorders
Authors: Parenti Ilaria , Leitão Elsa , Kuechler Alma , Villard Laurent , Goizet Cyril , Courdier Cécile , Bayat Allan , Rossi Alessandra , Julia Sophie , Bruel Ange-Line , Tran Mau-Them Frédéric , Nambot Sophie , Lehalle Daphné , Willems Marjolaine , Lespinasse James , Ghoumid Jamal , Caumes Roseline , Smol Thomas , El Chehadeh Salima , Schaefer Elise , Abi-Warde Marie-Thérèse , Keren Boris , Afenjar Alexandra , Tabet Anne-Claude , Levy Jonathan , Maruani Anna , Aledo-Serrano Ángel , Garming Waltraud , Milleret-Pignot Clara , Chassevent Anna , Koopmans Marije , Verbeek Nienke E. , Person Richard , Belles Rebecca , Bellus Gary , Salbert Bonnie A. , Kaiser Frank J. , Mazzola Laure , Convers Philippe , Perrin Laurine , Piton Amélie , Wiegand Gert , Accogli Andrea , Brancati Francesco , Benfenati Fabio , Chatron Nicolas , Lewis-Smith David , Thomas Rhys H. , Zara Federico , Striano Pasquale , Lesca Gaetan , Depienne Christel 
Published: December 2022

Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.