Congenital myaesthenic syndrome

Gene: TOR1AIP1

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to BIALLELIC, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 6 Dec 2024, 11:43 a.m. | Last Modified: 6 Dec 2024, 11:43 a.m.

Panel Version: 4.11

Comment on list classification: At least two unrelated multiplex families reported with muscle fatigability, limb girdle weakness and impaired transmission at the neuromuscular synapse. Given the strong functional support including a concordant mouse model, this gene can be promoted to Green status on this panel at the next GMS panel update.

Created: 8 Dec 2022, 3:28 p.m. | Last Modified: 8 Dec 2022, 3:28 p.m.

Panel Version: 3.3

At least 5 individuals from 2 unrelated families reported (PMID: 33215087; 34164833) specifically with a myasthenic syndrome in association with different homozygous LoF variants in this gene (c.127delC, p.Pro43fs and c.63dupC, p.Arg22Glnfs*88, respectively). Electromyography in patients revealed decremental responses on repetitive nerve stimulation. Muscle biopsy from one proband showed the protein encoded by TOR1AIP1 was absent in myonuclei. Both variants were shown to truncate the muscle isoform (termed LAP1B) while the LAP1C isoform remained intact.
Knockout mice exhibited fatigable muscle weakness and also decrement on repetitive nerve stimulation. Neuromuscular junctions were enlarged and fragmented, and the number of subsynaptic nuclei was significantly increased signifying impaired synaptic transmission.

Created: 8 Dec 2022, 3:20 p.m. | Last Modified: 14 Dec 2022, 11:26 a.m.

Panel Version: 3.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Congenital myasthenic syndrome

Publications

• 33215087
• 34164833

Red List (low evidence)

Comment on list classification: Info from Tracy Lester: TOR1AIP1 – should be amber on R80, not red, there is an unpublished case.

Created: 2 Dec 2019, 11 a.m. | Last Modified: 2 Dec 2019, 11 a.m.

Panel Version: 1.74

Applicable to panel, but currently not enough evidence to support Amber/Green rating

Created: 16 Oct 2019, 1:15 p.m. | Last Modified: 16 Oct 2019, 1:15 p.m.

Panel Version: 1.60

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.

I don't know

David Beeson info - TOR1AIP1: No other reports, but fatiguable muscle weakness, decrement on EMG, decrement on EMG and fatiguable muscle weakness in mouse model harbouring same mutation. Recessive. Present in siblings. No other cases reported for myasthenic syndrome.

Created: 29 Apr 2019, 4:33 p.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal