Expanding the genotype and phenotype spectrum of SYT1-associated neurodevelopmental disorder

Shelagh Joss,Frances Emslie,Jenny Thies,Abinayah John,Joshua J. Ziarek,Mathilde Nizon,Panayiotis Constantinou,Manju A. Kurian,Anna Kolesnik-Taylor,Fabian Bumbak,Marjolein H. Willemsen ,Martin Jakob Larsen ,Rebekah Barrick,Tjitske Kleefstra,Kate Baker,Majid Alfadhel,Lucy Loong,Lone Walentin Laulund,Daniel J. Scott,Sarah Gordon ,Elise Ng‐Cordell ,Holly Melland,Richard Y. Chang ,Rolf Pfundt,Jasper van der Smagt,Christina Fagerberg

doi:10.1016/j.gim.2021.12.002

Abstract

PurposeSynaptotagmin-1 (SYT1) is a critical mediator of neurotransmitter release in the central nervous system. Previously reported missense SYT1 variants in the C2B domain are associated with severe intellectual disability, movement disorders, behavioral disturbances, and electroencephalogram abnormalities. In this study, we expand the genotypes and phenotypes and identify discriminating features of this disorder. MethodsWe describe 22 individuals with 15 de novo missense SYT1 variants. The evidence for pathogenicity is discussed, including the American College of Medical Genetics and Genomics/Association for Molecular Pathology criteria, known structure–function relationships, and molecular dynamics simulations. Quantitative behavioral data for 14 cases were compared with other monogenic neurodevelopmental disorders. ResultsFour variants were located in the C2A domain with the remainder in the C2B domain. We classified 6 variants as pathogenic, 4 as likely pathogenic, and 5 as variants of uncertain significance. Prevalent clinical phenotypes included delayed developmental milestones, abnormal eye physiology, movement disorders, and sleep disturbances. Discriminating behavioral characteristics were severity of motor and communication impairment, presence of motor stereotypies, and mood instability. ConclusionNeurodevelopmental disorder–associated SYT1 variants extend beyond previously reported regions, and the phenotypic spectrum encompasses a broader range of severities than initially reported. This study guides the diagnosis and molecular understanding of this rare neurodevelopmental disorder and highlights a key role for SYT1 function in emotional regulation, motor control, and emergent cognitive function.

Highlights

The tightly regulated synaptic vesicle cycle involves the trafficking, docking, fusion, and recycling of neurotransmitter-filled vesicles at the presynaptic terminal
We previously reported 11 cases of de novo missense variants in SYT1.8,9 All affected individuals presented with hypotonia, developmental delay, and intellectual disability (ID) varying in severity from moderate to profound and one-third exhibited symptoms of an involuntary movement disorder
15 de novo variants in SYT1 were identified in 22 individuals (Figure 1A) (5 missense variants in 11 individuals have previously been described8,9)

Summary

Introduction

The tightly regulated synaptic vesicle cycle involves the trafficking, docking, fusion, and recycling of neurotransmitter-filled vesicles at the presynaptic terminal. SYT1 is a synaptic vesicle protein that couples action potentials to the synchronous exocytosis of neurotransmitters through its calcium sensing activity.[4] SYT1, the dominant synaptotagmin family member in the forebrain,[5,6] is a transmembrane protein with 2 cytoplasmic calcium-binding domains (C2A and C2B).[7] Membrane depolarization triggers an influx of calcium ions (Ca2+) into the nerve terminal, which bind to negatively charged aspartate residues that reside in loops at the “top” of each C2 domain This neutralizes the charge of the loops, acting as an electrostatic switch and allowing the hydrophobic tips of these loops to penetrate the negatively-charged plasma membrane, thereby facilitating the fusion of synaptic vesicle and plasma membranes.[4]

Methods

Results

Conclusion