Frontiers in Cell and Developmental Biology (Dec 2022)

The different clinical facets of SYN1-related neurodevelopmental disorders

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

DOI
https://doi.org/10.3389/fcell.2022.1019715
Journal volume & issue
Vol. 10

Abstract

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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.

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