Ataxia and cerebellar anomalies - narrow panel

Gene: MTCL1

Green List (high evidence)

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

Created: 5 Feb 2023, 5:18 p.m. | Last Modified: 5 Feb 2023, 5:18 p.m.

Panel Version: 3.30

Green List (high evidence)

Comment on list classification: New gene added by Zornitza Stark. There is sufficient evidence to promote this gene to Green at the next GMS panel update - two unrelated individuals with different LoF variants in this gene. Ataxia with cerebellar atrophy was the predominant presentation in both cases (PMIDs: 30548255; 32961396). Knockout animal model recapitulates human phenotypes and provides functional support.

Created: 13 May 2021, 10:27 a.m. | Last Modified: 13 May 2021, 10:27 a.m.

Panel Version: 2.175

- PMID: 30548255 (2019) - Homozygous MTCL1 truncating variant (c.1219delA; p.Lys407fs) was identified in a 23-year-old Polish patient with slowly progressive cerebellar ataxia, mild ID, seizures in childhood and episodic pain in the lower limbs triggered by physical exertion. Unaffected parents and sib were heterozygous carriers.

- PMID: 32961396 (2020) - Single individual with cerebellar ataxia, ID, spastic gait, dysarthria, intentional tremor, increased muscle tension and a homozygous nonsense variant (c.121G>T, p.E41*) in MTCL1.
-----
MTCL1 encodes a microtubule-associated protein highly expressed in cerebellar Purkinje cells and is crucial for maintaining Purkinje neuron axon initial segment. Mtcl1 knockout mice exhibit abnormal motor coordination due to axonal degeneration and Purkinje cell loss (PMID: 28283581)

Created: 13 May 2021, 10:21 a.m. | Last Modified: 13 May 2021, 10:21 a.m.

Panel Version: 2.174

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebellar ataxia

Publications

• 30548255
• 32961396

Green List (high evidence)

Two families reported with bi-allelic LOF variants, early onset ataxia and a supportive null mouse model.
Single family with mono-allelic variant in two individuals and adult-onset ataxia (not pertinent to this panel, and less compelling).
Sources: Literature

Created: 9 Dec 2020, 6:19 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
slowly progressive cerebellar ataxia; mild intellectual disability; seizures; episodic pain; spinocerebellar ataxia

Publications

• 30548255
• 28283581
• 32961396