Ataxia and cerebellar anomalies - narrow panel

Gene: UCHL1

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)

The mode of inheritance of this gene has been updated to BOTH monoallelic and biallelic, autosomal or pseudoautosomal following NHS Genomic Medicine Service approval.

Created: 2 May 2024, 11:50 a.m. | Last Modified: 2 May 2024, 11:50 a.m.

Panel Version: 5.3

Childhood onset cerebellar ataxia and has been reported in both Spastic paraplegia 79A, autosomal dominant, OMIM:620221 and Spastic paraplegia 79B, autosomal recessive, OMIM:615491, therefore, the mode of inheritance for this gene should be: BOTH monoallelic and biallelic, autosomal or pseudoautosomal.

Created: 28 Jul 2023, 12:04 p.m. | Last Modified: 28 Jul 2023, 12:04 p.m.

Panel Version: 4.22

In addition to previous reports of Spastic paraplegia 79, autosomal recessive (OMIM:615491), PMID: 35986737 reports a neurodegenerative disorder with spasticity, ataxia, neuropathy, and optic atrophy in cases with heterozygous UCHL1 variants. The variants included 13 heterozygous loss-of-function variants (15 families) and a heterozygous in-frame insertion (3 families). The affected individuals mainly presented with spasticity (24/31), ataxia (28/31), neuropathy (11/21), and optic atrophy (9/17), it was also noted in PMID: 35986737 that the condition onset in dominant cases was median 49 years (12-70 years) and in recessive was 7.5 years (2-10 years).

Created: 17 Jan 2023, 3:21 p.m. | Last Modified: 17 Jan 2023, 3:21 p.m.

Panel Version: 3.22

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: Upgraded from Red to Amber but there is sufficient evidence to promote this gene to Green at the next GMS panel update - ataxia and other cerebellar signs are a feature of this UCHL1-related neurodegenerative disorder. At least 4 unrelated families reported (PMIDs: 23359680; 28007905; 29735986; 32656641) with biallelic variants, supported by functional and animal model data.

Created: 11 May 2021, 10:07 a.m. | Last Modified: 11 May 2021, 10:07 a.m.

Panel Version: 2.162

Associated with relevant phenotype in OMIM (MIM# 615491) but is currently not listed in Gene2Phenotype.

- PMID: 23359680 (2013) - Three sibs born to consanguineous parents with an early-onset progressive neurodegenerative syndrome characterised by childhood-onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfuction, and spasticity with upper motor neuron dysfunction. Homozygosity mapping followed by WES revealed a homozygous missense variant, (c.20A>C; p.Glu7Ala) in UCHL1 which segregated with the disorder. Some in vitro functional analysis of the variant showing near complete loss of UCHL1 hydrolase activity.

- PMID: 28007905 (2017) - Three sibs, born of unrelated Norwegian parents, with childhood-onset optic atrophy, followed by spasticity and ataxia due to comp het variants in UCHL1, c.533G>A (p.Arg178Gln) and c.647C>A (p.Ala216Asp), cosegregating with the phenotype. Functional evaluation of the variants indicates different functional consequences as the insoluble Ala216Asp variant led to LoF, whereas the Arg178Gln led to increased enzyme activity.

- PMID: 29735986 (2018) - Two sibs harbouring a homozygous splice-site variant (c.459+2T>C) in the UCHL1 gene who presented an early-onset neurodegenerative disorder characterised by SPG, optic atrophy, seizures, and facial dysmorphism. Clinical description does not include ataxia however both sibs displayed cerebellar signs such as dysarthria, nystagmus, tremors and gait impairment.

- PMID: 32656641 (2020) - Two sibs with a childhood-onset neurodegenerative disorder starting with motor DD and optic atrophy leading to progressive visual loss, cerebellar ataxia, spastic paraparesis, and motor neuropathy. Both sibs developed hypertrophic cardiomyopathy in their 30s and died of sudden cardiac death at age 43 and 40, respectively. WES identified a novel homozygous (c.627_629del; p.Gly210del) deletion in UCHL1. Their unaffected mother was heterozygous for the variant but the father was unavailable for genetic testing.

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UCHL1-deficient mice display axonal degeneration, progressive sensory motor ataxia, and premature death. UCHL1 is thought to have important roles in axonal repair after injury, axonal transport, and synaptic function (PMID: 11555633; 33159930)

Created: 11 May 2021, 10:03 a.m. | Last Modified: 11 May 2021, 10:03 a.m.

Panel Version: 2.161

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 79, autosomal recessive, OMIM:615491

Publications

• 23359680
• 28007905
• 29735986
• 32656641
• 11555633
• 33159930

Green List (high evidence)

Ataxia is part of the phenotype. Two unrelated families and a mouse model.

Created: 13 Sep 2020, 7:59 a.m. | Last Modified: 13 Sep 2020, 7:59 a.m.

Panel Version: 2.12

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spastic paraplegia 79, autosomal recessive, MIM#615491

Publications

• 28007905
• 23359680
• 11555633

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