Hereditary neuropathy or pain disorder

Gene: SYT2

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted' following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 9:32 a.m. | Last Modified: 2 May 2024, 9:32 a.m.

Panel Version: 4.3

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the association of this gene to this panel (six unrelated cases and functional studies) and this gene should therefore be promoted to green rating in the next GMS review.

Created: 23 Aug 2023, 8:47 p.m. | Last Modified: 23 Aug 2023, 8:47 p.m.

Panel Version: 3.56

PMID:25192047 - Two unrelated multigenerational families (one from the USA and another from the UK) were reported with neuromuscular disorder and were identified with heterozygous SYT2 variants (c.920A>C/ p.Asp307Ala & c.923C>T/ p.Pro308Leu). Electrophysiological findings of affected members of these families in PMID:26519543 showed that the phenotype is suggestive of distal hereditary motor neuropathy, and that 1 patient was referred for presumed Charcot-Marie-Tooth disease (CMT). In addition, c.920A>C variant was characterised in drosophila model.

PMID:30533528 - A multigenerational family was identified with a missense variant in SYT2 gene (c.1112T>A/ p.Ile371Lys). The proband and her mother presented with a phenotype characterised by slowly progressive, predominantly motor neuropathy. This variant was characterised in a drosophila model, confirming the dominant-negative effect of the variant.

PMID:33105646 - A proband was reported with a de novo missense SYT2 variant (c.917C>T/ p.Ser306Leu) and the clinical phenotype was similar to the previous studies reported above.

PMID:33105646 - A de novo heterozygous deletion SYT2 variant (c.1082_1096del) was identified in a man referred for suspected CMS7A with a clinical phenotype characterised by distal lower limb weakness and pes cavus.

PMID:34037996 - A de novo heterozygous missense SYT2 variant (p.Leu365Pro) was identified in a man with CMS7A.

Autosomal dominant variants in SYT2 gene has been associated with CMS7A in OMIM (MIM #616040), but has not yet been associated with relevant phenotypes in Gene2Phenotype.

Created: 23 Aug 2023, 8:44 p.m. | Last Modified: 23 Aug 2023, 8:44 p.m.

Panel Version: 3.52

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Myasthenic syndrome, congenital, 7A, presynaptic, and distal motor neuropathy, autosomal dominant, OMIM:616040

Publications

• 25192047
• 26519543
• 30533528
• 33105646
• 34037996

I don't know

The case descriptions are somewhat confusing and perhaps the clinical picture is mixed but at least some of the cases have neuropathy.

Created: 2 Apr 2020, 7:39 a.m. | Last Modified: 2 Apr 2020, 7:39 a.m.

Panel Version: 1.4

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Myasthenic syndrome, congenital, 7, presynaptic; HMSN

Publications

• 25192047
• 30533528
• 26519543

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Possibly 2 families, clinical judgement required. PMID: 30533528 - missense variant in proband and mother (both affected). Characterization in Drosophila - dominant-negative effect on neurotransmitter release. PMID: 26519543 - 2 multigenerational families with dominant SYT2 mutations. Electrophysiologic testing revealed features indicative of a presynaptic deficit in neurotransmitter release

Created: 29 Apr 2019, 12:30 p.m.

Phenotypes
Myasthenic syndrome, congenital, 7, presynaptic

Publications

• 30533528
• 26519543

Variants in this GENE are reported as part of current diagnostic practice

I don't know

Gene rated Red : From feedback from Genomics England Clinical team (Anna de Burca). 3 families and functional data according to Natalie's review but more of a myastheia phenotype but overlaps with CMT . Congenital myasthenia gene; currently Green on Congenital myaesthenic syndrome Panel so recommend leave as Red on the R78 panel, but promote to Green on larger panel for WGS.

Created: 6 Dec 2019, 2:53 p.m. | Last Modified: 6 Dec 2019, 2:57 p.m.

Panel Version: 0.38

This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 1:24 p.m. | Last Modified: 6 Dec 2019, 1:24 p.m.

Panel Version: 0.20

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 5 p.m.

Review and rating submitted by Natalie Forrester (SWGLH - Bristol Genetics) on behalf of South West GLH for GMS Neurology specialist test group.

Created: 29 Apr 2019, 12:53 p.m.

Green List (high evidence)

Added the tags 'watchlist' and 'missense' as there are 2 multigenerational families reported, and only missense variants reported.

Created: 27 Jun 2018, 4:50 p.m.

Comment on publications: Two publications the same two variants identified in two mult-generational families - Pro308Leu and Asp307Ala.

Created: 29 Mar 2018, 2:19 p.m.

Green List (high evidence)

only 2 missense mutations are reported

Created: 9 Dec 2015, 4:49 p.m.

Variants in this GENE are reported as part of current diagnostic practice

Myasthenic syndrome

Created: 9 Dec 2015, 8:50 a.m.

Myasthenic syndrome

Created: 8 Dec 2015, 3:06 p.m.