Hereditary ataxia with onset in adulthood

Gene: TDP1

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 12:48 p.m. | Last Modified: 2 May 2024, 12:48 p.m.

Panel Version: 5.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: This gene can now be promoted to AMBER as there are three unrelated cases. The "founder-effect" tag has been added as they are all of Middle Eastern descent and harboured the same homozygous variant. However, the additional patient reported by Ian Berry (Leeds Genetics Laboratory) had the same variant in compound heterozygous state with another novel variant. As there is an additional variant reported, this gene can be considered for promotion to GREEN rating at the next major review.

Created: 5 Apr 2023, 5:48 a.m. | Last Modified: 24 Jul 2023, 1:23 p.m.

Panel Version: 4.15

As reviewed by Ian Berry (Leeds Genetics Laboratory), there are now three unrelated families reported in literature with Spinocerebellar ataxia with axonal neuropathy-1 (SCAN1) and identified with homozygous variant in TDP1 gene. However, all three families are of Arab descent (one family from Saudi Arabia and two families from Oman) and they presented with the same homozygous variant (p.His493Arg).

There are a number of functional studies characterising the function of H493R variant in vitro (PMIDs:15920477, 17948061 & 31723605).

This gene has been associated with phenotypes in OMIM (MIM #607250), but not in Gene2Phenotype.

Created: 5 Apr 2023, 5:43 a.m. | Last Modified: 5 Apr 2023, 10:05 a.m.

Panel Version: 4.6

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
?Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, OMIM:607250

Publications

• 12244316
• 15920477
• 17948061
• 31182267
• 31723605

Green List (high evidence)

TDP1(NM_018319.4):c.1478A>G p.(His493Arg) has now been reported in 3 separate families with significant segregation data (homozygous/consanguineous Arabic cases, 10 affected individuals, >>>20 meioses).

We have seen one WGS case with presumed compound heteorzygosity (parents not tested) for this variant + a predicted likely LOF variant.

Reported phenotype is combination of cerebellar ataxia and axonal neuropathy, with gait disturbance.

Created: 27 Mar 2023, 12:36 p.m. | Last Modified: 27 Mar 2023, 12:36 p.m.

Panel Version: 4.1

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
PMID: 12244316; PMID: 31182267

I don't know

Review and rating from 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: 15 Apr 2019, 10:21 a.m.

Red List (low evidence)

Single homozygous missense variant reported in one family. Insufficient evidence

Created: 15 Apr 2019, 10:06 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autosomal recessive spinocerebellar ataxia with axonal neuropathy, 607250

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