Congenital myaesthenic syndromeGene: SYT2
Mono-allelic disease, PMID 25192047 and 30533528: dominant missense variants in SYT2 reported as a rare cause of distal motor neuropathy and myasthenic syndrome, manifesting with stable or slowly progressive distal weakness of variable severity along with presynaptic NMJ impairment in three families. These variants are thought to have a dominant-negative effect on synaptic vesicle exocytosis, although the precise pathomechanism remains to be elucidated.
Bi-allelic disease: 32250532 and 32776697, 8 individuals from 6 families, with biallelic loss of function variants in SYT2, clinically manifesting with severe congenital onset hypotonia and weakness, with variable degrees of respiratory involvement. Electrodiagnostic findings consistent with a presynaptic congenital myasthenic syndrome (CMS) in some. Treatment with an acetylcholinesterase inhibitor pursued in 4 indviduals showed clinical improvement with increased strength and function.
Created: 2 Nov 2020, 9:52 a.m. | Last Modified: 2 Nov 2020, 9:52 a.m.
Panel Version: 2.5
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Myasthenic syndrome, congenital, 7, presynaptic, MIM# 616040
Comment on list classification: Promoted from red to green. PMID: 30533528 reported on a third unrelated case with a new variant in this gene. Therefore there is enough evidence to support a gene-disease association.
Created: 7 Aug 2019, 2:24 p.m. | Last Modified: 7 Aug 2019, 2:24 p.m.
Panel Version: 1.52
Review and rating from Michael Oldridge (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust), submitted by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group.
Created: 30 Apr 2019, 9:30 a.m.
Herrmann et al describe 2 multigenerational families with AD inheritiance with a combined LOD score of approx 2.4. Nerve conductions studies fit with a presynaptic CMS in both families (26519543 Whittaker 2015. also shown by Herrmann). Herrmann also constructed a drosophila model of one of the human mutations demonstrating dominant negative effect in synaptic transmission. 2 unrelated families, plus functional model - Green
Created: 29 Apr 2019, 4:33 p.m.
Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Myasthenic syndrome, congenital, 7, presynaptic, 616040
Comment on list classification: Kept rating as Red: only reported in 2 families so far.
Created: 2 Feb 2017, 3:54 p.m.
PMID:25192047, Hermann et al 2014, establishes another presynaptic myasthenic syndrome: In 4 affected members of a 3-generation American family. they identified a heterozygous c.920A-C, D307A mutation in SYT2. In 6 affected members of a 3-generation family from the UK, they identified a heterozygous c.923C-T, P308L mutation in SYT2.
Created: 2 Feb 2017, 3:43 p.m.
Comment on mode of inheritance: Mode of inheritance confirmed by OMIM.
Created: 2 Feb 2017, 3:39 p.m.
Phenotypes for gene: SYT2 were changed from Myasthenic syndrome, congenital, 7, presynaptic, 616040 to Myasthenic syndrome, congenital, 7, presynaptic, OMIM:616040
Publications for gene: SYT2 were set to 26519543; 25192047; 27472506 (Review); 30533528
Gene: syt2 has been classified as Green List (High Evidence).
Publications for gene: SYT2 were set to 26519543; 25192047; 27472506 (Review)
Publications for gene: SYT2 were set to 26519543
Publications for gene SYT2 were changed from 25192047; 27472506 (Review); 26519543 to 26519543
Source NHS GMS was added to SYT2.
Source Wessex and West Midlands GLH was added to SYT2.
22 February 2017: Reviews were assessed, and panel was revised according to expert review and additional curation.
This gene has been classified as Red List (Low Evidence).
Mode of inheritance for SYT2 was changed to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Phenotypes for SYT2 were set to Myasthenic syndrome, congenital, 7, presynaptic, 616040
SYT2 was added to Congenital myaestheniapanel. Sources: Radboud University Medical Center, Nijmegen