Ataxia and cerebellar anomalies - narrow panel

Gene: THG1L

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

Panel Version: 5.3

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: There is sufficient evidence available for the promotion of this gene to green rating in the next GMS review.

Created: 13 Dec 2023, 11:52 p.m. | Last Modified: 13 Dec 2023, 11:52 p.m.

Panel Version: 4.43

Ataxia was previously reported in four Ashkenazi Jewish families with the same p.Val55Ala founder variant. Although there was another case of different ancestry was identified with a different variant, it was not clear whether this patient had ataxia.

PMID:33682303 reported seven additional cases with ataxia from the same Ashkenazi Jewish population, where three patients had compound heterozygous variants (p.Cys51Trp and p.Val55Ala) and four patients were homozygous for the same p.Val55Ala variant.

PMID:37670026 - A 6-year-old boy with moderate cerebellar ataxia was identified with two different variants (c.224A > G; c.369-8T > G).

This gene has been associated with relevant phenotypes in both OMIM (MIM #618800) and Gene2Phenotype (with 'limited' rating in the DD panel).

Created: 13 Dec 2023, 11:50 p.m. | Last Modified: 13 Dec 2023, 11:50 p.m.

Panel Version: 4.40

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800

Publications

• 27307223
• 30214071
• 31168944
• 33682303
• 37670026

I don't know

PMID: 33682303 (2021) - reported seven individuals with biallelic variants in THG1L. Three were compound heterozygous for the p.(Cys51Trp) and p.(Val55Ala) variants, and four siblings were homozygous for the previously reported p.(Val55Ala) variant. The latter all had ataxia, however this information is not available for the compound heterozygotes
PMID: 33682303 (2023) reported one patient with moderate cerebellar ataxia and two previously unreported variants in this gene

Created: 4 Dec 2023, 2:14 p.m. | Last Modified: 4 Dec 2023, 2:14 p.m.

Panel Version: 4.40

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spinocerebellar ataxia, autosomal recessive 28

Publications

• 33682303
• 33682303

I don't know

Comment on list classification: Ataxia only reported in 3 Ashkenazi Jewish families with the same p.V55A founder variant. Unclear whether the fourth case with a different variant (p.L294P) displayed ataxia. Therefore, additional cases or functional analysis of the p.V55A variant are required prior to upgrading this gene to Green.

Created: 1 Mar 2021, 2:59 p.m. | Last Modified: 1 Mar 2021, 2:59 p.m.

Panel Version: 2.50

Associated with relevant phenotype in OMIM (MIM# 618800), but not yet in Gene2Phenotype.

- PMID: 27307223 (2016) - Homozygous p.V55A variant identified in three sibs of Ashkenazi Jewish descent with cerebellar signs including ataxia, developmental delay, dysarthria, pyramidal signs and cerebellar atrophy on brain MRI. Patient fibroblasts displayed abnormalities in mitochondrial fusion with increased fragmentation compared to controls when cultured with galactose.

- PMID: 31168944 (2019) - The same homozygous p.V55A variant detected in two additional unrelated Ashkenazi Jewish patients. Clinical features include developmental delay, ataxic gait, spasticity, and uncoordinated movements. No functional studies were performed.

- PMID: 30214071 (2019) - One individual with a homozygous missense variant (p.L294P) in THG1L ascertained from a congenital microcephaly cohort. Phenotypes include IUGR, GDD, epilepsy, autoimmune thrombocytopenia, transient neutropenia, and optic atrophy. Authors do note diffuse cerebral and cerebellar atrophy on brain imaging; however, it is unknown whether the individual exhibited any ataxic features.

Created: 1 Mar 2021, 2:51 p.m. | Last Modified: 1 Mar 2021, 2:51 p.m.

Panel Version: 2.49

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Spinocerebellar ataxia, autosomal recessive 28, OMIM:618800

Publications

• 27307223
• 31168944
• 30214071

Green List (high evidence)

Four Ashkenazi Jewish families reported, with same homozygous variant, p.V55A in affected individuals. Another individual from different ethnicity also reported. A carrier rate of 0.8%, but no THG1L V55A homozygotes, was found in a cohort of 3,232 unrelated Ashkenazi Jewish individuals, and no homozygotes found in Exac or gnomAD.
Sources: Literature

Created: 1 May 2020, 10:11 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Cerebellar ataxia

Publications

• 27307223
• 30214071
• 31168944