The different clinical facets of SYN1-related neurodevelopmental disorders
SYN1
(2022) Frontiers in Cell and Developmental Biology, volume 10, pp. 1 - 18
(Article)
Abstract
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
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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.
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Keywords: SYN1, autism spectrum disorders, genotype-phenotype correlation, neurodevelopmental disorders, reflex epilepsy, synapsins, Journal Article
ISSN: 2296-634X
Publisher: Frontiers Media S. A.
Note: Funding Information: This research was funded in whole, or in part, by the Wellcome Trust [203914/Z/16/Z] supporting DL-S. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. CD is supported by Universitätsklinikum Essen and received grants from the Deutsche Forschungsgemeinschaft (DFG). AB is funded by a BRIDGE—Translational Excellence Programme grant funded by the Novo Nordisk Foundation, grant agreement number: NNF20SA0064340. FB received funding from the Italian Ministry of Health. Funding Information: We thank the patients and their families for participating to this study. We acknowledge support from the Open Access Publication Fund of the University of Duisburg-Essen. One patient included in this study was diagnosed thanks to Defidiag (NCT04154891), a study supported by The French Ministry of Health and the Agence Nationale de la Recherche (ANR-10-IAHU-01). Publisher Copyright: Copyright © 2022 Parenti, Leitão, Kuechler, Villard, Goizet, Courdier, Bayat, Rossi, Julia, Bruel, Tran Mau-Them, Nambot, Lehalle, Willems, Lespinasse, Ghoumid, Caumes, Smol, El Chehadeh, Schaefer, Abi-Warde, Keren, Afenjar, Tabet, Levy, Maruani, Aledo-Serrano, Garming, Milleret-Pignot, Chassevent, Koopmans, Verbeek, Person, Belles, Bellus, Salbert, Kaiser, Mazzola, Convers, Perrin, Piton, Wiegand, Accogli, Brancati, Benfenati, Chatron, Lewis-Smith, Thomas, Zara, Striano, Lesca and Depienne.
(Peer reviewed)