Identification of a Novel de Novo Variant in the SYT2 Gene Causing a Rare Type of Distal Hereditary Motor Neuropathy

Abstract

Objective: To report the first de novo missense mutation in the SYT2 gene causing distal hereditary motor neuropathy. Methods: Genetic testing was carried out, including clinical exome sequencing for the proband and Sanger sequencing for the proband and his parents. We described the clinical and electrophysiological features found in the patient. Results: We reported a proband with a new de novo missense mutation, c.917C>T (p.Ser306Leu), in the C2B domain of SYT2. The clinical presentation was similar to that of phenotypes described in previous studies. A notable feature in our study was normal electrophysiological testing results of the patient. Conclusions: In this study we reinforced the association between SYT2 mutations and distal hereditary motor neuropathy. We also described the clinical presentation of the patient carrying this pathogenic variant and provided unusual results of electrophysiological testing. The results showed that a diagnosis of SYT2-associated neuropathy should be based on the similarity of clinical manifestations, rather than the results of electrophysiological testing.

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

“…Notably, a pathogenic variant has been found at the residue corresponding to Ser309 in the homologous SYT2 . 25 In the Ca 2+ -bound simulations, both Met303Val and Ser309Pro increased the mobility of the distal arginine apex (Arg399, Arg400) at the opposite end of the C2B domain ( Supplemental Figure 4 ).…”

“…Novel variants may exert dominant-negative effects, as seen for previously identified variants, 10 , 8 , 9 but we cannot preclude haploinsufficiency as a possible pathogenic mechanism. Ca 2+ -binding loops 1 and 3 of the C2B domain seem to be highly sensitive to variation as pathogenic missense variants cluster in these regions in both SYT1 and the homologous SYT2 , 25 , 33 , 34 and no missense SYT1 variants in these loops are recorded in the Genome Aggregation Database version 2.1.1. 22 Therefore, any de novo missense variant in the C2B Ca 2+ -binding loops should be investigated for possible pathogenicity, and variants in other highly conserved residues of the SYT1 C2 domains should also be considered.…”

A new de novo SYT2 mutation presenting as distal weakness. Neuropathy or neuromuscular junction dysfunction?

“…6,7 Heterozygous mutations in the SYT2 gene have been recently reported in patients presenting as a motor neuropathy from three unrelated families with a dominant pattern of inheritance 4,8,9 and from a case of de novo mutation without electrophysiological alterations. 10 The first reported variants were two missense mutations affecting consecutive residues within the calcium-binding pocket of the C2B domain of SYT2 protein, p.Asp307Ala, and p.Pro308Leu. 4 This domain seems to be the key driver synaptic vesicle fusion, [11][12][13] Figure 1C) and are expected to be particularly affected by the introduction of a lysine at position 371.…”

“…4,8,9 It deserves to be mentioned that the lack of electrophysiological alteration in the patient described is a 10-years-old male, and it could be related to the young age. 10 However, electrophysiological studies also revealed findings indicating a presynaptic NMJ defect, 13. Yoshihara M, Guan Z, Littleton JT.…”

Function of Drosophila Synaptotagmins in membrane trafficking at synapses

“…In addition, several SYTs are linked more loosely to pathogenesis in neurological disorders arising from other primary causes. The first mutations identified in human SYTs were found in the SYT2 C2B domain in patients presenting with non-progressive peripheral motor neuropathies with unusual similarities to Lambert–Eaton myasthenic syndrome (LEMS) [ 189 , 190 , 340 , 341 ]. LEMS is an autoimmune disorder commonly linked to auto-antibodies against the presynaptic Ca 2+ channel that disrupt NMJ function [ 342 ].…”